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Step 1 First Aid – Biochemistry – Flashcards

Ben Powell

2 November 2022

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Chromatin structure

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Negatively charged DNA loops twice around histone octamer (2 each of the positively charged H2A, H2B, H3, and H4) to form nucleosome bead. H1 ties nucleosomes together in a string. (Think of "beads on a string"; H1 is the only histone that is not in the nucleosome core.) In mitosis, DNA condenses to form mitotic chromosomes.

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Heterochromatin

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Condensed, transcriptionally inactive ("H eteroC hromatin = H ighly C ondensed.")

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Euchromatin

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Less condensed, transcriptionally active (Eu = true, "truly transcribed")

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Purines

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A, G 2 Rings ("PUR e A s G old = PUR ines")

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Pyrimidines

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C, T, U 1 ring ("CUT the PY (pie): PY rimidines")

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Functional groups of the nucleosides

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Guanine has a ketone. Thy mine has a methy l. Deamination of cytosine makes uracil.

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Base differences btw RNA and DNA

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Uracil is found in RNA; Thymine in DNA

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Base pair bonds

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G-C bond (3 H-bonds) is stronger than A-T bond (2 H-bonds). Incr G-C content --< higher melting temperature.

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AA's necessary for purine synthesis

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G lycine A spartate G lutamine

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Nucleoside

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Base + ribose

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Nucleotide

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Base + ribose + phosphate; linked by 3'-5' phosphodiester bond.

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Purines are made from...?

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IMP precursor (see bottom/right)

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Pyrimidines are made from...?

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Orotate precursor, with PRPP added later.

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Deoxyribonucleotide synthesis

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Ribonucleotides are synthesized first and are converted to deoxyribonucleotides by ribonucleotide reductase.

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ABX and anti-neoplastic drugs that function by interfering w/ nucleotide synthesis (list)

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Hydroxyurea 6-mercaptopurine 5-fluorouracil Methotrexate Trimethoprim

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Hydroxyurea

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Inhibits ribonucleotide reductase.

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6-mercaptopurine (6-MP)

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Blocks de novo purine synthesis.

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5-Fluorouracil (5-FU)

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Inhibits thymidilate synthase (decr dTMP).

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Methotrexate

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Inhibits dihydrofolate reductase (decr dTMP)

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Trimethoprim

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Inhibits bacterial dihydrofolate reductase (decr dTMP)

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Transition vs. transversion

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Transition: Substituting purine for purine or pyrimidine for pyrimidine ("TransI tion = I dentical type") Transversion: Substituting purine for pyrimidine or vice versa ("TransV ersion = conV ersion btw types")

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Genetic code: unambiguous

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Each codon specifies only 1 AA.

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Genetic code: degenerate/redundant

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; 1 codon may code for the same AA. (Methionine is encoded by 1 codon: AUG)

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Genetic code: Commaless, nonoverlapping

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Read from a fixed starting point as a continuous sequence of bases. *some viruses are an exception.

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Genetic code: universal

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Genetic code is conserved throughout evolution. *exceptions include mitochondria, archaebacteria, Mycoplasma , and some yeasts

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Silent mutation

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Same AA, often base change in 3rd position of codon (tRNA wobble)

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Missense mutation

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Changed AA (conservative -- new AA is similar in chemical structure)

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Nonsense mutation

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Change resulting in early stop codon ("Stop the nonsense !")

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Frame shift mutation

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Change resulting in misreading of all nucleotides downstream, usually resulting in a truncated, nonfunctional protein.

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Severity of damage in DNA mutations

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Nonsense ; missense ; silent

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Eukaryotic vs. prokaryotic DNA replication.

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Eukaryotic DNA replciation is more complex, but uses many analogous enzymes. In both: DNA replication is semiconservative and involves both continuous and discontinuous (Okazaki fragment) synthesis. For eukaryotes, replication begins at a consensus sequence of base pairs.

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Origin of replication

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Particular sequence in genome where DNA replication begins. May be single (prokaryotes) or multiple (eukaryotes).

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Replication fork

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Y-shaped region along DNA template where leading and lagging strands are synthesized.

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Helicase

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Unwinds DNA template at replication fork.

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Single-stranded binding protein

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Prevents strands from reannealing.

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DNA topoisomerases

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Create a nick in the helix to relieve supercoils created during replication. *Fluoroquinolones inhibit DNA gyrase (a specific prokaryotic topoisomerase)

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Primase

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Makes an RNA primer on which DNA polymerase III can initiate replication.

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DNA polymerase III

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Prokaryotic only. Elongates leading strand by adding deoxynucleotides to the 3' end. Elongates lagging strand until it reaches primer of preceding fragment. 3'--<5' exonuclease activity "proofreads" each added nucleotide. (5'--<3' synthesis; 3'--<5' proofreading w/ exonuclease)

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DNA polymerase I

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Prokaryotic only. Degrades RNA primer and fills in the gap w/ DNA. (excises RNA primer w/ 5'--<3' exonuclease)

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DNA ligase

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Seals.

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Single strand nucleotide excision repair

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Specific endonucleases release the oligonucleotide-containing damaged bases; DNA polymerase and ligase fill and reseal the gap, respectively. (mutated in xeroderma pigmentosum)

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Xeroderma pigmentosum

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Mutated single strand nucleotide excision repair gene, which prevents repair of thymidine dimers.; Dry skin w/ melanoma and other cancers ("children of the night").

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Single strand base excision repair

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Specific glycosylases recognize and remove damaged bases, AP endonuclease cuts DNA at apyrimidinic site, empyty sugar is removed, and the gap is filled and resealed.

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Single strand mismatch repair

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Unmethylated, newly synthesized string is recognized, mismatched nucleotides are removed, and the gap is filled and resealed. Mutated in hereditary nonpolyposis colorectal cancer (HNPCC).

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Double strand nonhomologous end joining

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Brings together 2 ends of DNA fragments. No requirement for homology.

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What direction is DNA/RNA made?

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They are both synthesized in the 5'--<3' direction. Remember that the 5' of the incoming nucleotide bears the triphosphate (energy source for bond). The 3' hydroxyl of the nascent chain is the target.

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What direction is mRNA read?

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5'--<3'.

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What direction is protein synthesized?

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N--<C

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3 Types of mRNA

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rRNA is the most abundant mRNA is the longest tRNA is the smalles ("R ampant, M assive, T iny")

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mRNA start codon

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AUG (or rarely GUG) ("AUG inAUG urates protein synthesis") In eukartyotes, codes for methionine, which may be removed before translation is completed. In prokaryotes, codes for formyl-methionine (f-Met).

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mRNA stop codons

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UGA, UAA, UAG UGA = U G o A way UAA = U A re A way UAG = U A re G one

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Functional organization of the gene

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Promoter

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Site where RNA polymerase and multiple other transcription factors bind to DNA upstream from gene locus (AT-rich upstream sequence w/ TATA and CAAT boxes). Mutation here commonly results in dramatic drop in amount of gene transcribed.

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Promoter

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Enhancer

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Stretch of DNA that alters gene expression by binding transcription factors.

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Stretch of DNA that alters gene expression by binding transcription factors.

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Enhancer

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Silencer

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Site where negative regulators (repressors) bind.

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Site where negative regulators (repressors) bind.

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Silencer

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Where are enhancers and silencers located?

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May be close to, far from, or even within (in an intron) the gene whose expression it regulates.

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Eukaryotic RNA polymerases

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RNA pol I -- makes rRNA RNA pol II -- makes mRNA RNA pol III -- makes tRNA (I, II, and III are numbered as their products are used in protein synthesis) No proofreading fxns, but can initiate chains. RNA pol II opens DA at promoter site.

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Prokaryotic RNA polymerase

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One RNA polymerase (a multisubunt complex) makes all of the 3 kinds of RNA.

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alpha-amantin

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Found in death cap mushrooms. Inhibits RNA pol II.

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RNA processing (in eukaryotes)

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Occurs in nucleus. After transcription: 1.) Capping on 5' end (7-methylguanosine) 2.) Polyadenylation on 3' end (~200 A's) 3.) Splicing out of introns Only processed RNA is transported out of the nucleus.

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hnRNA vs. mRNA

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The initial transcript is called heterogeneous nuclear RNA (hnRNA) The capped and tailed transcript is called mRNA.

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Polyadenylation signal

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AAUAAA

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Poly-A polymerase does not require...

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...does not require a template.

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pre-mRNA splicing (occurs in eukaryotes)

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1.) Primary transcript combines w/ snRNPs and other proteins to form spliceosome 2.) Lariat-shaped intermediate is generated 3.) Lariat is released to remove intron precisely and join 2 exons.

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Introns vs. exons

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Exons contain the actual genetic information coding for protein. Introns are intervening noncoding segments of DNA. ("IN trons stay IN the nucleus, whereas EX ons EX it and are EX pressed")

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Alternative splicing

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Different exons are combined to make unique proteins in different tissues (e.g., beta-thalassemia mutations)

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tRNA structure

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75-90 nucleotides, secondary structure, cloverleaf form, anticodon end is opposite 3' aminoacyl end. All tRNAs, both eukaryotic and prokaryotic, have CCA at 3' end along w/ a high percentage of chemically modified bases. The AA is covalently bound to the 3' end of tRNA.

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Charging of tRNA

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Aminoacyl-tRNA synthetase (1 per AA, "matchmaker," uses ATP) scrutinizes AA before and after it binds to tRNA. If incorrect, bond is hydrolyzed. The aa-tRNA bond has energy for formation of peptide bond. A mischarged tRNA reads usual codon but inserts wrong AA.

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What is responsible for the accuracy of AA selection?

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Aminoacyl-tRNA synthetase and binding of charged tRNA to the codon are responsible for accuracy of AA selection.

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Mechanism of tetracyclines

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Bind 30S subunit, preventing the attachment of aminoacyl-tRNA.

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tRNA wobble

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Accurate base pairing is required only in the first 2 nucleotide positions of an mRNA codon, so codons differing in the 3rd "wobble" position may code for the same tRNA/aa (due to degeneracy of genetic code).

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Protein synthesis: initiation

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Activated by GTP hydrolysis, initiation factors (eIFs) help assemble the 40S ribosomal subunit w/ the initiator tRNA released when the mRNA and the ribosomal subunit assemble w/ the complex. E ukaryotes: 40S + 60S = 80S (E ven) PrO karyotes: 30S + 50S = 70S (O dd)

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Protein synthesis: step 1 in elongation

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Aminoacyl-tRNA binds to Aa site (except for initiator methionine)

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Protein synthesis: step 2 in elongation

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Peptidyltransferase catalyzes peptide bond formation, transfers growing polypeptide to amino acid in A site.

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Protein synthesis: step 3 in elongation

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Ribosome advances 3 nucleotides toward the 3' end of RNA, moving peptidyl RNA to P site (translocation)

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mnemonic for the 3 sites in the ribosome

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"going APE " A site = incoming A minoacyl tRNA P site = accommodates growing P eptide E site = holds E mpty tRNA as it E xits

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Protein synthesis: termination

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Completed protein is released from ribosome thru simple hydrolysis and dissociates.

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Aminoglycosides as protein synthesis inhibitors

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Inhibit formation of the initiation complex and cause misreading of mRNA.

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Chloramphenicol as a protein synthesis inhibitor

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Inhibits 50S peptidyltransferase.

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Macrolides as protein synthesis inhibitors

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Bind 50S, blocking translocation.

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Clindamycin as a protein synthesis inhibitor

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Binds 50S, blocking translocation.

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Energy requirements of translation

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tRNA aminoacylation: ATP --< AMP (2 phosphoanhydride bonds) Loading tRNA onto ribosome: GTP --< GDP Translocation: GTP --< GDP Total energy expenditure = 4 high-energy phosphoanhydride bonds

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Posttranslational modifications: trimming

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Removal of N- or C-terminal propeptides from zymogens to generate mature proteins.

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Posttranslational modifications: covalent alterations

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Phosphorylation, glycosylation, and hydroxylation.

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Posttranslational modifications: Proteasomal degradation

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Attachment of ubiquitin to defective proteins to tag them for breakdown.

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Enzyme regulation methods

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Enzyme concentration alteration (synthesis and/or destruction) Covalent modification (e.g., phosphorylation Proteolytic modification (zymogen) Allosteric regulation (e.g., feedback inhibition) pH Temperature Transcriptional regulation (e.g., steroid hormones)

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Cell cycle phases are regulated by what three things?

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cyclins, CDKs, and tumor suppressors.

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Order (and important lengths) of cell cycle phases

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Mitotis (shortest phase): prophase - metaphase - anaphase - telophase. G1 and G0 are of variable duration. G = G ap or G rowth S = S ynthesis

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CDKs

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Cyclin-dependent kinases; constitutive and inactive.

