question

Purines

answer

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

question

Pyrimidines

answer

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

question

Functional groups of the nucleosides

answer

Guanine has a ketone. Thymine has a methyl. Deamination of cytosine makes uracil.

question

AA's necessary for purine synthesis

answer

G lycine A spartate G lutamine

question

Nucleoside

answer

Base + ribose

question

Nucleotide

answer

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

question

Deoxyribonucleotide synthesis

answer

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

question

Hydroxyurea

answer

Inhibits ribonucleotide reductase.

question

6-mercaptopurine (6-MP)

answer

Blocks de novo purine synthesis. from PRPP to IMP

question

5-Fluorouracil (5-FU)

answer

Inhibits thymidilate synthase

question

Methotrexate

answer

Inhibits dihydrofolate reductase

question

Trimethoprim

answer

Inhibits bacterial dihydrofolate reductase (decr dTMP)

question

Pyrimethamine

answer

Inhibits DHFR

question

HGPRT

answer

guanine ? GMP hypoxanthine ? IMP deficiency = Lesch-Nyhan Syndrome

question

APRT

answer

adenine ? AMP

question

Adenosine Deaminase

answer

adenosine ? inosine

question

Adenosine Deaminase Deficiency

answer

?ATP and dATP inhibit ribonucleotide reductase ? prevents DNA synthesis ? ? lymphocyte count a major cause of AR SCID

question

Lesch-Nyhan Syndrome

answer

absent HGPRT ? defective purine salvage excess uric acid production, ? de novo purine synthesis MR, self-mutilation, aggression, hyperuricemia, gout, dystonia tx: allopurinol, febuxostat (2nd line) H: hyperuricemia G: gout P: pissed off R: retardation dysTonia

question

Transition vs. transversion

answer

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")

question

Genetic code: unambiguous

answer

Each codon specifies only 1 AA.

question

Genetic code: degenerate/redundant

answer

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

question

Genetic code: Commaless, nonoverlapping

answer

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

question

Genetic code: universal

answer

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

question

Silent mutation

answer

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

question

Missense mutation

answer

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

question

Nonsense mutation

answer

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

question

Frame shift mutation

answer

Change resulting in misreading of all nucleotides downstream, usually resulting in a truncated, nonfunctional protein duchenne muscular dystrophy

question

Severity of damage in DNA mutations

answer

frameshift;Nonsense ; missense ;;silent

question

Eukaryotic vs. prokaryotic DNA replication.

answer

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.

question

Origin of replication

answer

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

question

Single-stranded binding protein

answer

Prevents strands from reannealing.

question

DNA topoisomerases

answer

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

question

Primase

answer

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

question

DNA polymerase III

answer

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.

question

DNA polymerase I

answer

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

question

Single strand nucleotide excision repair

answer

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

question

Xeroderma pigmentosum

answer

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

question

Single strand base excision repair

answer

Specific glycosylases recognize and remove damaged bases and creates AP site (apurinic/apyrimidinic) one or more nucleotides are removed by AP-endonuclease, which cleaves the 5' end. Lyase cleaves the 3' end DNA poly-Beta fill the gap and ligase seals

question

Single strand mismatch repair

answer

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

question

Double strand nonhomologous end joining

answer

Brings together 2 ends of DNA fragments. No requirement for homology. mutated in ataxia telangiectasia

question

What direction is DNA/RNA made?

answer

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.

question

3 Types of mRNA

answer

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

question

mRNA start codon

answer

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

question

mRNA stop codons

answer

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

question

Promoter

answer

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.

question

Enhancer

answer

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

question

Silencer

answer

Site where negative regulators (repressors) bind.

question

Eukaryotic RNA polymerases

answer

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 DNA at promoter site.

question

Prokaryotic RNA polymerase

answer

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

question

alpha-amantin

answer

Found in death cap mushrooms. Inhibits RNA pol II. severely hepatotoxic if ingested

question

RNA processing (in eukaryotes)

answer

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.

question

hnRNA vs. mRNA

answer

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

question

Polyadenylation signal

answer

AAUAAA

question

Poly-A polymerase does not require...

answer

a template.

question

pre-mRNA splicing (occurs in eukaryotes)

answer

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.

question

tRNA structure

answer

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. T-arm: thymine, pseudouridine, cytosine sequence for tRNA-ribo binding D-arm: dihydrouracil residue for tRNA recognition by the correct aminoacyl-tRNA synthetase acceptor stem: the 3' CCA is the AA aceptor site

question

Charging of tRNA

answer

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

question

tRNA wobble

answer

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).

question

Protein synthesis: initiation

answer

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)

question

Protein synthesis: step 1 in elongation

answer

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

question

Protein synthesis: step 2 in elongation

answer

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

question

Protein synthesis: step 3 in elongation

answer

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

question

Protein synthesis: termination

answer

stop codon recognized by release factor and completed polypeptide is released from the ribosome

question

Energy requirements of translation

answer

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

question

Posttranslational modifications: trimming

answer

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

question

Posttranslational modifications: covalent alterations

answer

Phosphorylation, glycosylation, and hydroxylation, methylation, acetylation, ubiquitination

question

CDKs

answer

Cyclin-dependent kinases; constitutive and inactive.

question

Cyclins

answer

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

question

Cyclin-CDK complexes

answer

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

question

Tumor suppressors (and the cell cycle)

answer

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

question

Permanent cells

answer

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

question

Stable (quiescent) cells

answer

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

question

Labile cells

answer

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

question

Rough Endoplasmic Reticulum (RER)

answer

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

question

Nissl bodies

answer

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

question

Free ribosomes

answer

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

question

2 important examples of cells rich in RER

answer

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

question

Smooth endoplasmic reticulum (SER)

answer

Site of steroid synthesis and detoxification of drugs and poisons.

question

2 important examples of cells rich in SER

answer

Liver hepatocytes Steroid hormone-producing cells of the adrenal cortex

question

Golgi apparatus: modifies N-oligosaccharides on ____?

answer

Asparagine.

question

Golgi apparatus: adds O-oligosaccharides on ____?

answer

Serine and threonine.

question

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

answer

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

question

Vesicular trafficking proteins: COPI

answer

Retrograde: Golgi --> ER

question

Vesicular trafficking proteins: COPII

answer

Anterograde: RER -->cis-Golgi

question

Vesicular trafficking proteins: Clathrin

answer

trans-Golgi --> lysosomes, plasma membrane --> endosomes (receptor-mediated endocytosis) LDL receptor activity

question

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

answer

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

question

signal recognition particle

answer

cytosolic ribonucleoprotein traffics proteins from ribosome to RER if defective or absent, proteins build up in cytosol

question

Microtubules

answer

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.

question

dynein v kinesin

answer

Dynein = retrograde to microtubule (+ -; -) Kinesin = anterograde to MT (- -; +)

question

Drugs that act on microtubules

answer

1.) Mebendazole/thiabendazole (antihelminthic) 2.) Griseofulvin (antifungal) 3.) Vincristine/vinblastine (anti-cancer) 4.) Paclitaxel (anti-breast cancer) 5.) Colchicine (anti-gout) "Microtubules Get Constructed Very Poorly"

question

Chédiak-Higashi syndrome

answer

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

question

Cilia structure

answer

9 + 2 arrangement of MT's.

