Biochemistry Day 2
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- Acetyl CoA from the ___ moves into the ___ via the ___ shuttle, where it combines with CO2/biotin to form ___-CoA for FA synthesis.
- mitochondria, cytoplasm, citrate shuttle, Malonyl-CoA
- What is the enzyme that catalyzes the reaction: FA + CoA --> Fatty acyl CoA?
- Fatty acyl CoA synthetase (durr.)
- What is the role of carnitine?
- Carnitine transports long chain FAs (like coenzyme A) into mitochondria
- What step in FA degradation does malonyl CoA inhibit?
- Malonyl CoA inhibits carnitine shuttle from moving FA from cytoplasm to mitochondria (recall: insulin inc. production malonyl-CoA)
- What happens if you are missing part of the carnitine shuttle?
- Can't use long chain FA as metabolic fuel in skeletal muscle, causing myoglobinemia and weakness following exercise
- Under what situations would you find ketone bodies?
-
1) diabetic ketoacidosis
2) prolonged starvation - Which organs utilize ketone bodies?
-
1) muscle
2) brain - Where are ketone bodies made, and from what substrate?
- Liver; HMG-CoA
- HMG-CoA --> ___ --> ___
- acetoacetate --> Beta-hydroxybutyrate
- Where does HMG-CoA come from?
- Acetyl-CoA --> acetoacetyl-CoA --> HMG-CoA
- Ketone bodies are metabolized by the brain to 2 molecules of:
- acetyl CoA
- Someone in ketoacidosis has breath that smells:
- fruity
- What is the rate limiting step in cholesterol synthesis?
- HMG-CoA --> mevalonate, via enzyme HMG-CoA reductase
- Which group of drugs inhibits HMG-CoA reductase?
- Statins, like Lovastatin
- What does LCAT stand for?
- lecithin cholesterol acyltransferase, which esterifies plasma cholesterol
- Which enzyme degrades your dietary TGs --> FFAs in the small intestine?
- pancreatic lipase
- Intestinal epithelial cells convert FFAs back into ___ and package them into ___.
- TGs, chylomicrons
- Chylomicron = TG + ___ + ___ + ___ + ___.
- E, A, C-II, B-48
- Which enzyme degrades chylomicrons and VLDL?
- lipoprotein lipase
- Chylomicron remnant is taken up by liver which puts out VLDL, consisting of:
- VLDL = TG + CE + E + B-100 + C-II
- What does hepatic TG lipase degrade?
- the remaining TG left in IDL
- LDL = ___ + ___.
- CE + B-100
- B-100 on LDL and IDL binds to:
- LDL receptor on Liver surface
- What enzyme degrades the TG stored in adipocytes?
- hormone-sensitive lipase
- What is "A" on the surface of a chylomicron?
- activates LCAT
- What is C-II on the surface of chylomicron & VLDL?
- cofactor for lipoprotein lipase (recall: this enzyme degrades chylomicrons & VLDL)
- What is the "E" on surface of chylomicron, remnant, VLDL, IDL?
- mediates "extra" (remnant) uptake -- whatever that means.
- What is the role of chylomicron?
- deliver TGs to tissues and Cholesterol to liver
- What happens if you have excess chylomicrons?
- pancreatitis, lipemia retinalis (creamy white vessels), eruptive xanthomas
- What is the role of VLDL?
- deliver liver TGs to tissues
- What happens if you have excess VLDL?
- pancreatitis
- B-48 and B-100 mediate ___ of chylomicrons and VLDL, respectively.
- secretion
- Which lipoprotein delivers TGs and Cholesterol to the liver?
- IDL
- Which lipoprotein delivers hepatic Cholesterol to peripheral tissues?
- LDL
- Excess LDL causes:
- atherosclerosis, xanthomas, arcus cornea (white/gray opaque ring around edge of cornea)
- What does HDL do?
- reverse Ch transport, from tissues --> Liver, also is storage for apoC and apoE which are needed for chylomicron and VLDL metabolism (recall: C-II cofactor for lipoprotein lipase, "E" for remnant uptake)
- Where is HDL secreted from?