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Cyclins

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Regulatory proteins that control cell cycle events; phase specific; activate CDKs

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Cyclin-CDK complexes

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Must both be activated and inactivated for cell cycle to progress.

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Tumor suppressors (and the cell cycle)

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Rb and p53 normally inhibit G1-to-S progression; mutations in these genes result in unrestrained cell growth.

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Permanent cells

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Remain in G0, regenerate from stem cells. (e.g., neurons, skeletal and cardiac muscle, RBCs)

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Stable (quiescent) cells

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Enter G1 from G0 when stimulated (e.g., Hepatocytes, lymphocytes)

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Labile cells

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Never go to G0, divide rapidly w/ a short G1 (e.g., Bone marrow, gut epithelium, skin, hair follicles)

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Rough Endoplasmic Reticulum (RER)

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Site of synthesis of secretory (exported) proteins and of N-linked oligosaccharide addition to many proteins.

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Nissl bodies

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RER in neurons -- synthesize enzymes (e.g., ChAT) and peptide neurotransmitters.

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Free ribosomes

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unattached to any membrane; site of synthesis of cytosolic and organellar proteins.

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2 important examples of cells rich in RER

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Mucus-secreting goblet cells of the small intestine, Ab-secreting plasma cells.

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Smooth endoplasmic reticulum (SER)

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Site of steroid synthesis and detoxification of drugs and poisons.

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2 important examples of cells rich in SER

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Liver hepatocytes Steroid hormone-producing cells of the adrenal cortex

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Golgi apparatus: distribution center of ____ from ___ to ____?

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Distribution center of proteins and lipids from ER to the plasma membrane, lysosomes, and secretory vesicles .

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Golgi apparatus: modifies N-oligosaccharides on ____?

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Asparagine.

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Golgi apparatus: adds O-oligosaccharides on ____?

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Serine and threonine.

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Golgi apparatus: adds mannose-6-phosphate to ____? What does this do?

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Specific lysosomal proteins --< targets protein to the lysosome.

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Golgi apparatus: assembles ___ from ____?

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Assembles proteoglycans from core proteins.

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Golgi apparatus: sulfation of ____ and ____?

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sulfation of sugars in proteoglycans and selected tyrosine on proteins .

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Vesicular trafficking proteins: COPI

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Retrograde: Golgi --< ER

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Vesicular trafficking proteins: COPII

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Anterograde: RER --< cis-Golgi

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Vesicular trafficking proteins: Clathrin

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trans-Golgi --< lysosomes, plasma membrane --< endosomoes (receptor-mediated endocytosis)

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I-cell disease (inclusion cell dz): genetic/molecular basis?

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Inherited lysosomal storage d/o; failure of addition of mannose-6-phosphate to lysosome proteins (enzymes are secreted outside the cell instead of being targeted to the lysosome).

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I-cell dz (inclusion cell dz): Results?

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Coarse facial features, clouded corneas, restricted joint mvmt, and high plasma levels of lysosomal enzymes. Often fatal in childhood.

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Microtubules

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Cylindrical structure composed of a helical array of polymerized dimers of alpha- and beta-tubulin. Each dimer has 2 GTP bound. Incorporated into flagella, cilia, mitotic spindles. Grows slowly, collapses quickly. Also involved in slow axoplasmic transport in neurons.

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Molecular motor

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Transport cellular cargo twd opposite ends of MT tracks. Dynein = retrograde to microtubule (+ --< -) Kinesin = anterograde to MT (- ---< +)

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Drugs that act on microtubules

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1.) Mebendazole/thiabendazole (antihelminthic) 2.) Griseofulvin (antifungal) 3.) Vincristine/vinblastine (anti-cancer) 4.) Paclitaxel (anti-breast cancer) 5.) Colchicine (anti-gout)

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Chédiak-Higashi syndrome

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Microtubule polymerization defect resulting in decr phagocytosis. Results in recurrent pyogenic infxns, partial albinism, and peripheral neuropathy.

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Cilia structure

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9 + 2 arrangement of MT's.

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Axonemal dynein

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ATPase that links peripheral 9 doublets and causes bending of cilium by differential sliding of doublets.

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Kartagener's syndrome

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Immotile cilia due to a dynein arm defect. Results in male and female infertility (sperm immotile), bronchiectasis, and recurrent sinusitis (bacteria and particles not pushed out); associated w/ situs inversus.

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Actin and myosin

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Microvilli Muscle contraction Cytokinesis Adherens jxn

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Microtubules (what structures are they found in?)

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Cilia Flagella Mitotic spindle Neurons Centrioles

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Intermediate filaments

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Vimentin Desmin Cytokeratin Glial fibrillary acid proteins (GFAP) Neurofilaments

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Plasma membrane composition

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Asymmetric bilayer. Contains XOL (~50%), phospholipid (~50%), sphingolipids, glycolipids, and proteins. High XOL or long saturated FA content --< incr melting temp, decr fluidity.

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Vimentin stain

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Connective tissue

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Desmin stain

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muscle

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Cytokeratin stain

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epithelial cells

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GFAP stain

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neuroglia

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neurofilament stain

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neurons.

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Polymerase chain reaction (PCR): What is it? What are the steps?

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Molecular biology laboratory proccedure used to amplify a desired fragment of DNA. 1.) Denaturation -- DNA is denatured by heating to generate 2 separate strands. 2.) Annealing -- during cooling, excess premade DNA primers anneal to a specific sequence on each strand to be amplified. 3.) Elongation -- heat-stable DNA polymerase replicates the DNA sequence following each primer 3 steps are repeated multiple times for DNA sequence amplification.

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Agarose gel electrophoresis

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Used for size separation of PCR products (smaller molecules travel further); compared against a DNA ladder

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Mnemonic for different blotting procedures

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"SN oW DR oP " S outhern = D NA N orthern = R NA W estern = P rotein

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Southern blot

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A DNA sample is electrophoresed on a gel and then transferred to a filter. The filter is then soaked in a denaturant and subsequently exposed to a labeled DNA probe that recognizes and anneals to its complementary strand. The resulting ds labeled piece of DNA is visualized when the filter is exposed to film.

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Northern blot

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Similar technique [to Southern], except that Northern blotting involves radioactive DNA probe binding to sample RNA .

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Western blot.

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Sample protein is separated via gel electrophoresis and transferred to a filter. Labeled Ab is used to bind to relevant protein .

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Microarrays

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Thousands of nucleic acid sequences are arranged in grids on glass or silicon. DNA or RNA probes are hybridized to the chip, and a scanner detects the relative amts of complementary binding. Used to profile gene expression levels or to detect single nucleotide polymorphisms (SNPs).

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Enzyme-Linked Immunosorbent Assay (ELISA): What is it? What is it used for? How reliable is it?

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A rapid immunologic technique for testing Ag-Ab reactivity. Used in many laboratories to determine whether a particular Ab (e.g., anti-HIV) is present in a pt's blood sample. Both the sensitivity and the specificity of a ELISA approach 100%, but both false (+) and false (-) occur.

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Enzyme-Linked Immunosorbent Assay (ELISA): How is it performed?

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Pt's blood sample is probed w/ either: 1.) Test Ag (coupled to color-generating enzyme) -- to see if immune system recognizes it OR 2.) Test Ab (coupled to color-generating enzyme) -- to see if a certain Ag is present. If the target substance is present in the sample, the test soltn will have an intense color rxtn, indicating a positive test result.

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Sodium pump

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Na+/K+ ATPase is located in the plasma membrane w/ ATP site on cytoplasmic side. For each ATP consumed, 3 Na+ go out and 2 K+ come in. During cycle, pump is phosphorylated.

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Ouabain

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Inhibits sodium pump (Na+/K+) by binding the K+ site.

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Cardiac glycosides (digoxin and digitoxin)

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Directly inhibit Na+/K+ ATPase, which leads to indirect inhibition of Na+/Ca2+ exchange. Incr Ca2+ --< incr cardiac contractility.

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Collagen (generally)

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Most abundant protein in the human body. Extensively modified. Organizes and strengthens extracellular matrix.

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Type I collagen Where is this type of collagen found?

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90% Bone, skin, tendon, dentin, fascia, cornea, late wound repair Type I = bONE

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Type II collagen Where is this type of collagen found?

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Cartilage (including hyaline), vitreous body, nucleous pulposus. Type II = carTWO lage

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Type III collagen Where is this type of collagen found?

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(Reticulin) Skin, blood vessels, uterus, fetal tissue, granulation tissue

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Type IV collagen Where is this type of collagen found?

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Basement membrane or basal lamina Type IV = Under the floor (basement membrane)

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mnemonic for important tissue types and their respective types of collagen Where is this type of collagen found?

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"B e (S o T otally) C ool, R ead B ooks." I = B one, S kin, T endon II = C artilage III = R eticulin IV = B asement membrane

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Step 1: Synthesis (RER) inside fibroblasts

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Translation of collagen alpha chains (preprocollagen ) -- usually Gly-X-Y polypeptide (X and Y are proline, hydroxyproline, or hydroxylysine)

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Step 2: hydroxylation (ER) inside fibroblasts

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Hydroxylation of specific proline and lysine residues (requires Vitamin C ) *this step is inhibited in scurvy

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Step 3: Glycosylation (ER) inside fibroblasts

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Glycosylation of pro-alpha-chain lysine residues and formation of procollagen (triple helix of 3 collagen alpha chains) *this step is inhibited in osteogenesis imperfecta

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Step 4: Exocytosis

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Exocytosis of procollagen into extracellular space

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Step 5: Proteolytic processing outside fibroblast

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Cleavage of terminal regions of procollagen transforms it into insoluble tropocollagen

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Step 6: cross-linking outside fibroblasts

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Reinforcement of many staggered tropocollagen molecules by covalent lysine-hydroxylysine cross-linkage (by lysyl oxidase) to make collagen fibrils *this step is defective in Ehlers-Danlos syndrome

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Ehlers-Danlos syndrome: what is it basically? what are the signs/sx?

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Faulty collagen synthesis, causing: 1.) Hyperextensible skin 2.) Tendency to bleed (easy bruising) 3.) Hypermobile joints

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Ehlers-Danlos syndrome: may be associated with...?

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Joint dislocation Berry aneurysms Organ rupture

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Types of Ehlers-Danlos

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6 types. Inheritance and severity may vary. Can be autosomal dominant or recessive. Type III collagen is most frequently affected.

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Osteogenesis imperfecta (generally)

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Genetic bone d/o (brittle bone dz) caused by a variety of gene defects. May be confused w/ child abuse. Incidence is 1:10,000

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Osteogenesis imperfecta: most common form (autosomal dominant, abnormal type I collagen)

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1.) Multiple fractures w/ minimal trauma; may occur during the birthing process. 2.) Blue sclera due to the translucency of the connective tissue over the choroid. 3.) Hearing loss (abnormal middle ear bones) 4.) Dental imperfections due to lack of dentin

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Type II osteogenesis imperfecta

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Fatal in utero or neonatal period.

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Alport's syndrome: Due to....? Most common form...?

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Due to a variety of gene defects resulting in abnormal type IV collagen. (type IV collage is an imp. strxrl component of the basement membrane of the kidney, ears, and eyes) Most common form is X-linked recessive.

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Alport's syndrome: Characterized by...? Associated with...?

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Characterized by progressive hereditary nephritis and deafness. May be associated w/ ocular disturbances.

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Elastin

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Stretchy protein w/in lungs, large arteries, elastic ligaments, vocal cords, ligamenta flava (connect vertebrae --< relaxed and stretched conformations) Rich in proline and glycine, nonglycosylated forms. Tropoelastin w/ fibrillin scaffolding. Broken down by elastase, which is normally inhibited by alpha1-antitrypsin.

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Marfan's syndrome (cause)

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Caused by a defect in fibrillin

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Emphysema (one cause)

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Can be caused by alpha1-antitrypsin deficiency, resulting in excess elastase activity.

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Fluoresence in situ Hybridization (FISH)

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Fluorescent DNA or RNA probe binds to specific gene site of interest. Used for specific localization of genes and direct visualization of anomalies (e.g., microdeletions) at molecular level (when deletion is too small to be visualized by karyotype). Fluorescence = gene is present; no fluorescence = gene has been deleted.

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Cloning methods

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Cloning is the production of a recombinant DNA molecule that is self-perpetuating. 1.) DNA fragments are inserted into bacterial plasmids that contain ABX resistance genes. These plasmids can be selected for by using media containing the ABX, and amplified. 2.) Restriction enzymes cleave DNA at 4- to 6-bp palindromic sequences, allowing for insertion of a fragment into the plasmid. 3.) Tissue mRNA is isolated and exposed to reverse transcriptase, forming a cDNA (lacks introns) library.