question

Axonemal dynein

answer

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

question

Kartagener's syndrome

answer

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

question

Actin and myosin

answer

Microvilli, Muscle contraction, Cytokinesis, Adherens jxn actins long, structural polymers myosins dimeric, ATP driven motor that move on actin

question

Microtubules (what structures are they found in?)

answer

Cilia Flagella Mitotic spindle Neurons Centrioles axonal trafficking

question

Intermediate filaments

answer

Vimentin, Desmin, Cytokeratin, lamins, Glial fibrillary acid proteins (GFAP) Neurofilaments

question

Plasma membrane composition

answer

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

question

Vimentin stain

answer

Connective tissue intermediate filament

question

Desmin stain

answer

muscle intermediate filament

question

Cytokeratin stain

answer

epithelial cells intermediate filament

question

GFAP stain

answer

neuroglia intermediate filament

question

neurofilament stain

answer

neurons intermediate filament

question

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

answer

Molecular biology laboratory procedure 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.

question

Mnemonic for different blotting procedures

answer

"SN oW DR oP " Southern = DNA Northern = RNA Western = Protein

question

Southern blot

answer

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.

question

Northern blot

answer

Similar technique [to Southern], except that Northern blotting involves radioactive DNA probe binding to sample RNA . used for mRNA levels: gene expression

question

Western blot.

answer

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

question

Southwestern blot

answer

identifies DNA-binding proteins (ie TFs) uses labeled oligonucleotide probes

question

Microarrays

answer

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) and copy number variations (CNV) genotyping, clinical genetic tests, forensic, CA mutations, genetic linkage analysis

question

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

answer

A rapid immunologic technique used to test patients blood for direct or indirect evidence of an antigen: direct: test antibody to see if patient antigen present indirect: test antigen to see if pt antibody present ie: test for presence of pt anti-HIV Both the sensitivity and the specificity of a ELISA approach 100%, but both false (+) and false (-) occur.

question

Sodium pump

answer

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

question

Ouabain

answer

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

question

Cardiac glycosides (digoxin and digitoxin)

answer

Directly inhibit Na+/K+ ATPase, which leads to indirect inhibition of Na+/Ca2+ exchange. ? Ca2+ ? ? cardiac contractility.

question

Type I collagen Where is this type of collagen found?

answer

90% of total Bone, skin, tendon, dentin, fascia, cornea late wound repair Type I = bONE ? production in OI type 1

question

Type II collagen Where is this type of collagen found?

answer

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

question

Type III collagen Where is this type of collagen found?

answer

(Reticulin) Skin, blood vessels, uterus, fetal tissue, granulation tissue ? in uncommon vascular type of ehlers-danlos "ThreE D"

question

Type IV collagen Where is this type of collagen found?

answer

Basement membrane, basal lamina, lens Type IV = Under the floor defect in alport, AB in goodpastures

question

Collagen Synthesis process

answer

1. ? chains translated @ RER to preprocollagen (gly-X-Y, where X and Y are usually pro and lys) 2. specific pro and lys are hydroxylated @ RER (requires vit C, or scurvy if deficiency) 3. glycosylate hydroxylysine residues to form pro-?-chain @ RER, then procollagen triple ? helix forms with hydrogen and disulfide bonding (OI if problem forming triple helix) 4. procollagen exocytosed into extracellular space 5. peptide cleavage of terminal ends to form insoluble tropocollagen 6. many tropocollagens reinforced with covalent lys-hydroxylys cross-linkage to form fibrils (done with copper-containing lysyl oxidase--ehlers-danlos if xlink problem)

question

Ehlers-Danlos syndrome features

answer

Faulty collagen synthesis, causing: 1.) Hyperextensible skin 2.) Tendency to bleed (easy bruising) 3.) Hypermobile joints 6+ types, varying degrees of severity autosomal dominant or recessive may be associated with Joint dislocation, Berry aneurysms, Organ rupture, aortic aneurysm

question

Types of Ehlers-Danlos

answer

hypermobile joint type: most common classical type (joint and skin) mutation type 5 collagen vascular type (vasc and organ rupture) type 3 collagen

question

Osteogenesis imperfecta: most common form

answer

AD: ? production of otherwise normal type I collagen 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

question

Type II osteogenesis imperfecta

answer

Fatal in utero or neonatal period.

question

Menkes Disease

answer

connective tissue disease due to improper copper absorption and transport ?lysyl oxidase activity (the enzyme that x-links collagen) brittle "kinky" hair, growth retardation, hypotonia

question

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

answer

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.

question

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

answer

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

question

Elastin

answer

lungs, skin, large arteries, elastic ligaments, vocal cords, ligamenta flava Rich in proline and Glycine, nonhydroxylated forms Tropoelastin w/ fibrillin scaffolding. Broken down by elastase, which is normally inhibited by alpha1-antitrypsin. cross-linking takes place extracellulary and give elastin its elastic properties

question

Marfan's syndrome (cause)

answer

Caused by a defect in fibrillin, a glycoprotein that forms a sheath around elastin

question

Emphysema (one cause)

answer

Can be caused by alpha1-antitrypsin deficiency, resulting in excess elastase activity ? breaks down elastin

question

Fluoresence in situ Hybridization (FISH)

answer

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.

question

Sanger DNA sequencing

answer

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.

question

Cre-lox system in model systems

answer

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).

question

RNAi

answer

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.

question

Karyotyping

answer

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).

question

Genetic terms: Codominance

answer

both alleles in heterozygote contribute to phenotype blood groups alpha-1 antitrypsin def

question

Genetic terms: Variable expression

answer

phenotype varies among people with same genotype NF1 have varying disease severity

question

Genetic terms: Incomplete penetrance

answer

Not all individuals w/ a mutant genotype show the mutant phenotype. BRCA 1 do not always cause breast and ovarian CA

question

Genetic terms: Pleiotropy

answer

single gene ? multiple phenotypic effects. PKU ? light skin, MR, musty body odor

question

Genetic terms: Loss of heterozygosity

answer

If a patient inherits or develops a mutation in a tumor suppressor gene, the complementary allele must also be deleted/mutated before cancer develops. This is NOT true of oncogenes. RB requires 2 hits

question

Genetic terms: Dominant negative mutation

answer

Exerts a dominant effect . A heterozygote produces a nonfxnl altered protein that also prevents the normal gene product from functioning. TF mutation?nonfxn, but still bind preventing wild type binding

question

Genetic terms: Linkage disequilibrium

answer

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.

question

Genetic terms: Mosaicism

answer

Occurs when cells in the body have distinct genetic makeup (e.g., lyonization -- random X inactivation in females) mitotic error after fertilization somatic: propagates through multiple tissues and organs gonadal: mutation only in egg or sperm mcCune-albright: lethal if mutation is somatic, can survive if mosaic

question

Genetic terms: Locus heterogeneity

answer

Mutations at DIFFERENT loci can produce the SAME phenotype albinism

question

Allelic heterogeneity

answer

different MUTATIONS @ SAME loci can give same phenotype ?-thalassemia

question

Genetic terms: Heteroplasmy

answer

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

question

Genetic terms: Uniparental disomy

answer

Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent. heterodisomy (heterozygous) indicates meiosis 1 error isodisomy: meiosis 2 error or post zygotic chrom duplication of one pair, and loss of the other origninal pair euploid (correct # of chromosomes!) normal phenotype suspect if pt presents with AR disease and only 1 parent is carrier

question

Hardy-Weinberg equilibrium

answer

If a population is in H-W equilibrium and p and q are separate alleles, then: p² + 2pq + q? = 1 p + q = 1 prevalence of an X-linked recessive dz in males = q and in females = q² assumes: no mutation @locus natural selection NOT occurring completely random mating no net migration

question

Imprinting (def.)

