question

Chromatin structure

answer

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.

question

Heterochromatin

answer

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

question

Euchromatin

answer

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

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

question

Base differences btw RNA and DNA

answer

Uracil is found in RNA; Thymine in DNA

question

Base pair bonds

answer

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

question

AA's necessary for purine synthesis

answer

Glycine Aspartate Glutamine

question

Nucleoside

answer

Base + ribose

question

Nucleotide

answer

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

question

Purines are made from...?

answer

IMP precursor

question

Pyrimidines are made from...?

answer

Orotate precursor, with PRPP added later.

question

Deoxyribonucleotide synthesis

answer

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

question

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

answer

Hydroxyurea 6-mercaptopurine 5-fluorouracil Methotrexate Trimethoprim

question

*Hydroxyurea*

answer

Inhibits ribonucleotide reductase.

question

*6-mercaptopurine (6-MP)*

answer

Blocks de novo purine synthesis.

question

*5-Fluorouracil (5-FU)*

answer

Inhibits thymidilate synthase (decr dTMP).

question

*Methotrexate*

answer

Inhibits dihydrofolate reductase (decr dTMP)

question

*Trimethoprim*

answer

Inhibits bacterial dihydrofolate reductase

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)

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.

question

Severity of damage in DNA mutations

answer

1. Nonsense 2. missense 3. silent

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

What direction is mRNA read?

answer

5'--<3'.

question

What direction is protein synthesized?

answer

N--<C

question

3 Types of mRNA

answer

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

question

mRNA start codon

answer

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).

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

tRNA structure

answer

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. *CCA* *c*an *c*arry *a*mino acids

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.*

question

What is responsible for the accuracy of AA selection?

answer

Aminoacyl-tRNA synthetase AND binding of charged tRNA to the codon

question

Mechanism of *tetracyclines*

answer

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

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 (*Even*) Pr*O*karyotes: 30S + 50S = 70S (*Odd*)

question

Protein synthesis: *Step 1 in Elongation*

answer

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

question

Protein synthesis: *Step 2 in Elongation*

answer

*Peptidyltransferase* 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

*Mnemonic* for the *3 sites* in the ribosome (translation)

answer

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

question

Protein synthesis: *Termination*

answer

-Stop codon recognized by release factor -Completed protein is released from ribosome thru simple hydrolysis and dissociates.

question

*Aminoglycosides* as protein synthesis inhibitors

answer

Inhibit formation of the initiation complex *30s* and cause misreading of mRNA.

question

*Chloramphenicol* as a protein synthesis inhibitor

answer

Inhibits *50S peptidyltransferase*.

question

*Macrolides* as protein synthesis inhibitors

answer

Bind *50S*, *blocking translocation*

question

*Clindamycin* as a protein synthesis inhibitor

answer

Binds *50S*, blocking translocation.

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.

question

Posttranslational modifications: *Proteasomal Degradation*

answer

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

question

Enzyme regulation methods

answer

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)

question

Order (and important lengths) of *cell cycle phases*

answer

Mitotis (shortest phase): prophase - metaphase - anaphase - telophase. G1 and G0 are of variable duration.

question

Cell Cycle *Regulation*

answer

CDK Cyclin Tumor Suppressors

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

Cell Types: *Permanent cells*

answer

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

question

Cell Types: *Stable (quiescent) cells*

answer

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

question

Cell Types: *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. (Goblet cells are abundant with RER)

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

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

1. Liver hepatocytes 2. Steroid hormone-producing cells of the adrenal cortex

question

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

answer

proteins and lipids __*from*__ER__*to*__ the plasma membrane, lysosomes, and secretory vesicles .

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

Golgi apparatus: assembles ___ from ____?

answer

Assembles *proteoglycans* from *core proteins*

question

Golgi apparatus: sulfation of ____ and ____?

answer

sulfation of *sugars in proteoglycans* and *selected tyrosine* on proteins .

question

Vesicular trafficking proteins: *COPI*

answer

*Retrograde*: cis-Golgi --< ER

question

Vesicular trafficking proteins: *COPII*

answer

*Anterograde*: RER --< cis-Golgi

question

Vesicular trafficking proteins: *Clathrin*

answer

*Receptor-Mediated Endocytosis*: trans-Golgi --< lysosomes, plasma membrane --< endosomoes Example: LDL receptor

question

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

answer

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

question

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

answer

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

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

Molecular motor activity of Microtubules

answer

Transport cellular cargo twd opposite ends of MT tracks. 1. *Dynein* = retrograde to microtubule (+ --< -) 2. *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)

question

*Chédiak-Higashi syndrome*

answer

Microtubule polymerization defect resulting in *decreased phagocytosis*. Results in *recurrent pyogenic infections, 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 immotile), *bronchiectasis*, and *recurrent sinusitis* (bacteria and particles not pushed out); associated w/ situs inversus.

question

*Actin and myosin*

answer

1. *Microvilli* 2. Muscle contraction 3. Cytokinesis 4. Adherens jxn

question

Microtubules (what *structures* are they found in?)