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Sanger DNA sequencing

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Dideoxynucleotides halt DNA polymerization at each base, generating sequences of various lengths that encompass the entire original sequence. Terminated fragments are electrophoresed and the original sequence can be deduced.

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Transgenic studies in mice involve...

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1.) Random insertion of gene into mouse genome (constitutive) 2.) Targeted insertion or deletion of gene thru homologous recombination w/ mouse gene (coditional)

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Knock-out vs. Knock-in

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Knock-out = removing a gene Knock-in = inserting a gene

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Cre-lox system in model systems

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A gene can be manipulated at specific developmental points using an inducible Cre-lox system with an ABX-controlled promoter (e.g., to study a gene whose deletion causes an embryonic lethal).

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RNAi

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dsRNA is synthesized that is complementary to the mRNA sequence of interest. When transfeccted into human cells, dsRNA separates and promotes degradation of target mRNA, knocking down gene expression.

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Karyotyping

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A process in which metaphase chromosomes are stained, ordered, and numbered according to size, arm-length ratio, and banding pattern. Can be performed on a sample of blood, bone marrow, amniotic fluid, or placental tissue. Used to Dx chromosomal imbalances (e.g., autosomal trisomies, microdeletions, sex chromosome d/o's).

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Genetic terms: Codominance

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Neither of 2 alleles is dominant (e.g., blood groups)

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Neither of 2 alleles is dominant (e.g., blood groups) What is the genetic term?

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Codominance

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Genetic terms: Variable expression

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Nature and severity of the phenotype varies from 1 individual to another.

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Nature and severity of the phenotype varies from 1 individual to another. What is the genetic term?

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Variable expression

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Genetic terms: Incomplete penetrance

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Not all individuals w/ a mutant genotype show the mutant phenotype.

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Not all individuals w/ a mutant genotype show the mutant phenotype. What is the genetic term?

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Incomplete penetrance

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Genetic terms: Pleiotropy

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1 gene has < 1 effect on an individual's phenotype.

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1 gene has ; 1 effect on an individual's phenotype. What is the genetic term?

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Pleiotropy

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Genetic terms: Imprinting

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Differences in phenotype depend on whether the mutation is of maternal or paternal origin (e.g., Prader-Willi syndrome, Angelman's syndrome)

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Differences in phenotype depend on whether the mutation is of maternal or paternal origin (e.g., Prader-Willi syndrome, Angelman's syndrome) What is the genetic term?

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Imprinting

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Genetic terms: Anticipation

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Severity of dz worsens or age of onset of dz is earlier in succeeding generations (e.g., Huntington's dz)

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Severity of dz worsens or age of onset of dz is earlier in succeeding generations (e.g., Huntington's dz) What is the genetic term?

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Anticipation

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Genetic terms: Loss of heterozygosity

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If a patient inherits or develops a mutation in a tumor suppressor gene, the complementary allele must be deleted/mutated before cancer develops. This is not true of oncogenes.

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If a patient inherits or develops a mutation in a tumor suppressor gene, the complementary allele must be deleted/mutated before cancer develops. This is not true of oncogenes. What is the genetic term?

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Loss of heterozygosity

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Genetic terms: Dominant negative mutation

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Exerts a dominant effect . A heterozygote produces a nonfxnl altered protein that also prevents the normal gene product from functioning.

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Exerts a dominant effect . A heterozygote produces a nonfxnl altered protein that also prevents the normal gene product from functioning. What is the genetic term?

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Dominant negative mutation

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Genetic terms: Linkage disequilibrium

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Tendency for certain alleles at 2 linked loci to occur together more often than expected by chance. Measured in a population, not in a family, and often varies in different populations.

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Tendency for certain alleles at 2 linked loci to occur together more often than expected by chance. Measured in a population, not in a family, and often varies in different populations. What is the genetic term?

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Linkage disequilibrium

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Genetic terms: Mosaicism

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Occurs when cells in the body have different genetic makeup (e.g., lyonization -- random X inactivation in females)

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Occurs when cells in the body have different genetic makeup (e.g., lyonization -- random X inactivation in females) What is the genetic term?

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Mosaicism

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Genetic terms: Locus heterogeneity

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Mutations at different loci can produce the same phenotype (e.g., albumin)

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Mutations at different loci can produce the same phenotype (e.g., albumin) What is the genetic term?

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Locus heterogeneity

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Genetic terms: Heteroplasmy

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Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrial inherited dz's.

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Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrial inherited dz's. What is the genetic term?

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Heteroplasmy

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Genetic terms: Uniparental disomy

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Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent.

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Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent. What is the genetic term?

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Uniparental disomy

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Hardy-Weinberg equilibrium

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If a population is in H-W equilibrium and p and q are separate alleles, then: Dz prevalence: p^2 + 2pq + q^2 = 1 Allele prevalence: p + q = 1 2pq = heterozygote prevalence The prevalence of an X-linked recessive dz in males = q and in females = q^2

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Assumptions of Hardy-Weinberg (there are 4)

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1.) No mutation occurring at the locus 2.) No selection for any of the genotypes at the locus 3.) Completely random mating 4.) No migration

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Imprinting (def.)

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At a single locus, only 1 allele is active; the other is inactive (imprinted/inactivated by methylation). Deletion of the active allele --< dz. Most common example: Prader-Willi and Angelman's syndromes

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Prader-Willi and Angelman's syndromes: Location? Mechanism?

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Both syndromes due to inactivation or deletion of genes on chromosome 15. Can also occur as a result of uniparental disomy.

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P rader-Willi Syndrome

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Deletion of normally active P aternal allele. Mental retardation, hyperphagia, obesity,, hypogonadism, hypotonia.

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AngelM an's syndrome

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Deletion of normally active M aternal allele. Mental retardation, seizures, ataxia, inappropriate laughter ("happy puppet").

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Autosomal dominant. Often due to defects in structural genes. Many generations, both male and female, affected. Often pleiotropic and, in many cases, present clinically after puberty. Family Hx crucial to Dx.

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Autosomal recessive 25% of offspring from 2 carrier parents are affected. Often due to enzyme deficiencies. Usually seen in only 1 generation. Commonly more severe than dominant d/o's; pts often present in childhood.

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X-linked recessive. Sons of heterozygous mothers have a 50% chancce of being affected. No male-to-male transmission. Commonly more severe in males. Heterozygous females may be affected.

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X-linked dominant. Transmitted thru both parents. Either male or female offspring of the affected mother may be affected, while all female offspring of the affected father are diseased.

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Hypophosphatemic rickets

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(Archtypical example of X-linked dominant dz) Formerly known as vitamin D-resistant rickets. Inherited d/o resulting in incr phosphate wasting at proximal tubule. Results in rickets-like presentation.

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Mitochondrial inheritance. Transmitted only thru mother. All offspring of affected females may show signs of dz. Variable expression in population due to heteroplasmy.

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Mitochondrial myopathies, Leber's hereditary optic neuropathy

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(mitochondrial inheritance dz's) Degeneration of retinal ganglion cells and axons. Leads to acute loss of central vision.

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Autosomal Dominant dz's: Achondroplasia

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Cell-signaling defect of fibroblasts growth factor (FGF) receptor 3. Results in dwarfism; short limbs, but head and trunk are normal size. Associated w/ advanced paternal age.

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Autosomal Dominant dz's: APKD

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Formerly known as adult polycystic kidney dz. Always bilateral , massive enlargement of kidneys due to multiple large cysts. Pts p/w flank pain, hemature, HTN, progressive renal failure. 90% cases are due to a mutation in APKD1 (chromosome 16 ; 16 letters in "polycystic kidney"). Associated w/ polycystic liver dz, berry aneurysms, mitral valve prolapse. Infantile form is recessive.

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Autosomal Dominant dz's: Familial adenomatous polyposis

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Colon becomes covered w/ adenomatous polyps after puberty. Progresses to colon cancer unless resected. Deletion on chromosome 5 (APC gene ); 5 letters in "polyp".

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Autosomal Dominant dz's: Familial hypercholesterolemia (hyperlipidemia type IIA)

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Elevated LDL due to defective or absent LDL receptor. Heterozygotes (1:500) have cholesterol ~300 mg/dL. Homozygotes (very rare) have cholesterol ~700+ mg/dL, severe athersclerotic dz early in life, and tendon xanthomas (clasically in the Achilles tendon); MI may develop before age 20.

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Autosomal Dominant dz's: Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)

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Inherited d/o of blood vessels. Findings: telangiectasia, recurrent epistaxis, skin discolorations, arteriovenous malformations (AVMs).

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Autosomal Dominant dz's: Hereditary spherocytosis

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Spheroid erythrocytes due to spectrin or ankyrin defect; hemolytic anemia; Incr MCHC. Splenectomy is curative.

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Autosomal Dominant dz's: Huntington's dz

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Findings: depression, progressive dementia, choreiform mvmts, caudate atrophy, and decr levels of GABA and ACh in the brain. Sx manifest in affected indvls btw the ages of 20-50. Gene located on Chr 4 ; trinucleotide repeat d/o: (CAG) ("Hunting 4 food")

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Autosomal Dominant dz's: Marfan's syndrome

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Fibrillin gene mutation --< connective tissue d/o affecting skeleton, heart, and eyes. Findings: tall w/ long extremities, pectus excavatum, hyperextensive joints, and long, tapering fingers and toes (arachnodactyly, below); cystic medial necrosis of aorta --< aortic incompetence and dissecting aortic aneurysms; floppy mitral valve. Subluxation of the lenses.

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Autosomal Dominant dz's: Multiple endocrine neoplasias (MEN)

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Several distinct syndromes (I, II, III) characterized by familial tumors of endocrine glands, including those of the pancreas, parathyroid, thyroid, and adrenal medula. Men II and III associated w/ ret gene.

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Autosomal Dominant dz's: Neurofibromatosis type 1 (von Recklinghausen's dz)

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Findings: café-au-lait spots, neural tumors, Lisch nodules (pigmented iris hamartomas). Also marked by skeletal d/o's (e.g., scoliosis), optic pathway gliomas, pheochromocytoma, and incr tumor susceptibility. On long arm of chromosome 17 ; 17 letters in "von Recklinghausen"

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Autosomal Dominant dz's: Neurofibromatosis type 2

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Bilateral acoustic neuroma, juvenile cataracts. NF2 gene on chromosome 2 ; (type 2 = 22 )

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Autosomal Dominant dz's: Tuberous sclerosis

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Findings: facial lesions (adenoma sebaceum) hypopigmented "ash leaf spots" on skin cortical and retinal hamartomas seizures mental retardation renal cysts and renal angiomyolipomas cardiac rhabdomyomas incr incidence of astrocytomas. Incomplete penetrance, variable presentation.

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Autosomal Dominant dz's: von Hippel-Lindau dz

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Findings: Hemangioblastomas of retina/cerebellum/medulla about 1/2 of affected indvls develop multiple bilateral renal cell carcinomas and other tumors. Associated w/ deletion of VHL gene (tumor suppressor) on chromosome 3 (3p). Results in constitutive expression of HIF (transcription factor) and activation of angiogenic growth factors. Von Hippel-Linau = 3 words for chromosome 3.

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Autosomal recessive dz's (list)

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Albinism ARPKD (formerly known as infantile polycystic kidney dz) Cystic fibrosis Glycogen storage dz's Hemochromatosis Mucopolysaccharidoses (except Hunter's) Phenylketonuria Sickle cell anemias Sphingolipidoses (except Fabry's) Thalassemias

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Genetics of Cystic fibrosis

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Autosomal-recessive defect in CFTR gene on chromosome 7, commonly deletion of Phe 508. CFTR channel actively secretes Cl- into lungs and GI tract, and actively reabsorbs Cl- from sweat. *Most common lethal genetic dz of Caucasians

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Defective Cl- channel (as in mutCFTR in CF)

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Secretion of abnormally thick mucus that plugs lungs, pancreas and liver | Recurrent pulmonary infxns (Pseudomonas species and S. aures), chronic bronchitis, bronchiectasis, pancreatic insufficiency (malabsorption and steatorrhea), meconium ileus in newborns.

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"Other" problems in CF (besides those that result directly from defective Cl- channel)

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Infertility in males due to bilateral absence of vas deferens. Fat-soluble vitamin deficiencies (A, D, E, K). Can present as failure to thrive in infancy.

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Dx of CF?

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Incr concentration of Cl- ions in sweat test.

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Tx for CF?

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N-acetylcysteine to loosen mucous plugs (cleaves disulfide bonds w/in mucous glycoproteins).