answer

At a single locus, only 1 allele is active; the other is inactive (imprinted/inactivated by methylation). Deletion of the single active allele --> dz Most common example: Prader-Willi and Angelman's syndromes due to mutation/deletion @ chromosome 15 (can also result from uniparental disomy)

question

Prader-Willi Syndrome

answer

MATERNAL imprinting: mom's genes imprinted/silent + dad's deleted/mutated @ chromosome 15 Mental retardation, hyperphagia, obesity,, hypogonadism, hypotonia. 25% dute to maternal uniparental disomy

question

Angelman's syndrome

answer

PATERNAL imprinting: dad's genes imprinted/silent + mom's mutated/deleted @ chromosome 15 inappropriate laughter ("happy puppet") severe MR, seizures, ataxia 5% paternal uniparental disomy

question

Autosomal dominant

answer

structural gene defect often pleiotropic FHx crucial to dx

question

Autosomal recessive

answer

enzyme defect more severe than dominant may only be seen in 1 generation presents in childhood

question

X-linked dominant.

answer

females transmit to 50% of sons and daughters males transmit to all daughters but no sons Hypophosphatemic rickets

question

Hypophosphatemic rickets

answer

X-linked dominant dz Formerly known as vitamin D-resistant rickets ? phosphate wasting at proximal tubule rickets-like presentation

question

Mitochondrial inheritance.

answer

Transmitted only thru mother. All offspring of affected females may show signs of dz. Variable expression in population or family due to heteroplasmy. mitochondrial myopathies

question

Mitochondrial myopathies

answer

rare, present with myopathy, lactic acidosis, and CNS disease 2nd to failure of oxidative phos mm bx shows "ragged red fibers" mitochondrial inheritance

question

Achondroplasia

answer

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

question

ADPKD

answer

AD! Formerly known as adult polycystic kidney dz. bilateral, massive enlargement of kidneys due to multiple large cysts. 85% cases are due to a mutation in PKD1 @ chrom16 remainder due to PKD2 @ chrom4 Associated w/ polycystic liver dz, berry aneurysms, mitral valve prolapse

question

Familial adenomatous polyposis

answer

AD! Colon becomes covered w/ adenomatous polyps after puberty. Progresses to colon cancer unless resected. mutation @ APC gene on chrom 5 "5 letters in 'polyp' "

question

Familial hypercholesterolemia

answer

AD! Elevated LDL due to defective or absent LDL receptor. severe atherosclerotis early in life tendon xanthomas (classically in the Achilles tendon)

question

Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)

answer

AD! Inherited d/o of blood vessels. Findings: telangiectasia, recurrent epistaxis, skin discolorations, AVMs, GI bleeding, hematuria

question

Hereditary spherocytosis

answer

AD! spectrin or ankyrin defect hemolytic anemia, ? MCHC Splenectomy is curative.

question

Huntington's dz

answer

AD! depression, progressive dementia, choreiform mvmts, caudate atrophy, and ? GABA and ACh in the brain Chrom 4 ; trinucleotide repeat d/o: (CAG) "Hunting 4 food"

question

Marfan's syndrome

answer

AD! Fibrillin-1 gene mutation ? connective tissue d/o affecting skeleton, heart, and eyes. tall w/ long extremities, pectus excavatum, hyperextensive joints, arachnodactyly cystic medial necrosis of aorta ? aortic incompetence and dissecting aortic aneurysms, floppy mitral valve Subluxation of the lenses upward and temporally

question

Multiple endocrine neoplasias (MEN)

answer

AD! Several distinct syndromes (I, 2A, 2B) characterized by familial tumors of endocrine glands, including those of the pancreas, parathyroid, thyroid, and adrenal medula Men 2A and 2B associated w/ ret gene.

question

Neurofibromatosis type 1 (von Recklinghausen's dz)

answer

AD, 100% penetrance but variable expression café-au-lait spots, cutaneous neurofibromas NF 1 on chrom17 "17 letters in "von Recklinghausen" "

question

Neurofibromatosis type 2

answer

AD! Bilateral acoustic schwannomas, juvenile cataracts, meningiomas, ependymomas NF2 gene on chrom22 "type 2 = 22"

question

Tuberous sclerosis

answer

AD, Incomplete penetrance, variable presentation neurocutaneous + multi=organ involvement numerous benign hamartomas

question

von Hippel-Lindau dz

answer

AD! deleted VHL tumor suppressor @ chrom 3 numerous tumors, benign and malignant "Von Hippel-Lindau = 3 words for chromosome 3"

question

Autosomal recessive dz's (list)

answer

Albinism ARPKD Cystic fibrosis Glycogen storage dz's Hemochromatosis Mucopolysaccharidoses (except Hunter's), Sphingolipidoses (except Fabry's) Kartageners Phenylketonuria Sickle cell anemias Thalassemias Wilsons disease

question

Genetics of Cystic fibrosis

answer

Autosomal-recessive defect in CFTR gene on chromosome 7, commonly deletion of Phe 508. *Most common lethal genetic dz of Caucasians

question

CF genetics, pathophys

answer

AR defect @ CFTR gene on chrom7 (often Phe508 deletion) CFTR channel actively secretes Cl- into lungs and GI tract, and actively reabsorbs Cl- from sweat. misfolded protein ? retained in RER ? ? Cl (and H2O) secretion ? ? intracell Cl ? compensate ? Na reab via epi Na channels ? ? H20 reab ? abnrl thick mucus and negative transepi potential diff

question

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

answer

Recurrent pulmonary infxns (Pseudomonas), chronic bronchitis, bronchiectasis-;reticulonodular pattern on CXR pancreatic insufficiency (malabsorption and steatorrhea), meconium ileus in newborns, nasal polyps 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.

question

Dx of CF?

answer

Incr concentration of Cl- ions in sweat test (;60 meq/L) can present with contraction alkalosis and ?K (ECF like taking loop diuretic) bc ECF loss of H2O/Na and concomitant renal K/H wasting

question

Tx for CF?

answer

N-acetylcysteine to loosen mucous plugs (cleaves disulfide bonds w/in mucous glycoproteins). dornase alfa (DNAse) to clear PMN debris

question

X-linked recessive disease list

answer

"Be Wise, Fool's GOLD Heeds Silly HOpe" Bruton's agammaglobulinemia Wiskott-Aldrich syndrome Fabry disease G6PD deficiency Ocular albinism Lesch-Nyhan syndrome Duchenne's (and Becker's) muscular dystrophy Hemophilia A and B Hunter's syndrome Ornithine transcarbamylase deficiency

question

Duchenne's muscular dystrophy features

answer

X-linked recessive frame-shift mutation ? truncated dystrophin protein ? accelerated muscle breakdown. Weakness begins in pelvic girdle mm and progresses superiorly, Pseudohypertrophy of calf muscles due to fibrofatty replacement of muscle, gower maneuver dilated cardiomyopathy is common cause of death Onset before 5 yrs of age. ? CPK and aldolase western blot and muscle biopsy confirm

question

Becker's muscular dystrophy

answer

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

question

Dystrophin gene (DMD )

