UWorld 3.11.16 Flashcards
E. Coli, 3 major DNA polymerases; explain the relevant DNA repair mechanisms regarding them
All 3 of them have 3’->5’ proofreading exonuclease activity
DNA pol I- ALSO has 5’->3’ in order to remove RNA primer created by RNA primate and repair damaged DNA sequences
Give me the whole Krebs cycle, and what is the part of this path that produces a specific nucleoside triphosphate cofactor in order to produce phosphoenolpyruvate from oxaloacetate
Maleate leaves the mitochondria => in cytosol, forms oxaloacetate => using GTP and PEPCK (phosphoenolpyruvate carboxykinase) => phosphoenolpyruvate => pyruvate (via pyruvate kinase) => enters mitochondrion => carboxylate => oxaloacetate => citrate (via citrate synthase) [pyruvate also produces acetyl CoA via pyruvate dehydrogenase] => isocitrate (via aconitase) => alpha ketoglutarate (via isocitrate dehydrogenase, NAD+) => succinyl-CoA (via alpha ketoglutarate dehydrogenase complex, NAD+) => Succinate (via succinyl-CoA synthetase, GDP) => Fumarate (Succinate dehydrogenase, FAD) => malate (via Fumarase) => oxaloacetate (via malate dehydrogenase, NAD+)
Patient with DKA, glucose of 452 mg/dL in blood and high anion gap metabolic acidosis. Increased activity in which enzyme may be contributing to patient’s abnormal blood glucose finding?
DKA => increased triglyceride breakdown in adipose tissue b/c of insulin deficiency => free fatty acids & glycerol via hormone sensitive lipase => goes to the liver and phosphorylated to glycerol-3-phosphate via glycerol kinase => dihydroxyacetone phosphate by G3P dehydrogenase => produce ATP or glucose through gluconeogenesis
Drunkard found agitated and confused, disoriented, bruises on forehead, forearms, shins, bilateral horizontal nystagmus, unsteady gait with widely spaced legs and short steps. What reactions in the citric acid cycle would be affected?
Alcoholics => thiamine deficiency
Thiamine dependent enzymes:
1. Pyruvate dehydrogenase = pyruvate -> acetyl CoA
2. Alpha ketoglutarate dehydrogenase = alpha ketoglutarate -> succinyl CoA
3. Transketolase
If you administer glucose to thiamine deficient patients => rapid depletion of small amount of thiamine in circulation => neuronal injury within highly metabolic brain regions => acute Wernicke encephalopathy
Metabolism of ethanol by alcohol/aldehyde dehydrogenase consumes NAD+ => increased NADH/NAD+ ratio => inhibits all paths requiring NAD+, and with thiamine deficiency, esp thiamine dep reactions affected
Hiker dude complains of abdominal pain, vomiting, severe watery diarrhea and admits to eating a wild mushroom for funsies, he is ill appearing and jaundiced, liver edge is soft, tender, palpable, labs elevated ALT, AST, Bilirubin. What is inhibited b/c of the toxin?
RNA pol I- rRNA
Pol II- mRNA
pol III- tRNA
Amatoxins- amanita phalloides
-transported to liver via portal circulation, active transport by organic anion transporting polypeptide & sodium taurocholate co-transporter concentrates toxin within liver cells => bind to RNA pol II and halt mRNA synthesis
Test urine for alpha-amanitin
Random toxins and what they inhibit
Acyclovir, famciclovir, valacyclovir- inhibit viral DNA pol
Ricin (castor oil)- cleaves rRNA component of eukaryotic 60S -| protein synthesis
RNA pol I insensitive to amatoxins
eukaryotic pol III transcribes tRNA, 5S rRNA, small RNA molecules, only weakly affected by amatoxins
Fibroblasts synthesize polypeptide chains that assemble into triple helical structures, followed by fibrils, separate into amino acids. What is the highest quantity amino acid most likely to be found in this?
Collagen- most abundant protein, synthesized by fibroblasts, osteoblasts, chondroblasts
3 polypeptide alpha chains, held together by H bonds, triple helix, self assemble into fibrils, which cross link to form collagen fibers
Each alpha chain- every third amino acid is Glycine [GLY-X-Y]; glycine is the only amino acid that can fit between individual alpha chains
X- often proline
Y- hydroxyproline or hydroxylysine
Proline- kink in peptide chain => rigidity
Hydroxylysine- cross-linking => tensile strength
Infant develops transfusion dependent hemolytic anemia by 6mo of age; erythrocytes have insoluble aggregates of hemoglobin subunits; child developed normally in utero b/c at that time infant produced high quantities of what?