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X-linked recessive d/o's (list)

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B ruton's agammaglobulinemia W iskott-Aldrich syndrome F ragile X G 6PD deficiency O cular albinism L esch-Nyhan syndrome D uchenne's (and Becker's) muscular dystrophy H emophilia A and B F abry's dz H unter's syndrome "B e W ise, F ool's GOLD H eeds F alse H ope" Female carriers are rarely affected due to random inactivation of X chromosomes in each cell.

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Duchenne's muscular dystrophy

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X-linked frame-shift mutation --< deletion of dystrophin gene --< accelerated muscle breakdown. Weakness begins in pelvic girdle muscles and progresses superiorly. Pseudohypertrophy of calf muscles due to fibrofatty replacement of muscle; cardiac myopathy. Use of Gowers' maneuver, requiring assistance of the upper extremities to stand up, is characteristic. Onset before 5 yrs of age. D uchenne's = D eleted D ystrophin.

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Becker's muscular dystrophy

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X-linked mutated dystrophin gene. Less severe than Duchenne's. Onset in adolescence or early adulthood.

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Dystrophin gene (DMD )

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(associated w/ Duchenne's and Becker's muscular dystrophies) The longest known human gene --< incr rate of spontaneous mutation. Dystrophin helps anchor muscle fibers, primarily in skeletal and cardiac muscle.

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Dx of muscular dystrophies (Duchenne's, Becker's)

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Incr CPK and muscle biopsy.

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Fragile X syndrome

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X-linked defect affeccting the methylation and expression of the FMR1 gene. Associated w/ chromosomal breakage. The 2nd most common cause of genetic mental retardation (after Down syndrome). Trinucleotide repeat disorder (CGG)

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Fragile X syndrome: findings?

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Macro-orchidism (enlarged testes), long face w/ a large jaw, large everted ears, autism. "Fragile X = eX tra-large testes, jaw, ears."

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Trinucleotide repeat expansion dz's (list, specific trinucleotides, shared dz characteristic)

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Hunting ton's dz, my otonnic dystrophy, Fried rich's ataxia, fragile X syndrome. ("Try [tri nucleotide] hunting for my fried eggs [X ]") Huntington's = CAG MyoT onic dystrophy = CT G FraG ile X syndrome = CG G Friedreich's ataxia = GAA May show genetic anticipation (dz severity incr and age of onset decr in successive generations; germline expansion in females)

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D own syndrome (trisomy 21) (D rinking age = 21) Incidence?

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1:700 Most common chromosomal d/o and most common cuase of congenital mental retardation.

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D own syndrome (trisomy 21) (D rinking age = 21) Findings?

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Mental retardation, flat facies , prominent epicanthal folds , simian crease [below], gap btw 1st 2 toes, duodenal atresia, congenital hear dz (most commonly septum primum-type ASD). Assoc w/ incr risk of ALL and Alzheimer's dz (< 35 yrs of age)

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D own syndrome (trisomy 21) (D rinking age = 21) genetic cause in 95% of cases?

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Due to meiotic nondisjunction of homogous chromosomes (associated w/ advancced maternal age; from 1:1500 in women >20 to 1:25 in women <45)

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Meiotic nondisjunction

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Can occur in anaphase I: Or in anaphase II:

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D own syndrome (trisomy 21) (D rinking age = 21)

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Genetic cause in 4% of cases? Due to robertsonian translocation.

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D own syndrome (trisomy 21) Geneti cause in 1% of cases?

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Due to Down mosaicism (no maternal association)

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Down syndrome: results of pregnancy quad screen? results of ultrasound?

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Decr alpha-fetoprotein Incr Beta-hCG Decr estriol Incr Inhibin A Ultrasound shows nuchal translucency.

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E dward's syndrome (trisomy 18 ) (E lection age = 18 ) Incidence?

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1:8000 Most common trisomy resulting in live birth after Down syndrome.

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E dward's syndrome (trisomy 18 ) (E lection age = 18 ) Findings?

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Severe mental retardation Rocker-bottom feet micrognathia (small jaw) Low-set ears Clenched hands Prominent occiput Congenital heart dz Death usually occurs w/in 1 yr of birth.

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P atau's syndrome (trisomy 13 ) (P uberty ~age 13 ) Incidence?

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1:15,000

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P atau's syndrome (trisomy 13 ) (P uberty ~age 13 ) Findings?

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Severe mental retardation Rocker-bottom feet Microphthalmia Microcephaly Cleft lip/palate holoProsencephaly Polydactyly Congenital heart dz Death usually occurs w/in 1 yr of birth.

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Robertsonian translocation

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Nonreciprocal chromosomal transloccation that commonly involves chromosome pairs 13, 14, 15, 21, and 22. One of the most common types of translocation. Occurs when the long arms of two acrocentric chromosomes (chromosomes w/ the centromeres near the ends) fuse at the centromere and the 2 short arms are lost.

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Robertsonian translocation: balanced vs. unbalanced translocations?

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Balanced translocations normally do not cause any abnormal phenotype. Unbalanced translocations can result in miscarriage, stillbirth, and chromosomal imbalance (e.g., Down syndrome, Patau's syndrome).

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Chromosomal inversions

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Chromosome rearrangement in which a segment of a chromosome is reveresed end-to-end. May result in decr fertility.

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Chromosomal inversions: Pericentric vs. paracentric?

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Pericentric: Involves centromere; proceeds thru meiosis. Paracentric: does not involve centromere; does not proceed thru meiosis.

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Cri-du-chat syndrome: genetic basis?

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Congenital microdeletion of short arm of Chr 5 (46,XX or XY,5p-)

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Cri-du-chat: findings?

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Microcephaly Moderate to severe mental retardation High-pitched crying/mewing (Cri-du-chat = "cry of the cat") Epicanthal folds Cardiac abnormalities

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Williams syndrome: genetic basis?

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Congenital microdeletion of long arm of Chr 7 (deleted region includes elastin gene).

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Williams syndrome: findings?

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Distinctive "elfin" facies Mental retardation Well-developed verbal skills Cheerful disposition Extreme friendliness w/ strangers Cardiovascular problems

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22q11 deletion syndromes: general characteristics, genetic basis?

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Variable presentation, including: C left palate A bnormal facies T hymic aplasia --< T-cell deficiency C ardiac defects H ypocalcemia secondary to parathyroid aplasia Due to microdeletion at chromosome 22 q11. "CATCH-22 "

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22q11 deletion syndromes: developmental etiology?

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Due to aberrat development of 3rd and 4th branchial pouches

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22q11 deletion syndromes: what are they, and what are the main findings?

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DiGeorge syndrome: thymic, parathyroid, and cardiac defects. Velocardiofacial syndrome: palate, facial, and cardiac defects.

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Fat-soluble vitamins (list + their basic fxns)

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Vitamin A - vision Vitamin D - bone calcification, Ca2+ homeostasis Vitamin E - antioxidant Vitamin K - clotting factors

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Fat-soluble vitamins: toxicity?

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(A, D, E, K) Toxicity more common than for water-soluble vitamins, b/c they accumulate in fat.

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Fat-soluble vitamins: absorption?

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(A, D, E, K) Absorption dependent on gut (ileum) and pancreas. Malabsorption syndromes (steatorrhea), such as cystic fibrosis and sprue, or mineral oil intake can cause fat-soluble vitamin deficiencies.

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Water-soluble vitamins (list and basic fxns)

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Vitamin C - antioxidant, collagen synthesis Metabolic: Thiamine (B1) Riboflavin (B2) Niacin (B3) Pantothenic acid (B5) Pyridoxine (B6) Biotin (B7) Folate - blood, neural development Cobalamin (B12) - blood, CNS

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Water-soluble vitamins: list with alternative names and related enzymes/cofactors?

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B1 (thiamine: TPP) B2 (riboflavin: FAD, FMN) B3 (niacin: NAD+) B5 (pantothenic acid: CoA) B6 (pyridoxine: PLP) B12 (cobalamin) C (ascorbic acid) Also: Biotin, folate

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Water soluble vitamin deficiencies

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All was out easily from body except B12 and folate (stored in liver). B-complex deficiencies often result in dermatitis, glossitis, and diarrhea.

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Vitamin A (retinol): fxn? use? where is it found?

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Antioxidant; constituent of visual pigments (retinal). Retinol is vitamin A , so think Retin-A (used topically for wrinkles and acne). Found in liver and leafy vegetables.

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Vitamin A (retinol) deficiency?

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Night blindness, dry skin.

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Vitamin A (retinol) excess?

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Arthralgias, fatigue, HAs, skin changes, sore throat, alopecia. Teratogenic (cleft palate, cardiac abnormalities).

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Vitamin B1 (thiamine): fxn?

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In thiamine pyrophosphate (TPP), a cofactor for several enzymes: 1.) Pyruvate dehydrogenase (glycoslysis) 2.) alpha-ketoglutarate dehydrogenase (TCA cycle) 3.) Transketolase (HMP shunt) 4.) Branched-chain AA dehydrogenase

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Vitamin B1 (thiamine) deficiency: causes what? Where do you see this?

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Wernicke-Korsakoff syndrome and beriberi (both neurologic and cardiac manifestations). Seen in malnutrition as well as alcoholism (secondary to malnutrition and malabsorption).

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Wernicke-Korsakoff syndrome

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Due to Vitamin B1 (thiamine) deficiency. confusion, ophthalmoplegia, ataxia + memory loss, confabulation, personality change.

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Beri-beri

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Due to Vitamin B1 (thiamine) deficiency. (spell it B er1-B er1 ) Dry beriberi - polyneuritis, symmetrical muscle wasting. Wet beriberi - high-output cardiac failure (dilated cardiomyopathy), edema.

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Vitamin B2 (riboflavin) fxn?

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Cofactor in oxidation and reduction (e.g., FADH2) F AD and F MN are derived from riboF lavin (B2 = 2 ATP)

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Vitamin B2 (riboflavin) deficiency?

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C heilosis (inflammation of lips, scaling and fissures at corners of mouth), C orneal vascularization. "The 2 C 's"

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Vitamin B3 (niacin): fxn?

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Constituent of NAD+, NADP+ (used in redox rxtns). Derived from tryptophan. Synthesis requires vitamin B6. N AD derived from N iacin (B3 = 3 ATP)

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Vitamin B3 (niacin) deficiency?

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Glossitis. Severe deficiency leads to pellagra, which can be caused by Hartnup dz (decr tryptophan absorption), malignant carcinoid syndrome (incr tryptophan metabolism), and INH (decr vitamin B6) The 3 D's of pellagra: D iarrhea, D ermatitis, D ementia.

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Vitamin B3 (niacin) excess?

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Facial flushing (due to pharmacologic doses for Tx of hyperlipidemia)

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Vitamin B4 (pantothenate): fxn?

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Essential component of CoA (a cofactor for acyl transfers) and fatty acid synthase. "Pantothen-A is in Co-A "

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Vitamin B5 (pantothenate) deficiency?

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Dermatitis, enteritis, alopecia, adrenal insufficiency

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Vitamin B6 (pyridoxine) fxn?

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Converted to pyridoxal phosphate, a cofactor used in transamination (e.g., ALT and AST), decarboxylation rxtns, glycogen phosphorylase, and heme synthesis. Required for the synthesis of niacin from tryptophan.

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Vitamin B6 (pyridoxine) deficiency?

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Convulsions, hyperirritability, peripheral neuropathy (deficiency inducible by INH and oral contraceptives)

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B12 (cobalamin): fxn?

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Cofactor for homocysteine methyltransferase (transfers CH3 groups as methylcobalamin) and methylmalonyl-CoA mutase.

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B12 (cobalamin): Deficiency?

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Macrocytic, megaloblastic anemia; neurologic Sx (paresthesias, subacute combined degeneration) due to abnormal myelin. Prolonged deficiency leads to irreversible nervous system damage.

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B12 (cobalamin): what rxtns does it help to proceed?

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Homocysteine + N-methyl THF --(B12 + homocysteine methyl transferase)--< Methionine + THF Methylmalonyl-CoA --(B12 + methylmalonyl-CoA mutase)--< Succinyl-CoA

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B12 (cobalamin): found where?

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Found in animal products. Only synthesized by microorganisms.

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B12 (cobalamin): etiology of deficiency?

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Very large reserve pool (several yrs) stored primarily in liver. Deficiency is usually caused by malabsorption (sprue, enteritis, Diphyllobothrium latum ), lack of intrinsic factor (pernicious anemia, gastric bypass surgery), or absence of terminal ileum (Crohn's dz).

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Schilling test

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Used to detect the etiology of B12 (cobalamin) deficiency.

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Folic acid: fxn?

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Converted to tetrahydrofolate (THF), a coenzyme for 1-carbon transfer/methylation rxtns. Important for the synthesis of nitrogenous bases in DNA and RNA.

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Folic acid: deficiency?

