Biochem 2 2

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What are the regulatory enzymes in Fatty Acid Synthesis?: Acetyl CoA carboxylase- uses biotin as a cofactor.

Fatty Acid Synthase- multienzyme complex that provides the basis for Fatty formation.
What goes in and what comes out of the reaction of Fatty Acid synth?: Eight acetyl coAs, 14 NADPH, and 7 ATP used to make the 16 carbon palmitate.
What is one cycle in the fatty acid synth process?: The process starts with Malonyl CoA attaching to FAS.

Condesation, Reduction, Dehydration reactions add the two carbons of Malonyl CoA to FAS.

1 ATP, 1 Acetyl CoA and 2 NADPH are used per cycle.

7 cycles
What regulates FA synthesis?: Insulin stimulates by de-P-ating acetyl CoA carboxylase, activating Malonyl CoA synth.

Glucagon and Epi inhibit.
What is the purpose of the Citrate Shuttle and how does it work?: Acetyl CoA is made in the mitochondria, to get it to the cytoplasm, the Citrate shuttle is used.

Citrate-malate-pyruvate shuttle functions in transporting acetyl CoA from mitochondria to the cytosol.

Oxaloacetate + Acetyl CoA-> Citrate
Citrate crosses and is broken back down.

2 ATP, 1 NAD are used
1 NADPH is made
What happens in Fatty Oxidation?: Oxidation, hydration reactions yield 1 Acetyl CoA, NADH, FADH2. Total 17 ATP.
If there are an odd number of carbons in Fatty Ox, what happens to Propionyl CoA?: Propionyl CoA acn be converted to Succinyl CoA with biotin and B12.
Succinyl will net you
What regulates Fatty Breakdown?: Hormone-sensitive Lipase- Activated when phosphorylated. Epinephrine stimulates B-oxidation by activating a cAMP kinase which phosphorylates.
Insulin inhibits B-oxidation.
What is the purpose of the Carnitine Shuttle? How does it work?: Carnitine Transport shuttle helps move fatties from cytosol into the mitochondria for oxidation.

Carnitine Acyl Transferase attaches the fattie to Carnitine.
What happens with a defect in Carnitine synthesis?: Hypoglycemia, muscle pain, muscle atrophy (accumulation of fat)

Infants must be fed medium chain triacylglycerols (butter fat). Medium sized can bypass carnitine shuttle.
What are the steps of Exogenous Lipid Transport?: Cholesterols and Triglycerides are incorporated into chylomicrons. Chylomicrons are degraded by Lipoprotein Lipase on capillary endothelium to Glycerol and FFAs (Fuel for peripheral and stored in Adipose Cells)
Chylomicron remnant, rich in chol is taken up by the liver or transported there by HDL.
What are the steps in Endogenous Lipid Transport?: Liver secretes VLDL which is broken down into FFAs and LDL by LPL.
FFAs are fuel
LDL is taken up by liver or peripheral tissues by receptor. LDL is degraded into chol and chol esters.
chol esters- bound to chol ester transfer protein.
HDL- picks up esters and brings them to liver.
What is the function of a chylomicron? What happens with excess?: Secreted by intestine- delivers TGs to tissues and chol to liver.

Excess causes Pancreatitis, Eruptive Xanthomas, Lipemia retinalis.
What Apolipos are associated with Chylos?: A's- HDL formation
B-48- mediates secretion
C-II- cofactor for lipoprotein lipase
E- Mediates remnant uptake by liver
What is the function of a VLDL? What happens with excess?: Secreted by liver, delivers TGs from liver to tissues.

Excess causes pancreatitis.
What Apolipos are associated with VLDL?: B-100- binds LDL receptor
C-II- cofactor for LPL
E- mediates remnant uptake
What is the function of a LDL? What happens with excess?: Formed in peripheral tissue,
delivers cholesterol from liver to tissues

Excess- atherosclerosis, arcus corneae, xanthomas
What Apolipos are associated with LDL?: B-100- binds to LDL receptor
What is the function of a HDL? What happens with excess?: Secreted by liver and intestine, brings chol from periphery to liver.
Stores Apo C and Apo E, required for VLDL and chylo metabb.

No consequences of excess.
What Apolipos are associated with HDL?: A's- for HDL formation
A-I- activates LCAT (esterifies chol to trap it in HDL)
Chol ester transfer protein- mediates transfer of chol ester to other lipoproteins.
What is the purpose of IDL?: Formed in the degradation of VLDL. Delivers TGs and Chol to the liver to be degraded to LDL.
What are the major Lipoproteins?: A-I- Activates LCAT
B-100 - Binds to LDL receptor
C-II - Cofactor for LPL
E- Mediates Extra remnant uptake.
Breakdown Chol Synthesis: Rate-limiting Step What inhibits this step? What enzyme esterifies Chol? What are the products and the function of these products?: Takes place in the liver and intestine
HMG-CoA reductase is the rate limiting step. The target of Lovastatin which inhibits.