answer

Cilia Flagella Mitotic spindle Neurons Centrioles

question

*Intermediate filaments*

answer

Vimentin Desmin Cytokeratin Glial fibrillary acid proteins (GFAP) Neurofilaments

question

Plasma membrane *composition*

answer

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

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*

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+ go out and 2 K+ come 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*. *Incr Ca2+* --< incr cardiac contractility.

question

Collagen (generally)

answer

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

question

*Type I collagen* Where is this type of collagen found?

answer

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

question

*Type II collagen* Where is this type of collagen found?

answer

Cartilage (including hyaline), VITREOUS HUMOR, nucleous pulposus. *Type II = carTWOlage*

question

*Type III collagen* Where is this type of collagen found?

answer

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

question

*Type IV collagen* Where is this type of collagen found?

answer

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

question

Collagen *Synthesis*

answer

Involves: Synthesis in RER Hydroxylation of Proline and Lysine Glycosylation of lysine of procollagen chain Exocytosis Procollagen-->Tropocollagen Cross-linking of tropocollagen by covalent lysine-hydroxylysine bonds

question

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

answer

*Type III collagen is most frequently affected.* Faulty collagen synthesis in *cross linking in ECM* of lysine-OHlysine causing: 1.) Hyperextensible skin 2.) Tendency to bleed (easy bruising) 3.) Hypermobile joints

question

*Osteogenesis imperfecta* (generally)

answer

Genetic bone d/o (brittle bone dz) *Problems forming triple helix - procollagen in RER* 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

Osteogenesis imperfecta: most common form

answer

autosomal dominant, abnormal *type I collagen*

question

Type II osteogenesis imperfecta

answer

Fatal in utero or neonatal period.

question

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

answer

*abnormal type IV collagen* (type IV collage is an imp. component of the basement membrane of the kidney, ears, and eyes) Most common form is X-linked recessive.

question

*Scurvy*

answer

- Deficiency in *vitamin C* resulting in defected collagen synthesis - No *hydroxylation of Proline and Lysine in RER*

question

Elastin

answer

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.

question

Marfan's syndrome (cause)

answer

Caused by a *defect in fibrillin*

question

*Emphysema* (one cause)

answer

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

question

*Fat-soluble* Vitamins (list + their basic fxns)

answer

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

question

*Fat-soluble* vitamins: absorption?

answer

(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.

question

*Water-soluble* vitamins (list and basic fxns)

answer

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

question

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

answer

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

question

Water soluble vitamin *deficiencies*

answer

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

question

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

answer

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.

question

Vitamin A (retinol) *deficiency?*

answer

-Night blindness, - dry skin

question

Vitamin A (retinol) *excess?*

answer

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

question

*Vitamin B1 (thiamine):* fxn?

answer

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 (*AA metabolism*)

question

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

answer

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

question

*Wernicke-Korsakoff syndrome*

answer

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

question

*Beri-beri*

answer

Due to Vitamin B1 (thiamine) deficiency. (spell it *B er1-B er1* ) 1. *Dry* beriberi - polyneuritis, symmetrical muscle wasting. 2. *Wet* beriberi - high-output cardiac failure (dilated cardiomyopathy), edema.

question

*Vitamin B2* (riboflavin) fxn?

answer

*Cofactor* in oxidation and reduction (e.g., FADH2) *FAD and FMN* are derived from *riboflavin* (*B2 = 2 ATP*)

question

Vitamin B2 (riboflavin) *deficiency*?

answer

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

question

*Vitamin B3 (niacin)* fxn?

answer

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

question

Vitamin B3 (niacin) *deficiency*?

answer

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.*

question

Vitamin B3 (niacin) *excess*?

answer

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

question

*Vitamin B5 (pantothenate)* deficiency?

answer

Dermatitis, enteritis, alopecia, adrenal insufficiency

question

*Vitamin B6 (pyridoxine)* fxn?

answer

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.

question

Vitamin B6 (pyridoxine) *deficiency*?

answer

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

question

*B12 (cobalamin)*: fxn?

answer

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

question

B12 (cobalamin): *Deficiency*?

answer

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

question

B12 (cobalamin): *found* where?

answer

Found in animal products. *Only synthesized by microorganisms*.

question

B12 (cobalamin): *etiology of deficiency*?

answer

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).

question

*Folic acid:* fxn?

answer

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

question

Folic acid: deficiency?

answer

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

question

Folic acid: where is it found?

answer

FOL ate is from FOL iage (green leaves)

question

Etiology of folic acid deficiency?

answer

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

question

Folic acid and pregnancy

answer

Supplemental folic acid in early pregnancy reduces neural tube defects.

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

Biotin: fxn?

answer

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

question

Biotin: deficiency?

answer

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 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

question

Vitamin C (ascorbic acid): deficiency?

answer

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

question

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

answer

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

question

Vitamin D: forms?

answer

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

question

Vitamin D: fxn?

answer

Incr intestinal absorption of calcium and phosphate, incr bone resorption

question

Vitamin D: deficiency?

answer

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

question

Vitamin D: excess?

answer

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

question

Vitamin E: fxn?

answer

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

question

Vitamin E: deficiency?

answer

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

question

Vitamin K: fxn?

answer

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.

question

Vitamin K: synthesis?

answer

Synthesized by intestinal flora.

question

Vitamin K antagonist?

answer

Warfarin.