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Macrocytic, megaloblastic anemia; no neurologic Sx (as opposed to vitamin B12 deficiency). Most common vitamin deficiency in the USA. Seen in alcoholism and pregnancy.

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Folic acid: where is it found?

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FOL ate is from FOL iage (green leaves)

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Etiology of folic acid deficiency?

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Small reserve pool stored primarily in liver (eat green leaves!) Deficiency can be caused by several drugs (e.g., phenytoin, sulfonamides, MTX).

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Folic acid and pregnancy

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Supplemental folic acid in early pregnancy reduces neural tube defects.

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S-adenosyl-methionine (SAM): formation?

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ATP + methionine --< SAM

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S-adenosyl-methionine (SAM): fxn?

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SAM transfers methyl units. Regeneration of methionine (and thus SAM) is dependent on vitamin B12 and folate. ("SAM the methyl donor man")

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Biotin: fxn?

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Cofactor for carboxylation enzymes: 1.) Pyruvate carboxylase : Pyruvate --< oxaloacetate 2.) Acetyl-CoA carboxylase : Acetyl-CoA --< malonyl-CoA 3.) Propionyl-CoA carboxylase : Propionyl-CoA --< methylmalonyl-CoA

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Biotin: deficiency?

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Relatively rare. Dermatitis, alopecia, enteritis. Caused by ABX use or excessive ingestion of raw eggs. "AVID in in egg whites AVID ly binds biotin."

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Vitamin C (ascorbic acid): fxn?

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Antioxidant. Also: 1.) Facilitates iron absorption by keeping iron in Fe2+ state (more absorbable) 2.) Necessary for hydroxylation of proline and lysine in collagen synthesis. 3.) Necessary for dopamine Beta-hydroxylase, which converts dopamine to NE

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Vitamin C (ascorbic acid): deficiency?

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Scurvy: swollen gums, bruising, anemia, poor wound healing.

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Vitamin C (ascorbic acid): where is it found?

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Found in fruits and vegetables. British sailors carried limes to prevent scurvy (thus the origin of the word "limey")

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Vitamin D: forms?

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D2 = ergocalciferol -- ingested from plants, used as pharmacologic agent. D3 = cholecalciferol -- consumed in milk, formed in sun-exposed skin. 25-OH D3 = storage form. 1,25-(OH)2-D3 (calcitriol) = active form

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Vitamin D: fxn?

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Incr intestinal absorption of calcium and phosphate, incr bone resorption

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Vitamin D: deficiency?

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Rickts in children (bending bones), osteomalacia in adults (soft bones), hypocalcemic tetany. Drinking milk (fortified w/ vitamin D) is good for bones.

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Vitamin D: excess?

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Hypercalcemia, hypercalciuria, loss of appetite, stupor. Seen in sarcoidosis (incr activation of vitamin D by epithelioid macrophages)

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Vitamin E: fxn?

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Antioxidant (protects erythrocytes and membranes from free-radical damage). "E is for E rythrocytes"

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Vitamin E: deficiency?

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Incr fragility of erythrocytes (hemolytic anemia), muscle weakness, neurodysfxn.

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Vitamin K: fxn?

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Catalyzes gamma-carboxylation of glutamic acid residues on various proteins concerned w/ blood clotting. "K for K oagulation." Necessary for synthesis of factors II, VII, IX, X, and protein C and S.

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Vitamin K: synthesis?

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Synthesized by intestinal flora.

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Vitamin K antagonist?

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Warfarin.

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Vitamin K: deficiency?

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Neonatal hemorrhage w/ incr PT and incr aPTT, but normal bleeding time (neonates have sterile intestines and are unable to synthesize vitamin K). Neonates are give vitamin K injection at birth to prevent hemorrhage. Can also occur after prolonged use of broad-spectrum ABX.

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Zinc: fxn?

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Essential for the activity of 100+ enzymes. Important in the formation of Zinc fingers (a transcription motif)

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Zinc: deficiency?

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Delayed wound healing, hypogonadism, decr adult hair (axillary, facial, pubic). May predispose to alcoholic cirrhosis.

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Ethanol metabolism: chemical rxtns?

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Ethanol metabolism: kinetics?

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NAD+ is the limiting reagent. Alcohol dehydrogenase operates via zero-order kinetics.

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Fomepizole

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Inhibits alcohol dehydrogenase

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Disulfiram (antabuse)

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Inhibits acetaldehyde dehydrogenase (acetaldehyde accumulates, contributing to Sx of hangover)

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Ethanol hypoglycemia

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Ethanol metabolism increases NADH/NAD+ ratio in liver, causing a diversion of pyruvate to lactate and OAA to malate, thereby inhibiting gluconeogenesis and stimulating FA synthesis. Leads to hypoglycemia and hepatic fatty change (hepatocellular steatosis) seen in chronic alcoholics.

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Kwashiorkor

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Protein malnutrition resulting in skin lesions, edema, liver malfxn (fatty change). Clinical picture is small child w/ swollen belly. "Kwashiorkor results from a protein-deficient MEAL : M alnutrition, E dema, A nemia, L iver (fatty)"

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Marasmus

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Energy malnutrition resulting in tissue and muscle wasting, loss of subcutaneous fat, and variable edema. "M arasmus results in M uscle wasting"

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Metabolism sites: Mitochondria

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Fatty acid oxidation (beta-oxidation) Acetyl-CoA production TCA cycle Oxidative phosphorylation

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Metabolism sites: cytoplasm

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Glycolysis Fatty acid synthesis HMP shunt Protein synthesis (RER) Steroid synthesis (SER)

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Metabolism sites: both mitochondria and cytoplasm

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H eme synthesis U rea cycle G luconeogenesis "HUG s take two "

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Process: Glycolysis What is the rate-limiting enzyme?

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Phosphofructokinase-1 (PFK-1)

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Rate-limiting enzyme: Phosphofructokinase-1 (PFK-1) What is the process?

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Glycolysis

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Process: Gluconeogenesis What is the rate-limiting enzyme?

answer

Fructose bisphosphatase-2

question

Rate-limiting enzyme: Fructose bisphosphatase-2 What is the process?

answer

Gluconeogenesis

question

Process: TCA cycle What is the rate-limiting enzyme?

answer

Isocitrate dehydrogenase

question

Rate-limiting enzyme: Isocitrate dehydrogenase What is the process?

answer

TCA cycle

question

Process: Glycogen synthesis What is the rate-limiting enzyme?

answer

Glycogen synthase

question

Rate-limiting enzyme: Glycogen synthase What is the process?

answer

Glycogen synthesis

question

Process: Glycogenolysis What is the rate-limiting enzyme?

answer

Glycogen phosphorylase

question

Rate-limiting enzyme: Glycogen phosphorylase What is the process?

answer

Glycogenolysis

question

Process: HMP shunt What is the rate-limiting enzyme?

answer

Glucose-6-phosphate dehydrogenase (G6PD)

question

Rate-limiting enzyme: Glucose-6-phosphate dehydrogenase (G6PD) What is the process?

answer

HMP shunt

question

Process: De novo pyrimidine synthesis What is the rate-limiting enzyme?

answer

Aspartate transcarbamoylase (ATCase)

question

Rate-limiting enzyme: Aspartate transcarbamoylase (ATCase) What is the process?

answer

De novo pyrimidine synthesis

question

Process: De novo purine synthesis What is the rate-limiting enzyme?

answer

Glutamine-PRPP amidotransferase

question

Rate-limiting enzyme: Glutamine-PRPP amidotransferase What is the process?

answer

De novo purine synthesis

question

Process: Urea cycle What is the rate-limiting enzyme?

answer

Carbamoyl phosphate synthetase

question

Rate-limiting enzyme: Carbamoyl phosphate synthetase What is the process?

answer

Urea cycle

question

Process: Fatty acid synthesis What is the rate-limiting enzyme?

answer

Acetyl-CoA carboxylase (ACC)

question

Rate-limiting enzyme: Acetyl-CoA carboxylase (ACC) What is the process?

answer

Fatty acid synthesis

question

Process: Fatty acid oxidation What is the rate-limiting enzyme?

answer

Carnitine acyltransferase I

question

Rate-limiting enzyme: Carnitine acyltransferase I What is the process?

answer

Fatty acid oxidation

question

Process: Ketogenesis What is the rate-limiting enzyme?

answer

HMG-CoA synthase

question

Rate-limiting enzyme: HMG-CoA synthase What is the process?

answer

Ketogenesis

question

Process: Cholesterol synthesis What is the rate-limiting enzyme?

answer

HMG-CoA reductase

question

Rate-limiting enzyme: HMG-CoA reductase What is the process?

answer

Cholesterol synthesis

question

Summary of biochemical pathways

answer

question

Glycolysis/ATP production

answer

Aerobic metabolism of glucose produces 32 ATP via malate-aspartate shuttle (heart and liver), 30 ATP via glycerol-3 phosphate shuttle (muscle) Anaerobic glycolysis produces only 2 net ATP per glucose molecule. ATP hydrolysis can be coupled to energetically favorable rxtns.

question

Structure of ATP (what are the 3 important moieties?)

answer

question

Subtance: Phosphoryl What is the activated carrier for this substance?

answer

ATP

question

Activated carriers: ATP What does substance does this carry?

answer

Phosphoryl

question

Subtance: Electrons What is the activated carrier for this substance?

answer

NADH, NADPH, FADH2

question

Activated carriers: NADH, NADPH, FADH2 What does substance does this carry?

answer

Electrons

question

Subtance: Acyl What is the activated carrier for this substance?

answer

Coenzyme A, lipoamide

question

Activated carriers: Coenzyme A, lipoamide What does substance does this carry?

answer

Acyl

question

Subtance: CO2 What is the activated carrier for this substance?

answer

Biotin

question

Activated carriers: Biotin What does substance does this carry?

answer

CO2

question

Subtance: 1-carbon units What is the activated carrier for this substance?

answer

Tetrahydrofolate

question

Activated carriers: Tetrahydrofolate What does substance does this carry?

answer

1-carbon units

question

Subtance: CH3 groups What is the activated carrier for this substance?

answer

SAM

question

Activated carriers: SAM What does substance does this carry?

answer

CH3 groups

question

Subtance: Aldehydes What is the activated carrier for this substance?

answer

TPP

question

Activated carriers: TPP What does substance does this carry?

answer

Aldehydes

question

Universal electron acceptors (list)

answer

Nicotinamides (NAD+, NADP+) and flavin nucleotides (FAD+)

question

NAD+ vs. NADP+

answer

NAD+ is generally used in catabolic processes to carry reducing equivalents away as NADH. NADPH is used in anabolic processes (steroid and FA synthesis) as a supply of reducing equivalents.

question

NADPH: Product of...? Used in... (3 things)?

answer

Product of the HMP shunt. Used in: 1.) Anabolic processes 2.) Respiratory burst 3.) P-450

question

Hexokinase vs. glucokinase: why are the 2 enzymes similar?

answer

Phosphorylation of glucose to yield glucose-6-phosphate serves as the 1st step of glycolysis (also serves as the first step of glycogen synethsis in the liver). Rxtn is catalyzed by either hexokinase or glucokinase, depending on location.

question

Hexokinase vs. glucokinase: Location?

answer

Hexokinase: ubiquitous. Glucokinase: Liver and Beta-cells of pancreas only.

question

Hexokinase vs. glucokinase: Affinity / Capacity?

answer

Hexokinase: high affinity (low Km), low capacity (low Vmax) Glucokinase: Low affinity (high Km), high capacity (high Vmax)

question

Hexokinase vs. glucokinase: response to insulin?

answer

Hexokinase: uninduced by insulin Glucokinase: induced by insulin

question

Hexokinase vs. glucokinase: Feedback?

answer

Hexokinase: Feedback inhibited by glucose-6-phosphate. Glucokinase: No direct feedback inhibition.

question

Hexokinase vs. glucokinase: Role in blood sugar hemostasis?

answer

Glucokinase phosphorylates excess glucose (e.g., after a meal) to sequester it in the liver. Allows liver to serve as a blood glucose "buffer".

question

Net glycolysis rxtn (cytoplasm)

answer

Glucose + 2 Pi + 2 ADP + 2 NAD+ | [yields] | 2 pyruvate + 2 ATP + 2 NADH + 2 H+ + 2H2O

question

Steps in glycolysis that require ATP: What are the substrates/products/enzymes?

answer

question

Steps in glycolysis that require ATP: Regulation?

answer Hexokinase (ubiquitous)/glucokinase (liver) -- (-) feedback from Glucose-6-Phosphate Phosphofructokinase 1 (rate limiting step): (-) feedback from ATP , citrate (+) feedback from AMP, fructose-2,6-bisphosphate

question

Steps in glycolysis that produce ATP: What are the substrates/products/enzymes?

answer

question

Steps in glycolysis that produce ATP: Regulation?