Lecithin Cholesterol Acyltransferase (LCAT) esterifies chol to trap it in HDL and prevents membrane chol uptake.

Cholesterol is oxidized to bile acids in liver as precursor for steroids.
Mevalonic Acid precursor for terpenes (Vitamin A, K, CoQ)
What are the products of sphingolipid synthesis?: Sphingomyelin- Lipid of nervous Tissue
Gangliosides- Acidic glycosphingolipids found in ganglion cells of the nervous system.
Sulfatides- Acidic glycosphingolipids found 1ly in nervous tissue.
Cerebrosides- Neutral glycosphingolipids found 1ly in the CNS myelin.

Degraded by lysosomes
Deficiency in degradation enzyme--> storage disease.
What are the functions of the following: Pancreatic Lipase LPL Hepatic TG Lipase Hormone-sensitive Lipase: Pancreatic- Degrades TGs in small intestine
LPL- degrades TGs in Chylos and VLDLs
Hepatic- degrades TGs in IDL
Hormone- degrades TGs in adipocytes
How are ketone bodies made?: Liver- FA and AA--> Acetoacetate and B-Hydroxybutyrate.

Ketone bodies found in prolonged starvation and diabetic ketoacidosis. Excreted in urine.

Breath smells fruity- acetone
31 y/o with sharp retrosternal chest pain when lifting heavy objects or walking up stairs. Pain is relieved by rest. Father and two uncles had MIs in 30s. What is the disease?: Familial Hypercholesterolemia (Type IIa)- codominant mutation in LDL receptor or AD with apoB100.
W/o--> increased LDL in plasma, but liver still senses less and secretes more.
Xanthomas(tendons, elbows and butt), xanthelasmas(eyelids), atherosclerosis.

Rx- Statin and cholestyramine. nicotinic acid

If homozygous- statins are useless
34 y/o with chronic, recurrent ab pain. Hx of pancreatitis, but currently not acute. orange-red papules on scalp, elbow, and knees.: Familial hyperTGemia IV- AD
Familial hyperchylo I- AR with lack of LPL or ApoCII
Mixed hyperTG (V) heterogenous with lack of LPL or ApoCII

Pathophys-
Type IV- reduced catabolism of TGs, increased production of VLDL
Types I and V- Chylos accumulate.
Clinical- Asymptomatic. Explosive Xanthomas, Lipemia retinalis with TGs>1000.
IV- vascular disease
I and V- pancreatitis, hepatospleno

Rx- niacin, fat-free diet.
statin for type 5.
38 y/o w/ 1 month out from MI. Chol deposits in the palmar creases of her hands and near her butt.: Dysbetalipoproteinemia (III)- AR disorder from Homozygotic Apo-E2- binding defective.
Apo E is involved in uptake of chylos, VLDL, adn IDL remnants. Defective Apo E = elevations in both VLDL TG and VLDL chol.
striae palmaris is pathognomonic. Vascular disease by 50. Elevated VLDL adn IDL, chylomicron remnants; normal LDL, HDL
Rx- Niacin and clofibrate
What is Familial combined hyperlipidemia (type IIb)?: AD disorder. Increased secretion of VLDL causing increased FFA flux driving assembly and secretion of B100.
Has insullin resistance. No xanthomas. elevated VLDL and LDL.
Rx- Lovastatin, cholestyramine, and niacin.
1 y/o at ophthalmologist becasue of corneala clouding. Small, large tongue, mild coarsening of facial features. Bilateral opacities and papilledema.: Hurler Disease- AR disorder caused by deficiency of alpha-L-Idurondiase
lysosome enzyme for breakdown of glycosaminoglycans. Guildup of dermatan sulfate and heparan sulfate. These proteins accumulate in skin and bones, physical deformities and in the heart, liver, and brain.
Clinically coarse face, joint stiffness, short, and valvular heart disease. Corneal clouding, large toungue, hearing loss, and retard.
What is Scheie syndrome?: Adult form of Hurler, deficiency of alpha-L-Iduronidase.
dermatan and heparan sulfate
8 y/o, rheumatologic clinic with joint stiffness. coarse facial features, large tongue, small jaw, and hepatosplenomegaly. Nonpainful, pebbly skin leasion on upper back.: Hunter Disease- X-linked recessive deficiency of iduronate sulfatase. Breaksdown GAGs.
Accumulation of dermatan sulfate, and heparan sulfate.
no corneal clouding. has pebbly skin lesions.
What are the main differences between Hurler's and Hunter's?: Hurler- alpha-L-Iduronidase. Corneal clouding, retard
Hunter- iduronate sulfatase, no clouding, pebbly skin, no retard
What are the mucopolysaccharidoses?: Hurler, scheie, hunter, sanfilippo
3 y/o son has behavioral problems, lashing out. Full term, uncomplicated pregs. Kid has a seizure disorder, developmental delay. On Pex, child has coarse facial features. Heparan sulfate in serum.: Sanfilippo Disease- AR disorder w/ a deficiency in a number of lysosomal enzymes- heparan N-sulfatas.
Buildup of heparan. accumulates in skin, bone, liver, brain. Retard, coarse facies, behavior problems and CNS disease- like seizure.
Rx- Psychotropic drugs.
What is Sly syndrome?: AR disorder caused by a deficiency of B-glucuronidase, an enzyme that is involved in GAG breakdown. physical deformities and hepatospleno.
7 month old Ashkenazi presents with lethargy. Exaggerated startle reaction. Fixed gaze, larger head. Fundoscopic has macular pallor with a cherry-red spot.: Tay-Sachs, AR disorder of hexosaminidase A.
Lysosomal enzyme that breaksdown gangliosides. Accumulation of GM2 gangliosides. which is toxic.