Within a few weeks of conception, fetus makes Gower = embryonic hemoglobin = zeta 2 epsilon 2- produced in embryonic yolk
Within a few weeks, fetal liver produces HbF = alpha 2 gamma 2- last few feet months of gestation, during first few weeks of postnatal life
HbA produced during final month of gestation, replaces HbF during postnatal life
Hemoglobin A2 produced in low levels in adults = 2 alpha 2 delta
Beta thalassemia
Thalassemia- hereditary hemolytic anemias from defective synthesis of globin chains
Beta thalassemia = defective synthesis of beta chains
2 genes for beta, need both to be KO => severe hemolytic anemia = beta thalassemia major => alpha chains precipitate => premature lysis of red blood cells
Gamma chains make up for absence of HbA in forming tetramers
Once gamma chains wear out => patients become symptomatic
Newborn develops vomiting, irritability, lethargy some days after birth, diapers smell like burned sugar. The defective enzyme usually uses what substance(s)?
Branched chain alpha keto acid dehydrogenase - 3 catalytic subunits- branched chain alpha ketoacid dehydrogenase, pyruvate dehydrogenase, alpha ketoglutarate require: 1. Thiamine Pyrophosphate 2. Lipoate 3. CoA 4. FAD 5. NAD "Tender Loving Care For Nancy"
Discuss relevant diseases with galactocerebrosidase, pyridoxine, folic acid, tetrahydrobiopterin/tyrosine
Galactocerebrosidase- liposomal hydrolysis of galactocerebroside (myelin), Krabbe disease- aut rec, infantile form btwn 2-5mo with irritability, developmental delay, muscle tone abnormalities
Pyridoxine (B6)- PP, transamination and decarboxylation steps in amino acid metabolism, heme & neurotransmitter synthesis; treat sideroblastic anemia and hyperhomocysteinemia with pyridoxine supplementation
Folic acid- transfer of single carbon moieties during nuclei can acid synthesis; Tx: hyperhomocysteinemia, prevention of neural tube defects in newborns
Phenylketonuria variant- deficiency of tetrahydrobiopterin (cofactor for phenylalanine hydroxylase, converts phenylalanine to tyrosine)
Infant suffers from seizures and hypotonia, cultured fibroblasts show inability to oxidize very long chain fatty acids and phytanic acid. Where is the defect localized to?
Peroxisomes
- inborn error of metabolism; absent or nonfunctional peroxisomes
- very long chain fatty acids, some branched chain fatty acids CANNOT undergo mitochondrial beta-oxidation => undergo special form of beta oxidation [very long fatty acids] or alpha oxidation [branched, such as phytanic acid]
- Zellweger syndrome- infants unable to properly form myelin in CNS => hypotonia, seizures, hepatomegaly, mental retardation, early death within months of initial presentation
- Refsum- defect in peroxisomal alpha oxidation, neurological disturbances from accumulation of phytanic acid within body- treat by avoiding chlorophyll in diet
Discuss what happens at the following sites:
- Mitochondria
- RER
- Proteasomes
- Lysosomes
- Golgi
Mitochondria- beta oxidation, keto genesis, TCA, ETC, initial & final steps of urea cycle, decarboxylation; does NOT metabolize very long chain fatty acids or fatty acids with branch points at odd-numbered carbons
RER- site of synthesis of proteins destined for organelles, cell membrane proteins, extra cellular proteins
Proteasomes- degrade unneeded or improperly formed intracellular proteins to small polypeptides/amino acids; degrade viral proteins for expression on MHC I recognition by T lymphocytes
Lysosomes- acidic fluid, degrade fatty acids, carbohydrates, proteins, nuclei can acids; mucopolysaccharidoses
Golgi- sort proteins from RER, route them to locations within membrane bound vesicles
Woman comes in with progressive joint pain and swelling in her hands for months, easy fatigability that has worsened, morning activities difficult from stiffness; joints reveal warmth, swelling, tenderness involving PIP, MIP, wrists bilaterally. What serum autoantibodies would specify this condition?