answer

Pyruvate kinase: (-) feedback from ATP, alanine (+) feedback from fructose-1,6-bisphosphate

question

Pyruvate dehydrogenase

answer Takes pyruvate (the product of glycolysis) and produces Acetyl-CoA, which can enter TCA/Krebs cycle. (-) feedback from: ATP, NADH, Acetyl-CoA

question

Regulation by fructose-2,6-bisphosphate

answer

F2,6BP is the most potent activator of PFK-1 (overrides inhibition by ATP and citrate) and is a potent regulator of glycolysis and gluconeogenesis

question

Glycolytic enzyme deficiency: Associated with...? Why? Due to deficiencies in...?

answer

Associated w/ hemolytic anemia . Inability to maintain activity of Na+/K+ ATPase leads to RBC swelling and lysis. (RBCs metabolize glucse anaerobically - no mitochondria - and thus depend solely on glycolysis. Due to deficiencies in pyruvate kinase (95%), phosphoglucose isomerase (4%), and other glycolytic enzymes.

question

Pyruvate dehydrogenase: net rxtn?

answer

Pyruvate + NAD+ + CoA | [yields] | acetyl-CoA + CO2 + NADH

question

Pyruvate dehydrogenase complex: 3 enzymes that require what 5 cofactors?

answer

1.) Pyrophosphate (B1, thiamine; TPP) 2.) FAD (B2, riboflavin) 3.) NAD (B3, niacin) 4.) CoA (B5, pantothenate) 5.) Lipoic acid

question

How does exercise active the pyruvate dehydrogenase complex?

answer

Incr NAD+/NADH ratio Incr ADP Incr Ca2+

question

Pyruvate dehydrogenase complex vs. alpha-ketoglutarate complex

answer

PD complex is similar to the a-KG complex (same cofactors, similar substrate and action), which converts alpha-ketoglutarate --< succinyl-CoA (TCA cycle)

question

Arsenic: inhibits...? Findings w/ poisoning?

answer

Inhibits lipoic acid (cofactor for pyruvate dehydrogenase complex and alpha-KG complex) Findings: vomiting, rice water stools, garlic breath.

question

Pyruvate dehydrogenase deficiency: Causes...? Etiology?

answer

Causes backup of substrate (pyruvate and alanine), resulting in lactic acidosis. Can be congenital or acquired (as in alcoholics due to B1 deficiency).

question

Pyruvate dehydrogenase deficiency: findings?

answer

Neurologic defects

question

Pyruvate dehydrogenase deficiency: Tx?

answer

Incr intake of ketogenic nutrients (e.g., high fat content or incr lysine and leucine) *L ysine and L eucine are the only purely ketogenic amino acids.

question

Pyruvate metabolism: Alanine?

answer

Alanine (made via ALT): carries amino groups to the liver from muscle [#1 above]

question

Pyruvate metabolism: oxaloacetate?

answer OAA (formed via PC) can replenish TCA cycle or be used in gluconeogenesis [#2 above]

question

Pyruvate metabolism: Acetyl-CoA

answer

#3: transition from glycolysis to the TCA cycle

question

Pyruvate metabolism: Lactate?

answer

#4: End of anaerobic glycolysis (major pathway in RBCs, leukocytes, kidney medulla, lens, testes, and cornea)

question

Cori cycle

answer

Allows lactate generated during anaerobic metabolism to undergo hepatic gluconeogenesis and become a source of glucose for muscle/RBCs. This comes at a cost of a net loss of 4 ATP/cycle. Shifts metabolic burden to the liver.

question

Pyruvate --< acetyl-CoA produces what?

answer

1 NADH + 1 CO2

question

The TCA cycle (Krebs) produces what?

answer

3 NADH, 1 FADH2, 2 CO2, 1 GTP per acetyl-CoA = 12 ATP/acetyl-CoA (2x everything per glucose).

question

Where does the TCA cycle rxtn take place?

answer

In the mitochondria.

question

alpha-ketoglutarate dehydrogenase complex

answer

Part of TCA cycle. Requires the same cofactors as the pyruvate dehydrogenase complex (B1, B2, B3, B5, lipoic acid)

question

Enzymes of TCA (Krebs cycle) + schematic

answer

"C itrate I s K rebs' S tarting S ubstrate F or M aking O xaloacetate." *note the irreversible enzymes above in bold

question

What does the ETC do, and how does it relate to oxidative phosphorylation?

answer

NADH electrongs from glycolysis and the TCA cycle enter mitochondria via the malate-aspartate or glycerol-3-phosphate shuttle. FADH2 electrons are transferred to complex II (at a lower energy level than NADH). The passage of electrons results in the formation of a proton gradient that, coupled to oxidative phosphorylation, drives the production of ATP.

question

ATP produced via ATP synthase

answer

1 NADH --< 3 ATP 1 FADH2 --< 2 ATP

question

Oxidative phosphorylation poisons: ETC inhibitors?

answer

Directly inhibit electron transport, causing a lower proton gradient and block of ATP synthesis. E.g., Retenone, CN-, antimycin A, CO

question

Oxidative phosphorylation poisons: ATPase inhibitors

answer

Directly inhibit mitochondrial ATPase, causing an incr proton gradient. No ATP is produced b/c electron transport stops. E.g., Oligomycin

question

Oxidative phosphorylation proteins: uncoupling agents

answer

Incr permeability of membrane, causing a decr proton gradient and incr O2 consumption. ATP synthesis drops, but electron transport continues. E.g., 2,4-DNP, aspirin, thermogenin in brown fat.

question

Gluconeogenesis, irreversible enzymes: Pyruvate carboxylase Location? Rxtn? Requires...?

answer

In mitochondria. Pyruvate --< Oxaloacetate. Requires biotin, ATP. Activated by acetyl-CoA.

question

Gluconeogenesis, irreversible enzymes: PEP carboxykinase Location? Rxtn? Requires...?

answer

In cytosol. Oxaloacetate --< phosphoenolpyruvate. Requires GTP.

question

Gluconeogenesis, irreversible enzymes: Fructose-1,6-bisphosphatase Location? Rxtn? Requires...?

answer

In cytosol. Fructose-1,6-bisphosphate --< fructose-6-phosphate

question

Gluconeogenesis, irreversible enzymes: Glucose-6-phosphatase Location? Rxtn? Requires...?

answer

In ER. Glucose-6-P --< glucose.

question

Mnemonic for the irreversible enzymes of gluconeogenesis?

answer

"P athway P roduces F resh G lucose" P yruvate carboxylase P EP carboxykinase F ructose-1,6-bisphosphatase G lucose-6-phosphatase

question

Where does gluconeogenesis occur (anatomically)?

answer

Occurs primarily in liver. Enzymes also found in kidney, intestinal epithelium.

question

Deficiency of gluconeogenesis enzymes causes...?

answer

Causes hypoglycemia. (Muscle cannot participate in gluconeogenesis.)

question

Fatty acids and gluconeogenesis

answer

Odd-chain FA's yield 1 propionyl-CoA during metabolism, which can enter the TCA cycle, undergo gluconeogenesis, and serve as a glucose source. Even-chain FA's cannot produce new glucose, sine they yield only acetyl-CoA equivalents.

question

HMP shunt (pentose phosphate pathway): What does it do? Where does it occur (in the cell)? What is the net ATP requirement or yield?

answer

Produces NADPH, which is req'd for FA and steroid biosynthesis and for glutathione reduction inside RBCs. 2 distinct phases (oxidative and non-oxidative), both of which occur in the cytoplasm. No ATP is used or produced.

question

HMP shunt (pentose phosphate pathway): Where does it occur (anatomically)?

answer

Lactating mamary glands, liver, adrenal cortex (sites of FA or steroid synthesis), RBCs

question

HMP shunt (pentose phosphate pathway): Oxidative rxtns (irreversible) -- key enzymes? products?

answer

Key enzymes: Glucose-6-phosphate dehydrogenase (rate-limiting step) Products: NADPH (for FA and steroid synthesis, glutathione reduction, and cytochrome P-450)

question

HMP shunt (pentose phosphate pathway): Nonoxidative (reversible) -- key enzymes? products?

answer

Key enzymes: Transketolases (require thiamine). Products: Ribose-5-phosphate (for nucleotide synthesis); G3P, F6P (glycolytic intermediates)

question

Respiratory burst (oxidative burst)

answer

Involves activation of membrane-bound NADPH oxidase (e.g., in neutrophils, macrophages). Plays an important role in the immune response --< results in the rapid release of reactive oxygen species. [note enzymes/rxtns in schematic below]

question

Glucose-6-Phosphate dehydrogenase deficiency: molecular explanation?

answer

NADPH is necessary to keep glutathione reducced, which in turn detoxifies free radicals and peroxides. Decr NADPH in RBCs leads to hemolytic anemia due to poor RBC defense against oxidizing agents (e.g., fava beans, sulfonamides, primaquine, antituberculosis drugs).

question

Glucose-6-phosphate dehydrogenase deficiency: Genetics? Findings in blood?

answer

X-linked recessive d/o; most common human enzyme deficiency; more prevalent among blacks. Incr malarial resistance. H einz bodies -- altered H emoglobin precipitated w/in RBCs Bite cells -- result from the phagocytic removal of Heinz bodies by macrophages.

question

Fructose intolerance: Deficiency? Genetics? Biochem/molecular problem?

answer

Hereditary deficiency in aldolase B . Autosomal recessive. Fructose-1-phosphate accumulates, causing a decr in available phosphate, which results in inhibition of glycogenolysis and gluconeogenesis. [fructose metabolism in liver -- above]

question

Fructose intolerance: Sx?

answer

Hypoglycemia, jaundice, cirrhosis, vomiting.

question

Fructose intolerance: Tx?

answer

Decr intake of both fructose and sucrose (glucose + fructose)

question

Essential fructosuria: Defect? Genetics? Biochem/molecular problem?

answer

Involves a defect in fructokinase . Autosomal recessive. A benign, asymptomatic condition, since fructose doesn't enter cells. [above: fructose metabolism in liver]

question

Essential fructosuria: Sx?

answer

Fructose appears in blood and urine (benign)

question

D/o of fructose metabolism vs. galactose metabolism?

answer

D/o's of fructose metabolism cause milder Sx than analogous d/o's of galactose metabolism.

question

Classic galactosemia: Deficiency? Genetics? Biochem/molec problem?

answer

Absence of galactose-1-phosphate uridyltransferase . Autosomal recessive. Damage is caused by accumulation of toxic substances (including galactitol, which accumulates in the lens of the eye).

question

Classic galactosemia: Sx?

answer

Failure to thrive, jaundice, hepatomegaly, infantile cataracts, mental retardation.

question

Classic galactosemia: Tx?

answer

exclude galactose and lactose (galactose + glucose) from diet.

question

Galactokinase deficiency: Deficiency? Genetics? Biochem/molec problem?

answer

Hereditary deficiency of galactokinase . Autosomal recessive. Galactitol accumulates if galactose is present in diet. Relatively mild condition.

question

Galactokinase deficiency: Sx?

answer

Galactose appears in blood and urine, infantile cataracts. May initially present as failure to track objects or to develop a social smile.

question

Lactase deficiency: what is it?

answer

Age-dependent and/or hereditary lactose intolerance (blacks, Asians) due to loss of brush-border enzyme.

question

Lactase deficiency: Sx? Tx?

answer

Bloating, cramps, osmotic diarrhea. Tx by avoiding dairy products or adding lactase pills to diet.

question

Amino acids: which form is found in proteins?

answer

Only L-form AA's are found in proteins.

question

Essential Glucogenic amino acids

answer

Met, Val, Arg, His Glucogenic AA's can be converted into glucose via gluconeogenesis.

question

Essential AA's

answer

Met, Val, Arg, His Ile, Phe, Thr, Trp Leu, Lys All essential AA's need to be supplied in diet. (classified as glucogenic and/or ketogenic)

question

Glucogenic/ketogenic AA's

answer

Ile, Phe, Thr, Trp Glucogenic AA's can be converted into glucose via gluconeogenesis. Ketogenic AA's form ketone bodies.

question

Ketogenic AA's

answer

Leu, Lys Ketogenic AA's form ketone bodies.

question

Acidic AA's

answer

Asp and Glu (negatively charged at body pH)

question

Basic AA's

answer

Arg, Lys, and His Arg is the most basic. His has no charge at body pH. Arg and His are req'd during periods of growth. Arg and His are elevated in histones, which bind (-) charged DNA.

question

Urea cycle: fxn/purpose?

answer

Amino acid catabolism results in the formation of common metabolites (e.g., pyruvate, acetyl-CoA), which serve as metabolic fuels. Excess nitrogen (NH4+) generated by this process is converted to urea and excreted by the kidneys.