Infant- neurodegenerative with macrocephaly, loss of motor skills, increased startle reaction, hepatosplenomegaly, mauclar pallor with cherry-red spot.
Juvenile-onset- dementia and ataxia.
Adult-onset- childhood clumsiness, progressive motor weakness in teens, spinocerebellar or LMN symps in adult, psychosis.
7 y/o with seizres. Degenerating motor skills. Ataxic gait, can't write without shaking. cherry-red spot.: Sandhoff's Disease- deficiency of B-hexosaminidase A and B.
Accumulation of GM2 gangliosides.

fatal, cherry-red spot, no splenomegaly. similar to Tay-Sachs.
What is GM1 gangliosidosis?: fatal AR disorder with a deficiency in B-galactosidase. Retard, hepatomegaly, physical deformities.
13 y/o with episodic burning pain in his hands, feet, arms, legs after playing soccer. pain episodes occur only after strenuous activity. Telangiectasias that are dark red, punctate and nonblanching. Leasions are growing and more numerous. Normal neuro.: Fabry- X-linked recessive disorder of alpha-galactosidase A. Cleaves ceramide trihexoside a step in glycosphingolipid metabolism.
Accumulation of ceramide trihexoside in skin, heart, kidneys, and CNS.
Telangiectasias (angiokeratomas) do not blanch
acroparethesia- episodic burning pain of hands, feet, proximal extremities.
Corneal and leticualr lesions may be detectable. tortuosity of conjunctival and retinal vessels. Heart and Renal failure.

hypohidrosis.
What is the Rx for Fabry disease? Acroparesthesia Renal Failure: Aco- Phenytoin and Carbamazepine
Renal- dialysis and kidney transplant.
1 y/o with seizures and spastic movements. Diminished vision, dyspnea, hepatosplenomegaly, and failure to thrive. BM has foam cells with sphingomyeline and chol.: Niemann Pick- AR sphingomyelinase deficiency.
disorder of glycosphingolipid catabolism. Accumulation of sphingomyelin accumulates in the histiocytic lysosomes of the brain, liver, spleen, BM and lung

NPD A- first 6 months of life.
NPD B- later onset.

Retard, hepatospleno, osteo. Progressive pulmonary disease
What is Farber disease?: AR disorder with a deficiency of ceramidase- joint deformities, skin nodules, retard and death.
13 y/o Swedish boy comes in with increased forgetfulness. Been held back many times and is now forgetting common, everyday facts. He is more injury prone, with small fractures. Some hepatospleno, nuero has defects in lateral gaze tracking. Wrinkled tissu: Gaucher Disease- AR disorder of B-glucocerebrosidase.
Part of clycoshpingolipic catabolism. Glucosylceramide accumulates in brain, liver, spleen, and BM. Gaucher cells are lipid-laden macrophages. Infarction, necrosis, and cortical bone destruction.