answer

(associated w/ Duchenne's and Becker's muscular dystrophies) The longest known human gene ? ? rate of spontaneous mutation. Dystrophin helps anchor muscle fibers, primarily in skeletal and cardiac muscle: connects intracellular cytoskeleton (actin) to transmembrane proteins alpha, beta dystroglycan (connected to ECM) loss causes myonecrosis

question

myotonic type 1 muscular dystrophy

answer

CTG repeat @ DMPK gene?abnrl expression of myotonin protein kinase myotonia, muscle wasting, frontal balding, cataracts, testicular atrophy, arrythmias

question

Fragile X syndrome

answer

X-linked defect affecting the methylation and expression @ FMR1 gene, CGG trinucleotide repeat Macro-orchidism post-puberty (enlarged testes), long face w/ a large jaw, large everted ears, autism, mitral valve prolapse "fragile X = Xtra large testes, ears, jaw"

question

Trinucleotide repeat expansion dz's

answer

HUNTing for MY FRIED eggs (X) huntingtons: CAG myotonic dystrophy: CTG friedreich ataxia: GAA fragile X: CGG

question

D own syndrome findings

answer

Mental retardation flat facies prominent epicanthal folds single palmar crease gap btw 1st 2 toes duodenal atresia hirschsprungs congenital heart (most commonly septum primum-type ASD) brushfield spots ? risk of ALL, AML, Alzheimer's dz (> 35 yrs of age)

question

Down syndrome genetic cause

answer

1:700 95% meiotic nondisjunction of homologous chromosomes 5% Robertsonian translocation 1% mosaicism (no maternal association, post fert mitotic error)

question

Down syndrome preg screen

answer

1st tri: US + labs nuchal translucency + hypoplastic nasal bone ? PAPP-A, ? free B-hCG 2nd tri: quad screen ? AFP, ? B-hCG, ? estriol, ? inhibin A

question

Edward's syndrome findings

answer

trisomy 18, 1:8000 Severe mental retardation Rocker-bottom feet micrognathia Low-set ears Clenched hands Prominent occiput Congenital heart dz Death usually occurs w/in 1 yr of birth. "Edwards, Ears, Election (18)"

question

Edwards Syndrome: Labs

answer

first tri: ?PAPP-A, ?free B-hCG quad: ? all AFP, B-hCG, estriol, ?/nrl inhibin A

question

P atau's syndrome Findings?

answer

trisomy 13, 1:15000 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. "P: Patau, liP/Palate, holoProsencephaly, Polydactlyly, Puberty (13)"

question

Patau Syndrome labs

answer

first tri screen: ?free B-hCG, PAPP-A +nucal translucency

question

Robertsonian translocation

answer

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.

question

Robertsonian translocation: balanced vs. unbalanced translocations?

answer

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).

question

Cri-du-chat syndrome

answer

Congenital microdeletion of short arm of Chr 5 (46,XX or XY,5p-) Microcephaly Moderate to severe mental retardation, High-pitched crying/mewing Epicanthal folds Cardiac abnormalities (VSD)

question

Williams syndrome

answer

Congenital microdeletion of long arm of Chr 7 (deleted region includes elastin gene) Distinctive "elfin" facies Mental retardation hypercalcemia, ? sensitivity to vitD Well-developed verbal skills Cheerful disposition Extreme friendliness w/ strangers Cardiovascular problems "williams founded in 1793"

question

22q11 deletion syndromes

answer

"CATCH-22" : aberrant development of 3rd and 4th branchial pouches Variable presentation, including: Cleft palate Abnormal facies Thymic aplasia ? T-cell deficiency Cardiac defects Hypocalcemia secondary to parathyroid aplasia 22q11 microdeletion ie DiGeorge, Velocardiofacial syndromes

question

DiGeorge syndrome

answer

thymic, parathyroid, and cardiac defects. 22q11 deletion syndrome

question

Velocardiofacial syndrome

answer

palate, facial, and cardiac defects. 22q11 deletion syndrome

question

Water soluble vitamin deficiencies

answer

water-soluble vitamins: all vitBs + vitC All wash out easily from body except B12 and folate/B9 (stored in liver). B-complex deficiencies often result in dermatitis, glossitis, and diarrhea.

question

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

answer

liver and leafy vegetables Antioxidant; constituent of visual pigments (retinal). essential for diff of epi cells to special tissue (panc, mucus-secreting cells) prevents squamous metaplasia. used to tx measles, AML M3

question

Vitamin A (retinol) deficiency?

answer

Night blindness (nyctalopia), dry, scaly skin (xerosis cutis) alopecia corneal degen (keratomalacia) immune suppression

question

Vitamin A (retinol) excess?

answer

Arthralgias skin changes ( scaliness) alopecia cerebral edema pseduotumor cerebri osteoporosis hepatic abnrl Teratogenic (cleft palate, cardiac abnormalities).

question

Vitamin B1: fxn?

answer

=thiamine TPP: a cofactor for several dehydrogenase enzymes 1.) Pyruvate dehydrogenase (link glycolysis to TCA) 2.) alpha-ketoglutarate dehydrogenase (TCA cycle) 3.) Transketolase (HMP shunt) 4.) Branched-chain ketoacid dehydrogenase "ATP: ?-Ketoglutarate, Transketolase, Pyruvate dehydrogenase"

question

Vitamin B1 deficiency

answer

impaired glucose breakdown?atp depletion worsened by glucose infusion, high aerobic tissues (brain, heart) affected first Wernicke-Korsakoff syndrome and beriberi Seen in malnutrition as well as alcoholism (secondary to malnutrition and malabsorption). dx by ? RBC transketolase activity following B1 administration

question

Wernicke-Korsakoff syndrome

answer

Due to Vitamin B1 (thiamine) deficiency Triad: confusion, ophthalmoplegia, ataxia +confabulation, personality change, memory loss (permanant) damage to the medial dorsal nucleus of thalmus, mammilllary bodies

question

Beri-beri

answer

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

question

Vitamin B2: fxn?

answer

= riboflavin component of FAD, DMN cofactor in redox rxns eg: the succinate dehydrogenase rxn in TCA

question

Vitamin B2 deficiency?

answer

=riboflavin "the 2 Cs of vitB2" Cheilosis (inflammation of lips, scaling and fissures at corners of mouth), Corneal vascularization

question

Vitamin B3: fxn?

answer

=niacin Constituent of NAD+, NADP+ used in redox rxns Derived from tryptophan Synthesis requires vitaminB2 and B6. tx dyslipidemia, lower VLDL and raises HDL

question

Vitamin B3 deficiency?

answer

=niacin Glossitis Severe deficiency leads to pellagra Pellagra: dermatitis, dementia, diarrhea can be caused by Hartnup dz (? tryptophan absorption), malignant carcinoid syndrome (? tryptophan metabolism), and isoniazid (? vitamin B6)

question

Vitamin B3 excess?

answer

=niacin Facial flushing (due to pharmacologic doses for Tx of hyperlipidemia) from prostaglandin, not histamine hyperglycemia, hyperuricemia

question

Vitamin B5: fxn and deficiency?

answer

=pantothenate component of coenzyme A cofactor for acyl transfer and FA synthesis deficiency: Dermatitis enteritis alopecia adrenal insufficiency

question

Vitamin B6 fxn?

answer

=pyridoxine Converted to PLP, a cofactor used in: transamination rxns (e.g., ALT and AST) decarboxylation rxns glycogen phosphorylase syn of cystathionine, heme, niacin, histamine, NT (serotonin, epi, NE, dopa, GABA)

question

Vitamin B6 deficiency?