- liver, intestine
- Which apolipoprotein helps form structure of HDL?
- apoA (recall: A-I activates LCAT)
- Which lipoproteins carry most of the body's cholesterol?
- LDL, HDL
- Type 1 hyperchylomicronemia
- lipoprotein lipase deficiency or altered cofactor C-II; inc. chylomicrons, inc. TG & Cholesterol
- Type 2a hypercholesterolemia
- dec. LDL receptors; inc. LDL, inc. Cholesterol
- Type 2b combined hyperlipidemia
- liver overproduction of VLDL; inc. VLDL & LDL; inc. TG & Cholesterol
- Type 3 dysbetalipoproteinemia
- altered apoE; inc. IDL & VLDL; inc. TG & Cholesterol
- Type 4 hypertriglyceridemia
- liver overproduction of VLDL; inc. VLDL only; inc. TG
- Type 5 mixed hypertriglyceridemia
- inc. production/dec. clearance of VLDL & chlyomicrons; inc. VLDL & chylomicrons; inc. TG & Cholesterol
-
Heme synthesis:
Start with succinyl CoA + Glycine --> ... --> HEME - succinyl CoA + Gly --> ALA (committed step, ALA synthetase) --> porphobilinogen --> preuroporphyrinogen --> uroporphyrinogen III --> coproporphyrinogen --> protoporphyrin (+ Fe) --> HEME
- Acute intermittent porphyria affects which step in heme synthesis?
-
porphobilinogen --> pre-uroporphyrinogen
* missing enzyme uroporphyrinogen I synthetase, porphobilinogen & ALA accumulate in urine - Porphyria cutanea tarda affects which step in heme synthesis?
-
uroporphyrinogen III --> coproporphyrinogen
* missing enzyme uroporphyrinogen decarboxylase, uroporphyrin accumulates in urine (tea colored), photosensitivity - Lead poisoning affects which 2 steps in heme synthesis?
- inhibits ferrochelatase and ALA dehydrase; coproporphyrin and ALA accumulate
- 5 sxs of porphyrias:
-
1) painful abdomen
2) pink urine (dk brown...?)
3) polyneuropathy
4) psychological disturbances
5) precipitated by drugs
* do not give barbiturates! -
Heme degradation:
HEME --> ___ --> ___ - biliverdin --> bilirubin (toxic to CNS and carried by albumin)
- Bilirubin is carried to the ___ where it is conjugated to ___ and excreted in ___.
- liver, glucuronate, bile
- ___ is the intestinal intermediate of bilirubin, some of which is reabsorbed and peed out.
- Urobilinogen
- Which form of Hb has low affinity for O2? Which has high affinity?
-
T/taut = low
R/relaxed = high - Hb exhibits positive ___ and negative ___ which accounts for its sigmoid O2 dissociation curve.
- cooperativity, allostery
- What has 200x the affinity for Hb than oxygen?
- carbon monoxide
- What are 5 things that favor the T/taut form of Hb?
-
1) inc. chloride
2) low pH
3) CO2
4) 2,3-BPG
5) temperature - Fetal Hb has ___ affinity for 2,3-BPG than adult Hb, thus has higher affinity for oxygen.
- lower
- What is methemoglobin?
- oxidized form of Hb (ferric, Fe3+) that does not bind O2 well but HIGH affinity for CN-
- What do you give in cyanide poisoning?
- Give nitrites to oxidize Hb into methemoglobin, to mop up CN.
- How do you Tx methemoglobinemia?
- methylene blue
- CO2 binding favors the ___ form of Hb to promote ___.
- T form, O2 unloading
- CO2 is transported from tissues to lungs mainly in the form of:
- bicarbonate
- What is PCR used for?
- make many copies of a desired fragment of DNA
- What is involved in a Southern blot?
- DNA sample, labelled DNA probe that anneals to its complementary strand in the sample
- What is involved in a Northern blot?
- RNA sample, radioactive DNA probe
- What is involved in a Western blot?