All have hepatospleno and CNS, visceral problems.
Type I- Adult. Early adult with progressive myoclonic seizures, aseptic necrosis.
Type II infantile, slow progression. retard.
Type III- juvenile, dementia

Rx- Cerezyme- recombinant B-glucocerebrosidase
Type 1 is the most compatable with life.
6 month old with failure to thrive. Child has been small and lethargic since birth. Not met milestones. Coarse facial features, gum deterioration. Corneal clouding. Elevated lysosomal enzymes in serum.: I-Cell Disease- AR disorder of N-acetylglucosamine-1-phosphotransferase. The enzyme makes the mannose-6-phosphate signal, sorts lysosomal enzymes.
Gingival hypoplasia. serum lysosomal enzymes.
9 month old who is irritable. stiff, jerky movements. hyperactive deep tendon reflexes and hamstring rigidity. No moro reflex-> hearing or visual acuity diminished. Weak suck reflex.: Krabbe- AR with deficiency of galactosylceramidase. Accumulation of galactocerebroside and galactosyl sphyingosine in the brain and demylenation.
30 month old white boy has deterioration of standing and walking. Wide gait and ataxia. hyperreflexive deep tendon. Some seizure activity. lumbar puncture has increased protein.: Metachromatic Leukodystrophy- AR disorder with deficiency of the lysosomal enzyme, arylsulfatase A.
Accumulation of galactosylceramide sulfate or sulfatide.
Infantile- mental retard
Adult/Juvenile- ataxia, optic atrophy
Adults- dementia and behavioral disturbances.
Labs- Metachromasia of nerves with staining.
What is adrenal leukodystrophy?: rare, fatal X-linked recessive disorder with the defective breakdown of VLFAs. Accumulation of chol esters in CNS white matter, nerves, adrenals, and testes. Childhood- gait deterioration, spasticity from demyelination, seizures, loss of vision and Addison Disease.
How is heme synthesis regulated?: Aminolevulinic Acid synthase- 1ry regulator inhibited by high levels of hemin.

Barbituates can induce cytP450.
What are the pyphorias that can result in defects in Heme synthesis?: Ferrochelotase and ALA dehydrase are inhibbed by lead. Aminolevulinic Acid and Corporphyrinogen accumulate in the urine.

Acute Intermittent- Deficiency in uroporphyrinogen I causes porpobilinogen and ALA accumulation in urine.

Porphyriaa cutanea tarda- Deficiency in uroporphyrinogen decarboxylase- Uroporhyrin accumulates in urine- tea-colored. Photosensitivity.

Congenital Erythropoietic Porphyria- deficient uroporphyrinogen II cosynthetase

5 Ps Painful abdomen, Pink Urine, Polyneuropathy, Psych disturbances, Precipitated by drugs.
What are the major enzymes involved in Heme synthesis?: ALA synthetates
ALA dehydrase
Urophyrinogen I synthetase
Urophyrinogen Decarboxylase
Uroporphyrinogen III cosynthetase
What is the process of heme degradation in the following: Macrophage Liver Intestine: Macrophage-
Heme Oxygenase degrades to biliverdin
Biliverdin Reductase degrades to bilirubin.

Liver-
Bilirubin Glucuronyl Transferase degrades Bili to Bilirubin Diglucuronide.

Intestine
Bilirubin Diglucuronide->Bilirubin->Urobilinogen->Stercobilin
How is Hemoglobin regulated?: Taut form- Oxygen unloading. Activated by Increased Cl, Decreased pH, Increased CO2, Increased T, Increased levels of 2,3 bisphosphoglycerate seen in chronic hypoxemia or anemia.

CO2 binds to the globin chain.
Fetal Hb has less affinity for BPG and more for O2.
Hb has positive cooperativity and negative allostery. sigmoid O2 dissociation curve, myoglobin does not.
What happens in CO poisoning?: CO shifts the O2 curve to the left and plateaus the curve because it has 200x the affinity for hemoglobin.

It is reversible with mad amounts of O2.
CO poisoning causes headaches, dizziness, weakness, nausea and vomiting, chest pain, confusion, LOC, and death.
What the crap is methemoglobin?: Oxidizeded (Fe3+) form of hemoglobin that does not bind O2 well.
Amyl nitrite forms methemoglobin. It can be used as a treatment to CN- poisoning.

Treat with methylene blue.
26y/o woman w/ severe ab pain. Hx of epilepsy with medication including valproic acid, added within the last year. Normal CT of Abd, nl endoscopy, negative colonoscopy. No vomiting or diarrhea. Hypoactive deep tendon reflexes and a left footdrop.: Acute Intermittent Porphyria- AD diorder of uroporphyrinogen I synthetase. Catalyzes PBG to Preurophyrinogen. W/o -> excess PBG and ALA-> neuro damage.
Sx- ab pain from autonomic dysregulation, neuropsychiatric signs like blurred vision, hallucinations, hyporeflexia, neuropathy. Urine darkens with air. NOT photosensitive.