answer

=pyridoxine Convulsions hyperirritability peripheral neuropathy (deficiency inducible by INH and BCP) sideroblastic anemia bc impaired Hb syn and Fe excess

question

B12: fxn?

answer

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

question

B12 (cobalamin): Deficiency?

answer

=cobalamin Macrocytic, megaloblastic anemia hypersegmented PMNs + neurologic Sx due to abnormal myelin: (paresthesias, subacute combined degeneration of dorsal column, lateral corticospinal and spinocerebellar tracts) Prolonged deficiency leads to irreversible nervous system damage. ? homocysteine AND methylmalonic acid

question

B12: what rxns does it help to proceed?

answer

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

question

B12: etiology of deficiency?

answer

=cobalamin synthesized only by microorganisms, found in animal products Very large reserve pool (several yrs) stored primarily in liver. Deficiency is usually caused by malabsorption lack of intrinsic factor (pernicious anemia, gastric bypass surgery) absence of terminal ileum (Crohn's dz).

question

vit B9: fxn?

answer

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

question

vit B9: deficiency?

answer

= folic acid Macrocytic, megaloblastic anemia hyperseg PMN glossitis NO neurologic Sx (opposite of vitB12 deficiency). Most common vitamin deficiency in the USA Alcoholism and Pregnancy. ?homocysteine, NORMAL methylmalonic acid

question

vit B9: where is it found?

answer

= folic acid FOLate is from FOLiage (green leaves) absorbed in jejunum

question

Etiology of folic acid deficiency?

answer

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

question

S-adenosyl-methionine (SAM): formation?

answer

ATP + methionine --> SAM

question

S-adenosyl-methionine (SAM): fxn?

answer

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

question

vit B7: fxn?

answer

biotin Cofactor for carboxylation enzymes: 1.) Pyruvate carboxylase : Pyruvate 3C ? oxaloacetate 4C 2.) Acetyl-CoA carboxylase : Acetyl-CoA 2C ? malonyl-CoA 3C 3.) Propionyl-CoA carboxylase : Propionyl-CoA 3C ? methylmalonyl-CoA 4C

question

vit B7: deficiency?

answer

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

question

Vitamin C (ascorbic acid): fxn?

answer

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

question

Vitamin C (ascorbic acid): deficiency?

answer

Scurvy: swollen gums bruising anemia hemarthrosis poor wound healing perifollicular and subperiosteal hemorrhages corkscrew hair weak immune response

question

vit C excess

answer

NVD fatigue calcium oxalate nephrolithiasis ?Fe toxicity if transfusions, hemochromatosis

question

Vitamin D: forms?

answer

D2 = ergocalciferol: ingested from plants D3 = cholecalciferol: consumed in milk, formed in sun-exposed skin (basale) 25-OH D3 = storage form 1,25-(OH)2-D3 (calcitriol) = active form

question

Vitamin D: fxn?

answer

Incr intestinal absorption of calcium and phosphate, incr bone resorption

question

Vitamin D: deficiency?

answer

Rickets in children (bending bones, pain, deformity) osteomalacia in adults (soft bones, mm weakness), hypocalcemic tetany. breastfed infants should have oral Vit D ?risk if: low sun, pigmented skin, premie

question

Vitamin D: excess?

answer

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

question

Vitamin E: fxn?

answer

=tocopherol/tocotrienol Antioxidant (protects erythrocytes and membranes from free-radical damage). can enhance warfarin anticoagulant effects "E is for E rythrocytes"

question

Vitamin E: deficiency?

answer

Incr fragility of erythrocytes (hemolytic anemia) acanthocytosis muscle weakness posterior column and spinocerebellar tract demyelination neuro similar to B12, but no megaloblastic anemia, hyperseg PMN, or ? methylmalonic acid

question

Vitamin K: fxn?

answer

Catalyzes gamma-carboxylation of glutamic acid residues on various proteins concerned w/ blood clotting. activates II, VII, IX, X, protein C and S warfarin antagonizes vitK Synthesized by intestinal flora

question

Vitamin K: deficiency?

answer

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.

question

Zinc: fxn?

answer

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

question

Zinc: deficiency?

answer

Delayed wound healing hypogonadism ?adult hair (axillary, facial, pubic) dysgreusia, anosmia acrodermatitis enteropathica (oral/perianal dermatitis) May predispose to alcoholic cirrhosis.

question

Ethanol metabolism: kinetics/breakdown rxn

answer

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

question

Fomepizole

answer

Inhibits alcohol dehydrogenase antidote for methanol or ethylene glycol poisoning

question

Disulfiram (antabuse)

answer

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

question

Ethanol in liver

answer

? NADH/NAD+ ratio in liver, causing: pyruvate to lactate ? lactic acidosis oxaloacetate to malate ? inhibits gluconeogenesis ? fasting hypoglycemia glyceraldehyde-3P to glycerol-3P ? combines with FA to make TG ? fatty liver disfavors TCA prodxn of NADH ? ? utilize acetyl-CoA for ketogenisis and lipogenesis ? ketoacidosis, hepatosteatosis

question

Fomepizol v Disulfiram

answer

fomepizol: inhibits alcohol dehydrogenase antidote for methanol/ethylene glycol poisoning disulfiram: inhibits acetaldehyde dehydrogenase ?acetaldehyde ? ? hangover

question

Kwashiorkor

answer

Protein malnutrition ? skin lesions, edema, liver malfxn (fatty change bc ? apolipoprotein synthesis) Malnutrition Edema Anemia Liver (fatty)

question

Marasmus

answer

Total calorie malnutrition ? tissue and mm wasting, loss of subQ fat, and variable edema "Marasmus results in Muscle wasting"

question

Mitochondrial metabolic rxns

answer

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

question

cytoplasmic metabolic rxns

answer

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

question

Metabolism sites: both mitochondria and cytoplasm

answer

Heme synthesis Urea cycle Gluconeogenesis "HUGs take two "

question

Glycolysis What is the rate-limiting enzyme and reg

answer

Phosphofructokinase-1 (PFK-1) inc: AMP, fructose-2,6-bisphosphate dec: ATP, Citrate

question

Gluconeogenesis What is the rate-limiting enzyme and reg

answer

Fructose 1,6 bisphosphatase inc: ATP, acetyl-CoA dec: AMP, fructose-2,6-bisphosphate

question

TCA cycle What is the rate-limiting enzyme and reg

answer

Isocitrate dehydrogenase inc: ADP dec: ATP, NADH

question

Glycogen synthesis What is the rate-limiting enzyme and reg

answer

Glycogen synthase inc: G6P, insulin, cortisol dec: epi, glucagon

question

Glycogenolysis What is the rate-limiting enzyme and reg

answer

Glycogen phosphorylase inc: epi, glucagon, AMP dec: G6P, insulin, ATP

question

HMP shunt What is the rate-limiting enzyme and reg

answer

Glucose-6-phosphate dehydrogenase (G6PD) inc: NADP+ dec: NADPH

question

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

answer

carbamoyl phosphate synthase II

question

De novo purine synthesis What is the rate-limiting enzyme and reg

answer

Glutamine-PRPP amidotransferase dec: AMP, IMP, GMP

question

Urea cycle What is the rate-limiting enzyme and reg

answer

Carbamoyl phosphate synthetase 1 inc: n-acetylglutamate

question

Fatty acid synthesis What is the rate-limiting enzyme and reg

answer

Acetyl-CoA carboxylase (ACC) inc: insulin, citrate dec: glucagon, palmitoyl-CoA

question

Fatty acid oxidation What is the rate-limiting enzyme and reg

answer

Carnitine acyltransferase I dec: malonyl-CoA

question

Ketogenesis What is the rate-limiting enzyme?