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, decr adult hair (axillary, facial, pubic). May predispose to alcoholic cirrhosis.

question

Ethanol metabolism: kinetics?

answer

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

question

Fomepizole

answer

Inhibits alcohol dehydrogenase

question

Disulfiram (antabuse)

answer

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

question

Ethanol hypoglycemia

answer

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.

question

Kwashiorkor

answer

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)"

question

Marasmus

answer

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

question

Metabolism sites: Mitochondria

answer

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

question

Metabolism sites: cytoplasm

answer

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

question

Metabolism sites: both mitochondria and cytoplasm

answer

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

question

Process: Glycolysis What is the rate-limiting enzyme?

answer

Phosphofructokinase-1 (PFK-1)

question

Process: Gluconeogenesis What is the rate-limiting enzyme?

answer

Fructose bisphosphatase-2

question

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

answer

Isocitrate dehydrogenase

question

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

answer

Glycogen synthase

question

Process: Glycogenolysis What is the rate-limiting enzyme?

answer

Glycogen phosphorylase

question

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

answer

Glucose-6-phosphate dehydrogenase (G6PD)

question

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

answer

Aspartate transcarbamoylase (ATCase)

question

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

answer

Glutamine-PRPP amidotransferase

question

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

answer

Carbamoyl phosphate synthetase

question

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

answer

Acetyl-CoA carboxylase (ACC)

question

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

answer

Carnitine acyltransferase I

question

Process: Ketogenesis What is the rate-limiting enzyme?

answer

HMG-CoA synthase

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

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

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

answer

NADH, NADPH, FADH2

question

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

answer

Coenzyme A, lipoamide

question

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

answer

Biotin

question

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

answer

Tetrahydrofolate

question

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

answer

SAM

question

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

answer

TPP

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

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+ --> 2 pyruvate + 2 ATP + 2 NADH + 2 H+ + 2H2O

question

Regulation of glycolysis

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: 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 --> 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."

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.

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.

question

Hereditary 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.

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.

question

Essential fructosuria: Sx?

answer

Fructose appears in blood and urine (benign)

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

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

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, 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.

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

question

Purine salvage deficiencies: Lesch-Nyhan syndrome

answer

Defective purine salvage owing to absence of HGPRT 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 dz's: generallly How many types? Molec path? List?

answer

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 "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) Gluconeogenesis is intact.

question

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

answer

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. M cArdle's = M uscle

question

Lysosomal storage dz's (generally)

answer

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.

question

Mnemonic for Niemann-Pick dz?

answer

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

question

Mnemonic for Tay-Sachs?

answer

Tay-SaX lacks heXosaminidase

question

Mnemonic for Hunter's syndrome?

answer

Hunters see clearly (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.

question

Fatty acid metabolism: synthesis

answer

"SY trate = SY nthesis"

question

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)

question

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.

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

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Stored ATP, creatine phosphate, anaerobic glycolysis

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

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(;--- as used in sprint) + Oxidative phosphorylation

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

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Glycogen and FFA oxidation; glucose conserved for final sprinting.

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Metabolic fuel use: Fasting and starvation (generally)

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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

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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)

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

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

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

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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.

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Cholesterol synthesis

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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

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Essential fatty acids

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

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Lipid transport enzymes: Pancreatic lipase

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Degradation of dietary TG in small intestine

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Lipid transport enzymes: Lipoprotein lipase (LPL)

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Degradation of TG circulating in chylomicrons and VLDLs

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Lipid transport enzymes: Hepatic TG lipase (HL)

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Degradation of TG remaining in IDL

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Lipid transport enzymes: Hormone-sensitive lipase

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Degradation of TG stored in adipocytes

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Lipid transport enzymes: Lecithin-cholesterol acyltransferase (LCAT)

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Catalyzes esterification of XOL

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Lipid transport enzymes: Cholesterol ester transfer protein (CETP)

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Mediates transfer of XOL-esters to other lipoprotein particles.

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Major apolipoproteins: A-I

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A -I A ctivates LCAT

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Major apolipoproteins: B-100

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

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Major apolipoproteins: C-II

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C -II is a C ofactor for lipoprotein lipase.

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Major apolipoproteins: B-48

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Mediates chylomicron secretion.

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Major apolipoproteins: E

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E mediates E xtra (remnant) uptake

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Lipoprotein fxns (generally)

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

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Mnemonic for LDL vs. HDL

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

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Type of lipoprotein: Chylomicron Function and route? Apolipoproteins?

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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

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Type of lipoprotein: VLDL Function and route? Apolipoproteins?

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

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Type of lipoprotein: LDL Function and route? Apolipoproteins?

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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

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Type of lipoprotein: HDL Function and route? Apolipoproteins?

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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.

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

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

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

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

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

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

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

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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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