Rx- Hemin- decreases ALA synth. limit exogenous and endogenous roids, alcohol, barbituates, valproate
What is Hereditary coproporphyria?: AD disorder from defective coproporphyrinogen oxidase. Similar symptoms to Intermittent porphyria but pts are photosensitive.
6 month old with vesicular lesions on the face and hands that came on after a picnic. Friable bullae, splenomegaly, increased hair on forearms, face, and hands.: Congenital Erythropoietic Porhyria- AR deficiency of urophyrinogen III cosynthase.
Accumulation of uroporphyrin I and coproporphyrin I in BM, erthrocytes, teeth, plasma, and urine. Increased hemolysis and increased susceptibility to infections. Severe photosensitivity, reddish brown teeth, splenomegaly.

Rx- Bloot transfusion to suppress erythropoiesis. spleno to reduce hemolysis, B-carotene to scavenge free radicals, BM transplant.
32 y/o man with bullae formation on his forearms, hands, and face. IV drug user and has not seen a physician for years. He tells you that he had similar problems as a child and that his brother has similar skin issues. small white plaques among the vesic: Porphyria cutaneous tarda- AD disorder deficiency of hepatic URO decarboxylase. Accumulation of Urophyrinogen III. Porphyrins deposit in the skin--> photosensitivity.
36 y/o man has recurrant abd pain, constipation, muscle pain, and headaches over 3 months. No Hx or FHx. Bluish tinge to gum-tooth line in his mouth and an ankle drop.: Inhibition of gama-aminolevulinic acid dehydrase and ferrochelatase. Increase in free erythrocyte protopophyrins. which can cause demylination and axonal degeneration, decreased RBC survival, increased hemolysis, renal tox and HTN
Clinical- Ab pain, constipation, irritability, difficulty concentrating, arthralgia. Lead-line in the gums.
Chelation with succimer helps as does penicillamine.
Aldosterone: Where is it made? What does it do? What regulates it?: Made in Zona Glomerulosa
Increases NA reabsorption, K and H secretion.
Stimulated by AngioT II, hyperkalemia, and ACTH
Cortisol: Where is it made? What does it do? What regulates it?: Zona fasiculata
Stimulates gluconeogenesis, immunosuppresses, anti-inflam, increases GFR, inhibits bone formation.
Stimulated- ACTH
Inhibited- Cortisol
Androgens: Where is it made? What does it do? What regulates it?: Zona reticularis
Female- pubic and axillary hair growth
Male- like Testosterone
Stimulated by ACTH
Inhibited by Cortisol
What are the key enzymes in steroidogenesis in the adrenal cortex?: 21B-hydroxylase-
17 hydroxyprogesterone-> 11 deoxycortisol

17a-hydroxylase-
progesterone-> 17a-hydroxyprogesterone
Pregnenolone->17-hydroxypregnenolone

11B-hydroxylase-
11-deoxycortisone->corticosterone->aldosterone
11-deoxycortisol->cortisol

3B-hydroxysteroid dehydrogenase-
Pregnenolone-> progesterone
17 hydroxypregnenolone->17a-hydroxyprogesterone
Baby goes into hypovolemic shock hours after birth and dies. Baby is deficient in aldosterone, cortisol, and androgens, why?: 3B-hydroxysteroid dehydrogenase deficiency- AR mutation
Results in deficiency in all three products of the adrenals. Without aldosterone, there is severe hypovolemia and hypotension.
Baby girl with abnl genitalia. Female on amniocentesis. Penis-like clitoris and scrotum like labia. Hypotensive and hyponatremic.: 21B-hydroxylase- AR mutation on chromosome 6
Deficiency in cortisol and aldosterone, excess of progesterone which goes to androgens.
Masculin external genitalia, hypotension, and salt wasting.

a congenital adrenal hyperplastic syndrome along with 17 and 11.
17 y/o without menarche, no breasts or pubic hair. bp of 180/100. Normal genitalia. Decreased K and increased HCO3: 17a-hydroxylase deficiency- AR mutation
deficiency of cortisol and adrenal sex hormones. Buildup of progesterone and pregnenolone. Excess of mineralocorticoids.
Clinical- HTN, and no puberty.
9 y/o girl with headaches. bp is 176/104, has pubic hair and masculinized external genitalia.: 11B-hydroxylase- AR deficiency
deficiency of cortisol and aldosterone, but build up of 11-deoxycortisone (which acts as a mineralocorticoid to cause HTN) and precursors. Excess of adrogen.

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