answer

HMG-CoA synthase

question

Cholesterol synthesis What is the rate-limiting enzyme and reg

answer

HMG-CoA reductase inc: insulin, thyroxine dec: glucagon, cholesterol

question

Glycolysis/ATP production: quantitative

answer

Aerobic metabolism of glucose: 32 ATP via malate-aspartate shuttle (heart and liver) 30 ATP via glycerol-3-P shuttle (muscle) Anaerobic glycolysis produces only 2 net ATP per glucose molecule arsenic causes glycolysis to produce zero net ATP

question

Activated carriers: Coenzyme A, lipoamide carry?

answer

Acyl

question

Activated carriers: Tetrahydrofolate carries?

answer

1-carbon units

question

Activated carriers: SAM carries?

answer

CH3 groups

question

Activated carriers: TPP carries?

answer

Aldehydes

question

NAD+ vs. NADPH

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... (4 things)?

answer

Product of the HMP shunt. Used in: 1.) Anabolic processes 2.) Respiratory burst 3.) cytP450 4) glutathione reductase

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

Net glycolysis rxtn (cytoplasm)

answer

Glucose + 2 Pi + 2 ADP + 2 NAD+ ? 2 pyruvate + 2 ATP + 2 NADH + 2 H+ + 2H2O

question

Steps in glycolysis that require ATP: Regulation?

answer

glucose-> G6P (hex/glucokinase) G6P inhibit hexokinase, F6P inhibit glucokinase F6P -> F1,6BP (PFK1) -: ATP, citrate +: AMP, F26BP

question

Steps in glycolysis that produce ATP: Regulation?

answer

1,3BPG->3PG (phosphoglycerate kinase) phosphoenolpyruvate->pyruvate (pyruvate kinase) -: ATP, alanine +: F16BP

question

Regulation by fructose-2,6-bisphosphate fasting and fed

answer

fasting: ?glucagon ? ?cAMP ? ?PKA ? ?FBPase2/?PFK2 ? ?gluconeogenesis/?glycolysis fed: ?insulin ? ?cAMP ? ?PKA ? ?PFK2/?FBPase2 ? ?glycolysis/?gluconeogenesis

question

Pyruvate dehydrogenase: net rxn?

answer

Pyruvate + NAD+ + CoA ? acetyl-CoA + CO2 + NADH active in fed state connects glycolysis and TCA

question

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

answer

B1/2/3/5 lipoic acid arsenic inhibits lipoic acid ? vomiting, rice-water stools, garlic breath activated by exercise: ?NAD/NADH ratio, ?ADP, ?Ca similar to ?KG-dehydrogenase complex (same exact cofactors needed)

question

what inhibits PDH

answer

ATP NADH Acetyl-CoA

question

Pyruvate dehydrogenase deficiency: MoA, s/sx, tx

answer

buildup of pyruvate, shunted to lactate (LDH) and alanine (ALT) neuro defects, lactic acidosis, ? serum alanine starting in infancy tx: inc intake of ketogenic nutrients (high fat, inc lysine and leucine)

question

Pyruvate metabolism: Alanine?

answer

via Alanine aminotransferase + B6 carries amino groups to the liver from muscle

question

Pyruvate metabolism: oxaloacetate?

answer

via Pyruvate carboxylase, + biotin can replenish TCA cycle or be used in gluconeogenesis

question

Pyruvate metabolism: Lactate?

answer

via LDH + B3 End of anaerobic glycolysis major pathway in RBCs, leukocytes, kidney medulla, lens, testes, and cornea

question

Pyruvate metabolism: Acetyl-CoA

answer

via pyruvate dehydrogenase (B1,2,3,5,lipoic acid) transition from glycolysis to the TCA cycle

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 = 10 ATP/acetyl-CoA (2x everything per glucose).

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)

answer

Can I Keep Selling Sex For Money Officer? Citrate Isocitrate alpha-keto-glutarate succinyl CoA succinate fumarate malate oxaloacetate

question

Oxidative phosphorylation poisons: ETC inhibitors?

answer

Directly inhibit electron transport, causing a LOWER proton gradient and block of ATP synthesis: rotenone antimicin A CN CO

question

Oxidative phosphorylation poisons: ATPase inhibitors

answer

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

question

Oxidative phosphorylation proteins: uncoupling agents

answer

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

question

Gluconeogenesis: irreversible enzymes

answer

Pathway Produces Fresh Glucose Pyruvate carboxylase: mitochondria PEPCK: cytosol F-1.6-BP: cytosol G-6-Pase: ER

question

pyruvate carboxylase

answer

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

question

PEPCK

answer

gluconeogenesis In cytosol Oxaloacetate --> phosphoenolpyruvate Requires GTP.

question

F-1,6-BPase

answer

gluconeogenesis cytosol Fructose-1,6-BP --> F6P + citrate - F2,6BP

question

G6Pase

answer

gluconeogenesis In ER G6P --> glucose mm lacks this enzyme so can't 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 as succinyl-CoA, undergo gluconeogenesis, and serve as a glucose source. Even-chain FA's cannot produce new glucose, since they yield only acetyl-CoA equivalents.

question

HMP shunt (pentose phosphate pathway)

answer

Produces NADPH, which is req'd for FA and steroid biosynthesis and for glutathione reduction inside RBCs. also yields ribose for nucleotide synthesis and glycolytic intermediates 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): reactions

answer

oxidative irreversible, RLS

question

Respiratory burst (oxidative burst)

answer

1. NADPH oxidase: ? in CGD 2. superoxide dismutase 3. MPO (green heme-containing) 4. glutathione peroxidase (+selenium) 5. glutathione reductase (+selenium) 6. G6PD *if have CGD, catalase + organisms can ? H2O2 (s.aureus, aspergillus) **P.aeruginosa generates ROS to kill competing microbes

question

Lactoferrin

answer

protein in secretory fluids and PMNs that inhibits microbial growth via iron chelation

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). ifxn can also cause hemoysis (free rad via inflam rsp can diffuse into RBC and cause ox damage)

question

Glucose-6-phosphate dehydrogenase deficiency:

answer

X-linked recessive ?G6P dehydrogenase ? ?NADPH ??reduced glutathione ?detoxification of ROS and peroxide RBC: hemolytic anemia, heinz bodies, bite cells flares with ?oxidative injury: antimalarials fava beans sulfonamides anti-TB Rx infection/inflammation more prevalent among blacks Incr malarial resistance

question

Fructose intolerance

answer

AR deficiency in aldolase B Fructose-1-phosphate accumulates, causing a decr in available phosphate, which results in inhibition of glycogenolysis and gluconeogenesis. Hypoglycemia, jaundice, cirrhosis, vomiting. ? intake of both fructose and sucrose (glu + fruc)

question

Essential fructosuria:

answer

AR defect in fructokinase A benign, asymptomatic condition, since fructose doesn't enter cells. Fructose appears in blood and urine (benign)

question

galactosemia:

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). Failure to thrive, jaundice, hepatomegaly, infantile cataracts, mental retardation. exclude galactose and lactose (galactose + glucose) from diet.

question

Galactokinase deficiency:

answer

AR deficiency of galactokinase . Galactitol accumulates if galactose is present in diet. Relatively mild condition. Galactose appears in blood and urine, infantile cataracts. May initially present as failure to track objects or to develop a social smile.

question

Classic Galactosemia

answer

AR Uridyltransferase deficiency galactitol accumulates in body, lens of eye failure to thrive, jaundice, hepatomegaly, infantile cataracts, MR *e.coli sepsis in neonates!