question

Mnemonic to remeber the important molecules in the urea cycle

answer

"O rdinarily, C areless C rappers A re A lso F rivolous A bout U rination" O rnithine C arbamoyl phosphate C itrulline A spartate A rginosuccinate F umarate A rginate U rea

question

What do the atoms of urea come from?

answer

question

Transport of ammonium by alanine and glutamine

answer

question

Hyperammonemia: etiology?

answer

Can be acquired (e.g., liver dz) or hereditary (e.g., urea cycle enzyme deficiencies)

question

Hyperammonemia: Result?

answer

Results in exccess NH4+, which depletes alpha-ketoglutarate, leading to inhibition of the TCA cycle. Ammonia intoxication : tremor, slurring speech, somnolence, vomiting, cerebral edema, blurring of vision.

question

Tx for hyperammonemia

answer

Benzoate or phenylbutyrate to lower serum ammonia levels.

question

Phenylalanine derivatives

answer

1.) Phenylalanine --< Tyrosine --< Thyroxine + Dopa 2.) Dopa --< Melanin + Dopamine 3.) Dopamine --< NE --< Epi

question

Tryptophan derivatives

answer

Tryptophan --< Niacin + Serotonin Niacin --< NAD+/NADP+ Serotonin --< Melatonin

question

Histadine derivatives

answer

Histadine --< Histamine

question

Glycine derivatives

answer

Glycine --< Porphyrin --< heme

question

Arginine derivatives

answer

Arginine --< Creatinine, urea, NO

question

Glutamate derivatives

answer

Glutamate --< GABA (glutamate decarboxylase -- requires B6) Glutamate --< Glutathione

question

Phenylketonuria: due to...? What does this mean molecularly?

answer

Due to decr phenylalanine hydroxylase or decr tetrahydrobiopterin cofactor. Tyrosine becomes essential. Incr phenylalanine leads to excess phenylketones in urine.

question

Findings w/ PKU

answer

Mental retardation, growth retardation, seizures, fair skin, eczema, musty body odor (d/o of aromatic AA metabolism --< musty body odor ).

question

Tx for PKU

answer

Decr phenylalanine (contained in aspartame, e.g., NutraSweet) and incr tyrosine in diet.

question

Maternal PKU

answer

Lack of proper dietary therapy during pregnancy. Findings in infant: microcephaly, mental retardation, growth retardation, congenital heart defects.

question

PKU: genetics? incidence? screening?

answer

Autosomal recessive. Incidence ~ 1:10,000 Screened for 2-3d after birth.

question

Phenylketones

answer

Phenylacetate, phenyllactate, and phenylpyruvate. Present in excess in urine w/ PKU.

question

Alkaptonuria (ochronosis): What is it? Genetics? Prognosis?

answer

Congenital deficiency of homogentisic acid oxidase in the degradative pathway of tyrosine. Autosomal recessive. Benign dz.

question

Alkaptonuria (ochronosis): findings?

answer

Dark connective tissue, pigmented sclera, urine turns black on standing. May have debilitating arthralgias.

question

Albinism: etiologies (+ genetics, when applicable)?

answer

Congenital deficiency of either of the following: 1.) Tyrosinase (inability to synthesize melanin from tyrosine) -- Autosomal recessive 2.) Defective tyrosine transporters (decr amounts of tyrosine, and thus melanin) Can result from lack of migration of neural crest cells. Variable inheritance due to locus heterogeneity (vs. ocular albinism -- X-linked recessive)

question

Risk of what dz w/ albinism?

answer

Lack of melanin results in an incr risk of skin cancer.

question

3 Forms of homocystinuria

answer

1.) Cystathionine synthase deficiency (Tx: decr Met and Incr Cys, and incr B12 and folate in diet) 2.) Decr affinity of cystathionine synthase for pyridoxal phosphate (Tx: incr (++) vitamin B6 in diet) 3.) Homocysteine methyltransferase deficiency

question

Commonalities for all 3 forms of homocystinuria

answer

All are autosomal recessive. All forms result in excess homocysteine. Cystine becomes essential.

question

Findings w/ homocystinuria

answer

(++) homocysteine in urine, mental retardation, osteoporosis, tall stature, kyphosis, lens subluxation (downward and inward), and atherosclerosis (stroke and MI)

question

Cystinuria: Etiology? Genetics/incidence?

answer

Hereditary defect of renal tubular AA transporter for cysteine, ornithine, lysine, and arginine in the PCT of the kidneys. Autosomal recessive and common (1:7,000)

question

Cystinuria: findings? Tx?

answer

Excess cystine in urine can lead to precipitation of cystine kidney stones (cystine staghorn calculi). Tx: acetazolamide to alkalinize urine *Cystine is make of 2 cysteines connected by a disulfide bond.

question

Maple syrup urine dz: etiology?

answer

Blocked degradation of branched amino acids (I le, L eu, V aline) due to decr alpha-ketoglutarate dehydrogenase. ("I L ove V ermont maple syrup from maple trees with branches .")

question

Maple syrup urine dz: findings?

answer

Causes severe CNS defects, mental retardation, and death. Urine smells like maple syrup.

question

Purine salvage deficiencies: Adenosine deaminase deficiency

answer

Excess ATP and dATP imbalances nucleotide pool via feedback inhibition of ribonucleotide reductase. | Prevents DNA synthesis and thus decr lymphocyte count. One of the major causes of SCID. [ADA is #3 below]

question

SCID (sever combined immunodeficiency dz)

answer

SCID happens to kids (e.g., "bubble boy"). 1st dz to be Tx w/ experimental human gene therapy. One of the major causes of SCID: ADA deficiency [defect in purine salvage -- #3, below]

question

Purine salvage deficiencies: Lesch-Nyhan syndrome

answer

Defective purine salvage owing to absence of HGPRT [#1, below], which converts hypoxanthine to IMP and guanine to GMP. Results in excess uric acid production.

question

Lesch-Nyhan syndrome: findings?

answer

Retardation, self-mutilation, aggression, hyperuricemia, gout, choreoathetosis.

question

Lesch-Nyhan syndrome: genetics?

answer

X-linked recessive. HGPRT gene: "H e's G ot P urine R ecovery T rouble"

question

Orotic aciduria: etiology? genetics?

answer

Inability to convert orotic acid UMP (de novo pyrimidine synthesis pathway) due to defect in either orotic acid phosphoribosyltransferase or orotidine 5'-phosphate decarboxylase. Autosomal recessive.

question

Orotic aciduria: findings?

answer

Incr orotic acid in urine, megaloblastic anemia (does not improve w/ administration of vitamin B12 or folic acid), failure to thrive. No hyperammonemia (vs. OTC deficiency -- incr orotic acid w/ hyperammonemia).

question

Orotic aciduria: Tx?

answer

Oral uridine administration.

question

Insulin: when/where is it made? What are its basic effects?

answer

Made in Beta-cells of panccreas in response to ATP from glucose metabolism acting on K+ channels and depolarizing cells. Required for adipose and skeletal muscle uptake of glucose. Inhibits glucagon release by alpha-cells of pancreas.

question

C-peptide

answer

Serum C-peptide is not present w/ exogenous insulin intake (proinsulin --< insulin + C-peptide)

question

Anabolic effects of inuslin (list of 6)

answer

1.) Incr glucose transport ("In sulin moves glucose In to cells." 2.) Incr glycogen synthesis and storage 3.) Incr TG synthesis and storage 4.) Incr Na+ retention (kidneys) 5.) Incr protein synthesis (muscles) 6.) Incr cellular uptake of K+

question

Tissues that don't need insulin for glucose uptake

answer

"BRICK L " B rain R BCs I ntestine C ornea K idney L iver

question

GLUT1 transporter

answer

RBCs, brain

question

GLUT2 transporter

answer

(bidirectional) Beta-islet cells, liver, kidney

question

GLUT4 transporter

answer

(insulin responsive) Adipose tissue, skeletal muscle

question

Glycogen synthase: metabolism and activity?

answer

Fed state: *GS* (active) vs. Fasting state: GS-P (phosphorylated, inactive)

question

Glycogen synthase: regulation in liver and muscle?

answer

Regulation in liver: (+): Insulin, Glucose (-): Glucagon, epinephrine Regulation in muscle: (+): Insulin (-): Epinephrine

question

Glycogen phosphorylase (in muscle, V): metabolism and activity?

answer

Is phosphorylated/dephosphorylated similarly to glycogen synthase, with the opposite resulting activity: GP (inactive) in fed state vs. *GP-P* (active, phosphorylated) in fasting state

question

Glycogen phosphorylase (in muscle, V): regulation in liver and muscle?

answer

Regulation in liver: (+): Epinephrine, Glucagon (-): Insulin Regulation in muscle: (+): AMP, Epinephrine (-): ATP, Insulin

question

Phosphorylation and Insulin vs. Glucagon

answer

Insulin de phosphorylates (decr cAMP --< decr PKA) Glucagon phosphorylates (incr cAMP --< incr PKA)

question

Glycogen structure

answer

Branches have alpha(1,6) bonds; Linkages have alpha(1,4) bonds.

question

Glycogen in skeletal muscle

answer

Glycogen undergoes glycogenolysis to form glucose, which is rapidly metabolized during exercise.

question

Glycogen in hepatocytes

answer

Glycogen is stored and undergoes glycogenolysis to maintain blood sugar at appropriate levels.

question

Glycogen synthesis

answer

question

Glycogenolysis/glycogen synthesis cycle

answer

question

Glycogen synthesis dz's: generallly How many types? Molec path? List?

answer

12 types, all resulting in abnormal glycogen metabolism and an accumulation of glycogen w/in cells. V ery P oor C arbohydrate M etabolism: V on Gierke's dz (type 1) P ompe's dz (type 2) C ori's dz (type 3) M cArdle's dz (type 5)

question

Glycogen storage dz's: Von Gierke's dz (type I) Findings? Deficient enzyme? Comments?

answer

Findings: severe fasting hypoglycemia, (++) glycogen in liver, incr blood lactate, hepatomegaly. Deficient enzyme: Glucose-6-phosphatase [see below]

question

Glycogen storage dz's: Pompe's dz (type II) Findings? Deficient enzyme? Comments?

answer

Findings: cardiomegaly and systemic findings leading to early death. Deficient enzyme: Lysosomal alpha-1,4 glucosidase (acid maltase) [see below] "P ompe's trashes the P ump (heart, liver, and muscle)."

question

Glycogen storage dz's: Cori's dz (type III) Findings? Deficient enzyme? Comments?

answer

Findings: milder form of type I w/ normal blood lactate levels. Deficient enzyme: Debranching enzyme (alpha-1,6-glucosidase) [see below] Gluconeogenesis is intact.

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Glycogen storage dz's: McArdle's dz (type V) Findings? Deficient enzyme? Comments?

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Findings: incr glycogen in muscle, but cannot break it down, leading to painful muscle cramps, myoglobinuria w/ strenuous exercise. Deficient enzyme: Skeletal muscle glycogen phosphorylase. [see below] M cArdle's = M uscle

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Lysosomal storage dz's (generally)

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Each is caused by a deficiency in one of the many lysosomal enzymes. Results in an accumulation of abnormal metabolic products. Include sphingolipidoses and mucopolysaccharidoses.

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Lysosomal storage dz's, sphingolipidoses: Fabry's dz Findings? Deficient Enzyme? Accumulated substrate? Inheritance?