- protein sample, labelled antibody bind to relevant protein
- What does an ELISA test for?
- antigen:antibody reactivity (patient's blood probed with either test Ag to see if immune system recognizes it, or test Ab to see if certain Ag present)
- How are ELISA's sensitivity and specificity?
- close to 100% (awesome)
- How does ELISA indicate a positive test result?
- peroxidase enzyme generates color change in solution
- Pleiotropy =
- 1 gene has > 1 effect on phenotype
- Imprinting =
- differences in phenotype depend on if mutation was maternal or paternal origin
- Loss of heterozygosity =
-
1st hit is mutation in tumor suppressor gene.
2nd hit knocks out remaining allele.
Cancer develops. - Dominant negative mutation =
- heterozygote makes nonfunctional/altered protein that prevents normal gene product from functioning
- Mosaicism =
- when cells in the body have different genetic makeup
- Locus heterogeneity =
- mutations at different loci produce same phenotype (albinism)
- Linkage disequilibrium =
- tendency for certain alleles at 2 linked loci to be inherited more often than expected by chance (occurs in POPULATIONS not families)
- 4 rules of Hardy-Weinberg =
-
1) no mutations
2) no selection of genotypes
3) random mating
4) no migration in/out - Auto dominant disorders:
-
- many generations
- males and females
- often structural genes
- often present after puberty - Auto recessive disorders:
-
- often due to enzyme deficiencies
- usu. seen in only 1 generation
- usu. present in childhood - X-recessive disorders:
-
- no male to male transmission
- sons of heterozygote moms have 50% chance affected
- usu. more severe in males
- heterozygote females MAY be affected - X-dominant disorders:
-
- transmitted thru both parents
- all daughters of affected male are diseased
* hypophosphatemic rickets! - Mito inheritance:
-
- only thru mother
* Leber's hereditary optic neuropathy, mitochondrial myopathies - Adult Polycystic Kidney disease presents with:
- pain, hematuria, HTN, progressive renal failure
- Mutation in Adult Polycystic Kidney disease:
- chromosome 16, APKD1
- Adult Polycystic Kidney disease is associated with: (3)
-
- berry aneurysms
- polycystic liver dz
- mitral valve prolapse - Familial hypercholesterolemia (hyperlipidemia type IIa) has elevated ___ due to defective ___.
- LDL, LDL receptors
- Homozygotes with familial hypercholesterolemia have cholesterol ~ ___ and what sxs (3)?
- 700, with severe atherosclerosis early, tendon xanthomas, MI maybe by age 20
- Marfan's syndrome is a mutation in which gene?
- fibrillin
- What does Marfan's syndrome look like?
- tall, long extremities, hyperextensive joints; aortic incompetence and dissecting aortic aneurysms; subluxation of lens
- Neurofibromatosis 1 (von Recklinghausen) findings:
- cafe au lait spots, neural tumors, Lisch nodules (pigmented iris hamartomas), scoliosis, pheochromocytoma
- What are si/sx of NF2?
- bilateral acoustin neuroma, optic pathway gliomas, juvenile cataracts
- Where do you see ash leaf spots, facial lesions (adenoma sebaceum), cortical and retinal hamartomas, seizures, mental retardation, renal cysts, cardiac rhabdomyomas?
- tuberous sclerosis
- What auto dominant disease has hemangioblastomas of retina/medulla/cerebellum and multiple bilateral renal cell carcinomas?
- von Hippel-Lindau disease (VHL gene on ch3)
- What is the genetic defect with Huntington's?
- CAG triplet expansion on ch4
- How does Huntington's present?
- depression, progressive dementia, chorea, caudate atrophy, low GABA and Ach, onset ~ 20-50 yrs
- What happens in Familial adenomatous polyposis?
- colon covered with adenomatous polyps after puberty --> colon cancer unless resected
- Where is the deletion in FAP?
- ch5
- What is the molecular defect in achondroplasia?