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sorbitol

answer

alt method to trap glucose (via aldose reductase) some tissues then convert sorbitol to fructose by sorbitol dehydrogenase def (cataracts, retinopathy, perif neuropathy, seen with chronic hypergly in DM) lens, schwann cells, retina, and kidney only have aldose reductase

question

Lactase deficiency: lactose tolerance test findings

answer

stool dec pH, breath inc H content with lactose tol test biopsy nrl lactose ? glucose + galactose

question

Essential Glucogenic amino acids

answer

MetHisVal *his has no net charge @ body pH, but is basic

question

Essential AA's

answer

glucogenic: Met, His, Val ketogenic: Leu, Lys glu and keto: Phe, Trp, Thr, Ile

question

Acidic AA's

answer

Asp and Glu (negatively charged at body pH)

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Basic AA's

answer

Arg, Lys, and His. Arg is the most basic, His has no charge at body pH Arg and His required during periods of growth Arg and Lys are elevated in histones

question

urea cycle

answer

Ordinarily, Careless Crappers Are Also Frivolous About Urination Ornithine Carbamoyl Phosphate Citrulline Aspartate Arginosuccinate Fumarate Urea *N-acetylglutamate required cofactor for Carbamoyl Phosphate Synthetase I

question

What do the atoms of urea come from?

answer

NH3, CO2, aspartate

question

Hyperammonemia

answer

Results in exccess NH4+ ? depletes alpha-ketoglutarate, leading to inhibition of the TCA cycle. Ammonia intoxication : tremor, slurring speech, somnolence, vomiting, cerebral edema, blurring of vision. tx: limit protein. bonzoate or phenylbutryate (both bind AA and lead to excretion may dec levels. lactulose to acidify GI and trap NH4

question

Hyperammonemia: tx

answer

limit protein benzoate or phenylbutryate (both bind AA and lead to excretion may dec levels) lactulose to acidify GI and trap NH4

question

n-acetylglutamate deficiency

answer

cofactor for carbamoyl phosphate synthase 1 cause hyperammonemia same as carbamoyl phosphate synthase 1, but consider if: ? ornithine with nrl urea cylcle enzyme suggestive

question

ornithine transcarbamylase def

answer

most common urea cycle disorder X-R (others AR) first few days of life excess carbamoyl phosphate converted to orotic acid (pyrimidine synthesis pathway) ? orotic acid in blood and urine, ? BUN, sx hyperammonia no megaloblastic anemia (vs orotic aciduria)

question

Phenylalanine derivatives

answer

1.) Phenylalanine -->(BH4)Tyrosine --> Thyroxine or Dopa (BH4) Dopa --> Melanin + Dopamine (B6) Dopamine --> (vit C) NE -->(SAM) Epi

question

Tryptophan derivatives

answer

Tryptophan --(B6)> Niacin -> NAD/NADP typtophan->(BH4, B6)serotonin-> melatonin

question

Histadine derivatives

answer

Histadine --(B6)> Histamine

question

Glycine derivatives

answer

Glycine --(B6)> Porphyrin --> heme

question

Arginine derivatives

answer

Arginine --> Creatinine, urea, NO (BH4)

question

Glutamate derivatives

answer

Glutamate --(B6) GABA Glutamate --> Glutathione

question

catecholamine synthesis

answer

PKU: phenylalanine hydroxylase Alkaptonuria: homogentisate oxidase Albinism: tyrosinase

question

Phenylketonuria

answer

AR ? phenylalanine hydroxylase OR ? tetrahydrobiopterin cofactor (malig PKU) Mental retardation, growth retardation, seizures, fair skin, eczema, musty body odor screened 2-3 days after birth ? phenylalanine and ? 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

Alkaptonuria (ochronosis)

answer

AR, benign deficiency of homogentisic acid oxidase in the degradative pathway of tyrosine to fumarate. Dark connective tissue pigmented sclera urine turns black on standing. May have debilitating arthralgias. (homogentisic acid toxic to cartilage)

question

3 Forms of homocystinuria and their txs

answer

1.) Cystathionine synthase deficiency: ?Met and ? Cysteine and B12 and folate in diet 2.) ? affinity of cystathionine synthase for pyridoxal phosphate: ??? vitB6 and cysteine in diet 3.) Homocysteine methyltransferase deficiency: ? methionine in diet *all AR

question

Homocysteinuria: s/sx

answer

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

question

Cystinuria: Etiology

answer

AR defect of renal PCT/intestinal AA transporter for COLA: cysteine ornithine lysine arginine hexagonal cystine urine stones *(cysteine=cysteine S=S bond) common (1:7000)

question

Cystinuria: dx, tx

answer

dx: urinary cyanide-nitroprusside test Tx: ? stone solubility acetazolamide and K-citrate to alkalinize urine chelating agents good hydration

question

Maple syrup urine dz: etiology?

answer

Blocked degradation of branched amino acids due to AR ? ?-ketoglutarate dehydrogenase (B1) ? ? ?-ketoacids in blood, esp leucine. I Love Vermont Maple Syrup: Isoleucine, Leucine, Valine severe CNS defects, MR, and death tx: dietary ILV restriction, thiamine supplements

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

Glycogen regulation by insulin and glucagon/epi

answer

glucagon and epi (?adrenergic @ liver, mm): ?AC ? ?cAMP ? ?PKA ? phosphorylate/activate glycogen phosphorylase kinase ? glycogenolysis ? ? glucose (PKA also inhibits glycogen synthase) epi @ liver ?-adrenergic also activates glycogen phosphorylase kinase but via ?Ca insulin activates glycogen synthase AND protein phosphatase ? inactivates glycogen phosphorylase ? glycogenesis ? ? glycogen, ? glucose

question

Phosphorylation and Insulin vs. Glucagon

answer

Insulin dephosphorylates (? cAMP --> ? PKA) Glucagon phosphorylates (? cAMP --> ? PKA)

question

Glycogen structure

answer

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

question

Glycogen metabolism: mm vs liver

answer

mm: glycogen ? G1P ? G6P ? rapidly metabolized liver: glycogen stored ? glycogenolysis to maintain BGL during fast

question

Glycogen metabolism

answer

1. UDP-glucose pyrophosphorylase 2. glycogen synthase 3. branching enzyme 4. glycogen phosphorylase 5./6. debranching enzyme

question

Glycogen storage diseases

answer

Very Poor Carb Metabolism Von Gierke (type I) Pompe (type II) Cori (type III) McArdle (type IV) *all AR

question

Von Gierke's Disease (type I)

answer

? Glucose-6-phosphatase severe fasting hypoglycemia, ??? glycogen in liver, ? blood lactate, hepatomegaly tx: frequent oral glucose, avoid fructose and galactose

question

Pompe's dz (type II)

answer

? Lysosomal ?-1,4 glucosidase (acid maltase) cardiomegaly and systemic findings leading to early death "Pompe's trashes the Pump (heart, liver, and muscle)."