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Findings: peripheral neuropathy of hands/feet, angiokeratomas, CV/renal dz. Def. enzyme: alpha-galactosidease A Accum substrate: Ceramide trihexose Inheritance: XR

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What sphingolipidosis (lysosomal storage dz) does this describe? [don't look at the picture if you want to guess] Findings: peripheral neuropathy of hands/feet, angiokeratomas, CV/renal dz. Def. enzyme: alpha-galactosidease A Accum substrate: Ceramide trihexose Inheritance: XR

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Fabry's dz

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Lysosomal storage dz's, sphingolipidoses: Gaucher's dz (most common) Findings? Deficient Enzyme? Accumulated substrate? Inheritance?

answer

Findings: hepatosplenomegaly, aseptic necrosis of femur, bone crises, Gaucher's cells (macrophages that look like crumpled tissue paper) Def enzyme: Beta-glucocerebrosidase Accum substrate: glucocerebroside Inheritance: AR

question

What sphingolipidosis (lysosomal storage dz) does this describe? [don't look at the picture if you want to guess] Findings: hepatosplenomegaly, aseptic necrosis of femur, bone crises, Gaucher's cells (macrophages that look like crumpled tissue paper) Def enzyme: Beta-glucocerebrosidase Accum substrate: glucocerebroside Inheritance: AR

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Gaucher's dz (most common)

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Lysosomal storage dz's, sphingolipidoses: Niemann-Pick dz Findings? Deficient Enzyme? Accumulated substrate? Inheritance?

answer

Findings: progressive neurodegeneration, hepatosplenomegaly, cherry-red spot on macula, lysosomes w/ onion skin. Def. enzyme: sphingomyelinase Accum substrate: sphingomyelin Inheritance: AR

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What sphingolipidosis (lysosomal storage dz) does this describe? [don't look at the picture if you want to guess] Findings: progressive neurodegeneration, hepatosplenomegaly, cherry-red spot on macula, lysosomes w/ onion skin. Def. enzyme: sphingomyelinase Accum substrate: sphingomyelin Inheritance: AR

answer

Niemann-Pick dz

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Lysosomal storage dz's, sphingolipidoses: Tay-Sachs dz Findings? Deficient Enzyme? Accumulated substrate? Inheritance?

answer

Findings: progressive neurodegeneration, developmental delay, optic atrophy, globoid cells. Def. enzyme: hexosaminidase A Accum substrate: GM2 ganglioside. Inheritance: AR

question

What sphingolipidosis (lysosomal storage dz) does this describe? [don't look at the picture if you want to guess] Findings: progressive neurodegeneration, developmental delay, optic atrophy, globoid cells. Def. enzyme: hexosaminidase A Accum substrate: GM2 ganglioside. Inheritance: AR

answer

Tay-Sachs dz

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Lysosomal storage dz's, sphingolipidoses: Krabbe's dz Findings? Deficient Enzyme? Accumulated substrate? Inheritance?

answer

Findings: Peripheral neuropathy, developmental delay, optic atrophy, globoid cells Def. enzyme: Galactocerebrosidase Accum substrate: Galactocerebroside Inheritance: AR

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What sphingolipidosis (lysosomal storage dz) does this describe? [don't look at the picture if you want to guess] Findings: Peripheral neuropathy, developmental delay, optic atrophy, globoid cells Def. enzyme: Galactocerebrosidase Accum substrate: Galactocerebroside Inheritance: AR

answer

Krabbe's dz

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Lysosomal storage dz's, sphingolipidoses: Metachromatic leukodystrophy Findings? Deficient Enzyme? Accumulated substrate? Inheritance?

answer

Findings: central and peripheral demyelination w/ ataxia, dementia. Def. enzyme: Arylsulfatase A Accum substrate: Cerebroside sulfate Inheritance: AR

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What sphingolipidosis (lysosomal storage dz) does this describe? [don't look at the picture if you want to guess] Findings: central and peripheral demyelination w/ ataxia, dementia. Def. enzyme: Arylsulfatase A Accum substrate: Cerebroside sulfate Inheritance: AR

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Metachromatic leukodystrophy

question

Lysosomal storage dz's, mucopolysaccharidoses: Hurler's syndrome Findings? Deficient Enzyme? Accumulated substrate? Inheritance?

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Findings: developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly. Def. enzyme: alpha-L-iduronidase Accum substrate: Heparan sulfate, dermatan sulfate Inheritance: AR

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What mucopolysaccharidosis (lysosomal storage dz) does this describe? [don't look at the picture if you want to guess] Findings: developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly. Def. enzyme: alpha-L-iduronidase Accum substrate: Heparan sulfate, dermatan sulfate Inheritance: AR

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Hurler's syndrome

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Lysosomal storage dz's, mucopolysaccharidoses: Hunter's syndrome Findings? Deficient Enzyme? Accumulated substrate? Inheritance?

answer

Findings: Mild Hurler's + aggressive behavior, no corneal clouding. Def. enzyme: Iduronate sulfatase Accum substrate: Heparan sulfate, dermatan sulfate Inheritance: XR

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What mucopolysaccharidosis (lysosomal storage dz) does this describe? [don't look at the picture if you want to guess] Findings: Mild Hurler's + aggressive behavior, no corneal clouding. Def. enzyme: Iduronate sulfatase Accum substrate: Heparan sulfate, dermatan sulfate Inheritance: XR

answer

Hunter's syndrome

question

Mnemonic for Niemann-Pick dz?

answer

No man picks (Niemann-Pick ) his nose with his sphinger (sphingo myelinase).

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Mnemonic for Tay-Sachs?

answer

Tay-SaX lacks heX osaminidase

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Mnemonic for Hunter's syndrome?

answer

Hunters see cclearly (no corneal clouding) and aim for the X (X -linked recessive).

question

Lysosomal storage dz's: population at risk?

answer

Incr incidence of Tay-Sachs, Niemann-Pick, and some forms of Gaucher's dz in Ashkenazi Jews.

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Fatty acid metabolism: synthesis

answer

"SY trate = SY nthesis"

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Fatty acid metabolism: degradation

answer

"CAR nitine = CAR nage of FA's"

question

Carnitine deficiency

answer

Inability to utilize LCFAs and toxic accumulation

question

Acyl-CoA dehydrogenase deficiency

answer

Incr dicarboxylic acids, decr glucose and ketones

question

Where does FA degradation take place?

answer

Occurs where its products will be consumed: in the mitochondrion.

question

Ketone bodies: in liver?

answer

In the liver, FAs and AAs are metabolized to acetoacetate and Beta-hydroxybutyrate (to be used in muscle and brain)

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Ketone bodies: in prolonged starvation or diabetic ketoacidosis? ... in alcoholism? Why are these two cases related?

answer

In prolonged starvation or diabetic ketoacidosis, oxaloacetate is depleted for gluconeogenesis. In alcoholism, excess NADH shunts oxaloacetate to malate. Both processes stall the TCA cycle, which shunts glucose and FFA twd the production of ketone bodies.

question

Ketone bodies: made from...? How are they metabolized in brain? How are they excreted?

answer

Made from HMG-CoA. Metabolized in brain to 2 molecules of acetyl-CoA. Excreted in urine.

question

Ketone bodies: findings w/ elevated levels?

answer

Breath smells like acetone (fruity odor). Urine test for ketones does not detect beta-hydroxybutyrate (favored by high redox state).

question

Metabolic fuel use: 1g protein = ? 1g fat = ?

answer

1g protein = 4 kcal 1g fat = 9 kcal

question

Metabolic fuel use: in exercise (generally)

answer

As distances increase, ATP is obtained from additional sources.

question

Metabolic fuel use: in exercise -- 100-meter sprint (seconds)

answer

Stored ATP, creatine phosphate, anaerobic glycolysis

question

Metabolic fuel use: in exercise -- 1000-meter run (minutes)

answer

Stored ATP, creatine phosphate, anaerobic glycolysis (>--- as used in sprint) + Oxidative phosphorylation

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Metabolic fuel use: in exercise -- marathon (hours)

answer

Glycogen and FFA oxidation; glucose conserved for final sprinting.

question

Metabolic fuel use: Fasting and starvation (generally)

answer

Priorities are to supply sufficient glucose to brain and RBCs and to preserve protein.

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Metabolic fuel use: fasting and starvation -- days 1-3

answer

Blood glucose is maintained by: 1.) Hepatic glycogenolysis and glucose release 2.) Adipose release of FFA 3.) Muscle and liver shifting fuel use from glucose to FFA 4.) Hepatic gluconeogenesis from peripheral tissue lactate and alanine, and from adipose tissue glycerol and propionyl-CoA from odd-chain FFA metabolism (the only TG components that can contribute to gluconeogenesis)

question

Metabolic fuel use: fasting and starvation -- after day 3

answer

Muscle protein loss is maintained by hepatic formation of ketone bodies, supplying the brain and heart.

question

Metabolic fuel use: fasting and starvation -- after several weeks

answer

Ketone bodies become main source of energy for brain, so less muscle protein is degraded than during days 1-3. Survival time is determined by amount of fat stores. After this is depleted, vital protein degradation accelerates, leading to organ failure and death.

question

Cholesterol synthesis

answer

Rate-limiting step is catalyzed by HMG-CoA reductase* , which converts HMG-CoA --< mevalonate. 2/3 of plasma XOL is esterified by lecithin-cholesterol acyltransferase (LCAT). *Statins (e.g., lovastatin) inhibit HMG-CoA reductase

question

Essential fatty acids

answer

Linoleic and linolenic acids. Arichidonic acid, if linoleic acid is absent. Eicosanoids are dependent on essential FA's.

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Lipid transport overall flow-chart/schematic

answer

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Lipid transport enzymes: Pancreatic lipase

answer

Degradation of dietary TG in small intestine [not labeled in image below]

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Lipid transport enzymes: Lipoprotein lipase (LPL)

answer

Degradation of TG circulating in chylomicrons and VLDLs [active at several points in the schematic below]

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Lipid transport enzymes: Hepatic TG lipase (HL)

answer

Degradation of TG remaining in IDL [labeled at two points in the schematic below]

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Lipid transport enzymes: Hormone-sensitive lipase

answer

Degradation of TG stored in adipocytes [not labeled in schematic below]

question

Lipid transport enzymes: Lecithin-cholesterol acyltransferase (LCAT)

answer

Catalyzes esterification of XOL

question

Lipid transport enzymes: Cholesterol ester transfer protein (CETP)

answer

Mediates transfer of XOL-esters to other lipoprotein particles.

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Major apolipoproteins: A-I

answer

A -I A ctivates LCAT

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Major apolipoproteins: B-100

answer

B -100 B inds to LDL recceptor, mediates VLDL secretion.

question

Major apolipoproteins: C-II

answer

C -II is a C ofactor for lipoprotein lipase.

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Major apolipoproteins: B-48

answer

Mediates chylomicron secretion.

question

Major apolipoproteins: E

answer

E mediates E xtra (remnant) uptake

question

Lipoprotein fxns (generally)

answer

Lipoproteins are composed of varying proportions of XOL, TGs, and phospholipids. LDL and HDL carry most XOL.

question

Mnemonic for LDL vs. HDL

answer

LDL transports XOL from liver to tissues: "L DL is L ousy" HDL transports XOL from periphery to liver: "H DL is H ealthy"

question

Type of lipoprotein: Chylomicron Function and route? Apolipoproteins?

answer

Deligers dietary TGs to peripheral tissue. Delivers XOL to liver in the form of chylomicron remnants, which are mostly depleted of their triaclyglycerols. Secreted by intestinal epithelial cells. Apolipoproteins: B-48, A-IV, C-II, and E

question

Type of lipoprotein: VLDL Function and route? Apolipoproteins?

answer

Delivers hepatic TGs to peripheral tissue. Secreted by liver. Apo's: B-100, C-II, and E

question

Type of lipoprotein: LDL Function and route? Apolipoproteins?

answer

Delivers hepatic XOL to peripheral tissues. Formed by lipoprotein lipase modification of VLDL in the peripheral tissue. Taken up by target cells via receptor-mediated endocytosis. Apo's: B-100

question

Type of lipoprotein: HDL Function and route? Apolipoproteins?

answer

Mediates reverse XOL transport from periphery to liver. Acts as a repository for apoC and apoE (which are needed for chylomicron and VLDL metabolism). Secreted from both liver and intestine.

question

Familial dyslipidemia: Type I - hyperchylomicronemia What's increased? Elevated blood levels of...? Pathophys?

answer

Increased: chylomicrons Elevated blood levels: TG, XOL Pathophys: lipoprotein lipase deficiency or altered apoplipoprotein C-II

question

Increased: chylomicrons Elevated blood levels: TG, XOL Pathophys: lipoprotein lipase deficiency or altered apoplipoprotein C-II What familial dyslipidemia does this describe?

answer

Type I - hyperchylomicronemia

question

Familial dyslipidemia: Type IIa - familial hypercholesterolemia What's increased? Elevated blood levels of...? Pathophys?

answer

Increased: LDL Elevated blood levels: XOL Pathophys: Autosomal dominant; absent or decr LDL receptors.

question

Increased: LDL Elevated blood levels: XOL Pathophys: Autosomal dominant; absent or decr LDL receptors. What familial dyslipidemia does this describe?

answer

Type IIa - familial hypercholesterolemia

question

Familial dyslipidemia: Type IV - hypertriglyceridemia What's increased? Elevated blood levels of...? Pathophys?

answer

Increased: VLDL Elevated blood levels: TG Pathophys: hepatic overproduction of VLDL

question

Increased: VLDL Elevated blood levels: TG Pathophys: hepatic overproduction of VLDL What familial dyslipidemia does this describe?

answer

Type IV - hypertriglyceridemia

question

Abetalipoproteinemia: what is it? Genetics? Sx? Findings?

answer

Hereditary inability to synthesize lipoproteins due to deficiencies in apoB-100 and apoB-48. Autosomal recessive. Sx appear in the first few months of life. Findings: failure to thrive, steatorrhea, acanthocytosis, ataxia, night blindness.

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