- cell signalling defect with fibroblast growth factor 3 receptor
- Name 11 autosomal dominant diseases:
-
1) adult polycystic kidney
2) familial hypercholesterolemia
3) Marfan's
4) NF1
5) NF2
6) tuberous sclerosis
7) von Hippel-Lindau
8) Huntington's
9) FAP
10) Hereditary spherocytosis
11) achondroplasia - Name 11 autosomal recessive diseases:
-
1) cystic fibrosis
2) albinism
3) juvenile polycystic kidney
4) a1-antitrypsin deficiency
5) PKU
6) thalassemias
7) sickle cell anemia
8) glycogen storage disease
9) hemochromatosis
10) mucopolysaccharidoses (except Hunter's)
11) sphingolipidoses (except Fabry's) - What is the problem with cystic fibrosis and how do you Dx?
- defective Cl- channel (CFTR ch7) --> thick mucus plug lungs, liver, pancreas --> recurrent lung infections, pancreatic insufficiency [Dx high Cl- in sweat test]
- Which 2 bacteria species commonly infect ppl with cystic fibrosis?
- Pseudomonas, S. aureas
- Why are ppl with cystic fibrosis infertile?
- absent vas deferens
- How do you Tx cystic fibrosis?
- N-acetylcysteine to loosen mucous plugs
- Name 10 X-recessive diseases:
-
1) fragile X
2) Duchenne's musc. dystrophy
3) hemophilia A&B
4) Fabry's
5) Hunter's
6) G6PD deficiency
7) ocular albinism
8) Lesch-Nyan
9) Bruton's agammaglobulinemia
10) Wiskott-Aldrich - What is the genetic defect in Duchenne's muscular dystrophy?
- frame shift --> deletion in dystrophin gene --> accelerated muscle breakdown
- What disease manifests ~ 5yrs old with weakness in proximal limbs and pseudohypertrophy of calves?
- Duchenne's muscular dystrophy
- You can Dx muscular dystrophies with inc. ___ and a muscle biopsy.
- Creatine Phosphokinase (CPK)
- What is Beckers muscular dystrophy?
- milder Duchenne's with less severe mutation in dystrophin
- What disease presents with mental retardation, big jaw, big testes, everted ears?
- Fragile X syndrome - CGG triplet repeat (2nd most common cause of genetic mental retardation)
- Name 4 diseases that have triple repeat expansions:
-
1) Huntington's (CAG)
2) Friedrich's ataxia (GAA)
3) myotonic dystrophy (CTG)
4) fragile X (CGG) - What are the 7 most common congenital malformations?
-
1) heart defect
2) hypospadias
3) spina bifida
4) anencephaly
5) cleft lip
6) hip dislocation
7) pyloric stenosis - What are 3 autosomal trisomies?
-
1) Down's (21)
2) Edwards (18)
3) Patau's (13) - What do you find with Down's syndrome?
-
1) mental retardation
2) flat face
3) simian crease
4) heavy epicanthal folds
5) duodenal atresia
6) septum primum ASD
7) inc. risk ALL - What are signs of Edwards syndrome?
-
1) severe mental retardation
2) rocker bottom feet
3) small jaw
4) low set ears
5) clenched hands
6) congenital heart problem
7) prominent occiput
8) death by 1 yr - What are signs of Patau's?
-
1) severe mental retardation
2) small eyes
3) small head
4) cleft lip/palate
5) polydactyly
6) congenital heart problem
7) abnormal forebrain
8) death by 1 yr - What is Cri-du-chat?
- deletion of 5p, small head, mental retardation, high pitched crying, epicanthal folds, heart abnormalities (like VSD!)
- What is 22q11 syndromes? (CATCH-22)
-
1) cleft palate
2) abnormal facies
3) thymic aplasia
4) cardiac defect
5) hypocalcemia
6) microdeletion ch22q11 - Alcohol has highest risk of being teratogen at what time of gestation?
- 3-8 weeks --> mental retardation, small head, face abnormalities, limb dislocation, heart & lung fistulas
- What is the #1 cause of congenital malformations in the US?
- fetal alcohol syndrome