question

Cori's dz (type III)

answer

? Debranching enzyme (?-1,6-glucosidase) milder form of type I w/ normal blood lactate levels Gluconeogenesis is intact.

question

McArdle's dz (type V)

answer

? Skeletal muscle glycogen phosphorylase (myophosphorylase) ? glycogen in muscle but cannot break it down ? painful muscle cramps, myoglobinuria (red urine) w/ strenuous exercise, arrythmia from electrolyte abnormalities

question

Fabry Disease

answer

XR! lysosomal storage disease (sphingo) ? ?-galactosidase A ? ? Ceramide trihexoside peripheral neuropathy of hands/feet angiokeratomas CV/renal dz

question

Gaucher Disease

answer

AR lysosomal storage disease (sphingo) ??-glucocerebrosidase ? ?glucocerebroside hepatosplenomegaly pancytopenia aseptic necrosis of femur, bone crises Gaucher's cells (lipid laden macrophages that look like crumpled tissue paper) tx: recombinant glucocerebrosidase most common, Ashkenazi Jews

question

Niemann-Pick dz

answer

AR lysosomal storage disease (sphingo) ? sphingomyelinase ? ?sphingomyelin progressive neurodegeneration hepatosplenomegaly cherry-red spot on macula foam cells (lipid in macro) Ashkenazi Jews "No Man Picks his nose with his sphinger"

question

Tay-Sachs dz

answer

AR lysosomal storage disease (sphingo) ?hexosaminidase A ? ? GM2 ganglioside progressive neurodegeneration, developmental delay lysosome with onion skin cherry red spot on macula no hepatosplenomegaly. Ashkenazi Jews "Tay SaX"

question

Krabbe's dz F

answer

AR lysosomal storage disease (sphingo) ?Galactocerebrosidase ? ? Galactocerebroside, psychosine Peripheral neuropathy developmental delay optic atrophy globoid cells

question

Metachromatic leukodystrophy

answer

AR lysosomal storage disease (sphingo) ?Arylsulfatase A ? ?Cerebroside sulfate central and peripheral demyelination ataxia dementia

question

Hurler's syndrome

answer

AR lysosomal storage disease (muco) ?alpha-L-iduronidase ? ?Heparan sulfate, dermatan sulfate developmental delay gargoylism airway obstruction corneal clouding hepatosplenomegaly

question

Hunter's syndrome

answer

XR lysosomal storage disease: mucopolysaccaridoses ?Iduronate sulfatase ? ?Heparan sulfate, dermatan sulfate Mild Hurler's + aggressive behavior NO corneal clouding "Hunters see clearly and aggressively aim for the X"

question

Carnitine deficiency

answer

Inability to transport LCFAs into mitochondrial matrix ? toxic accumulation weakness hypotonia HYPOketotic hypoglycemia

question

Acyl-CoA dehydrogenase deficiency

answer

? Acetyl-CoA ? ?fasting glucose (Acetyl-CoA is a stimulating allosteric regulator of Pyruvate Carboxylase in gluconeogenesis) ?dicarboxylic acids ?glucose and ketones

question

Fatty acids: synthesis v degradation

answer

SYtrate SYnthesis CARnitine CARnage

question

Ketone bodies: in prolonged starvation or diabetic ketoacidosis? ... in alcoholism?

answer

In prolonged starvation or diabetic ketoacidosis, oxaloacetate is depleted for gluconeogenesis In alcoholism, excess NADH shunts oxaloacetate to malate Both processes cause ? acetyl-CoA ? ?TCA cycle ? shunts glucose and FFA to prodxn 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

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

answer

Blood glucose is maintained by: 1. Hepatic glycogenolysis 2. Adipose release of FFA 3. mm 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

1. ketone bodies from adipose stores 2. after ketone bodies depleted, vital proteins degraded ? organ failure, death *amt of excess stores determines survival time **RBCs lack mitochondria, cannot use ketones

question

Cholesterol synthesis

answer

HMG-CoA ? mevalonate. catalyzed by HMG-CoA reductase (RLS) *HMG-CoA reductase: insulin +, statins - 2/3 of plasma cholesterol is esterified by lecithin-cholesterol acyltransferase (LCAT).

question

Lipid transport enzymes: Pancreatic lipase

answer

Degradation of dietary TG in small intestine

question

Lipid transport enzymes: Lipoprotein lipase (LPL)

answer

@ vasc endothelial surface: degrades TG circulating in chylomicrons and VLDLs

question

Lipid transport enzymes: Hepatic TG lipase (HL)

answer

Degradation of TG remaining in IDL

question

Lipid transport enzymes: Lecithin-cholesterol acyltransferase (LCAT)

answer

Catalyzes esterification of cholesterol

question

Lipid transport enzymes: Cholesterol ester transfer protein (CETP)

answer

Mediates transfer of chol-esters from HDL to other lipoprotein particles (VLDL, IDL, LDL)

question

Major apolipoproteins: E

answer

E mediates Extra (remnant) uptake chylo, chylo rem, VLDL, IDL, HDL *NOT on LDL

question

Major apolipoproteins: A-I

answer

A-I Activates LCAT (esterification) chylomicron, HDL "beginning and end, from A to Z"

question

Major apolipoproteins: C-II

answer

C-II is a Cofactor for LPL chylomicron, VLDL, HDL

question

Major apolipoproteins: B-48

answer

Mediates chylomicron secretion chylomicron, chylomicron remnant

question

Major apolipoproteins: B-100

answer

B -100 B inds to LDL receptor VLDL, IDL, LDL

question

Lipoprotein composition

answer

varying proportions of cholesterol, TGs, and phospholipids LDL and HDL carry most cholesterol

question

Chylomicron fxn

answer

secreted by intestinal epithelial cells dietary TGs to peripheral tissue cholesterol to liver as chylo remnant after most TGs depleted @ periphery

question

Chylomicron apolipoprotein content

answer

E A1 CII B48

question

VLDL fxn

answer

secreted by liver ? hepatic TGs to peripheral tissue

question

VLDL apolipoprotein content

answer

E CII B100

question

IDL fxn

answer

formed by VLDL degradation delivers TGs and cholesterol to liver

question

IDL apolipoprotein content

answer

E B100

question

LDL fxn

answer

Formed by HL modification of IDL @ periphery Delivers hepatic cholesterol to peripheral tissues Taken up by target cells via receptor-mediated endocytosis

question

LDL apolipoprotein content

answer

only B100!

question

HDL fxn

answer

secreted from liver and intestine EtOH ? synthesis Mediates reverse cholesterol transport from periphery to liver Acts as a repository for apoC and apoE (needed for chylomicron and VLDL metabolism).

question

HDL apolipoprotein content

answer

ApoE ApoA1 ApoCII

question

familial dyslipidemias: Type I - hyperchylomicronemia

answer

AR (the other two are AD!) ? chylomicrons, TG, chol LPL deficiency or altered ApoCII pancreatitis, hepatosplenomegaly, eruptive/pruritic xanthomas *NO ? risk atherosclerosis!

question

familial dyslipidemias: Type IIa - familial hypercholesterolemia

answer

AD ? LDL, Chol absent/? LDL receptors heterozygous (1:500, chol 300) homozygous (rare, chol 700+) ? atherosclerosis ? may have MI before 20 tendon xanthomas corneal arcus

question

familial dyslipidemias: Type IV - hypertriglyceridemia

answer

AD ? VLDL, TG hepatic overproduction of VLDL pancreatitis

question

Abetalipoproteinemia

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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