Rheumatoid arthritis
Anti-cyclic citrullinated peptide antibodies
Tissue inflammation => arginine residues in vimentin (& other proteins) to be converted to citrulline => alter shape of proteins => antigens for immune response - exaggerated response in those with RA
Measure via ELISA
Name the condition that the autoantibodies to the following specify:
- Centromeres
- dsDNA
- Fc portion of human IgG
- Nuclear basic proteins
- Phospholipids
Anti-centromere = CREST
DsDNA = SLE
RF = Fc portion of human IgG- 80% of patients with RA, but diagnostic utility limited as they are found in 10% healthy individuals, 30% patients with SLE, all patients with mild cryoglobulinemia, etc.
ANA = nonspecific finding in connective tissue disorders- IgM forms of RA, but less frequently found than RF
Anti-phospholipid- SLE, anti phospholipid antibody syndrome => hypercoagulability, paradoxical partial thromboplastin time prolongation, recurrent miscarriages- spontaneous abortions
Deprive lab rats of folic acid, experience marked increase in marrow erythroid precursor cell production => apoptosis without further maturation. Supplementation with what would reduce erythroid precursor cell apoptosis?
Folate important in DNA synthesis and conversion of B12 to coenzyme form
5,10-methylenetetrahydrofolate + dUMP –> dihydrofolate + dTMP via thymidylate synthase
DNA synthesis impaired when deficiency of the 5,10 compound occurs
Common consequence => megaloblastosis
Salvage pathway using thymidine kinase accounts for 5-10% dTMP synthesis => supplement with thymidine to compensate for diminished dTMP
6 mo old girl brought to office, mother states girl isn’t growing much; physical exam shows hepatoma gala, height & weight below 10th percentile; labs show hypoglycemia and keto acidosis; liver biopsy - hepatic fibrosis without fat accumulation
Lots of multi-branched polysaccharide with abnormally short outer chains within cytosol of hepatocytes- what enzyme is most likely deficient?
Debranching enzyme - type III- Cori
- presents in infancy & childhood with liver & muscle involvement
- Sx: hypoglycemia, hepatoma gaily, keto acidosis
- has muscle weakness + hypotonia, unlike type I (Von Gierke)
- hepatic fibrosis but no fat invasion
- Key feature: cytosol is accumulation of glycogen with abnormally short outer chains (limit dextrins)
Glycogen phosphorylase shorten glycogen chains cleaving alpha-1,4-glycosidic linkages => liberate glucose-1-P => until 4 residues remain before branch point (limit dextrin) => debranching enzyme a. Glucosyltransferase cleaves outer 3 residues of the 4 and transfers to a nearby branch b. Alpha-1,6-glucose date removes single remaining branch residue => free glucose, linear glycogen chain that can be further shortened by glycogen phosphorylase
Discuss glycogen breakdown & associated diseases
Glycogen chain engulfed by lysosomes => acid alpha-glucosidase [acid maltase] => glucose
*impairment in this enzyme => type II = Pompe disease = normal glucose levels, severe cardiomegaly, glycogen accumulation in lysosomes
Glycogen phosphorylase- goes down the line until 4 glucose units are left = limit dextrin
*Type V- McArdle - muscle phosphorylase deficiency, weakness & fatigue with exercise, no rise in blood lactate levels after exercise, myoglobinuria
Debranching enzyme takes care of the limit dextrin
- Type III- Cori
- hepatomegaly, ketotic hypoglycemia, hypotonia & weakness, abnormal glycogen with very short outer chains
Glucose-6-phosphatase deficiency = Von Gierke (type I)
- liver, kidney (this enzyme not expressed much in skeletal muscle)
- hypoglycemia, lactic acidosis, hyperlipidemia, hyperuricemia, hepatic steatosis
Type IV Andersen- defective amylo-1,4-1,6-transglucosidase = glycogen branching enzyme => long, insoluble chains => hepatosplenomegaly + cirrhosis
- infantile cirrhosis
- failure to thrive
- hypotonia
- fatal
- increased glycogen, long branches
Type VI- Hers -defective phosphorylase -milder type I -hepatomegaly -growth retardation -hyperlipidemia -hypoglycemia -ketosis symptoms improve with age
Type VII- Tarui’s
- defect in phosphofructokinase
- hepatomegaly
- hyperlipidemia
- ketosis
- exercise-induced muscle cramps & weakness
- mildly elevated transaminases
- presents in childhood
Infant fails to gain weight, no enteropeptidase activity on surface of duodenal epithelium. Formation of what would be impaired by this condition?
Enteropeptidase deficiency => defective conversion of proenzyme trypsin open to active enzyme trypsin
Manifestations: diarrhea, growth retardation, hypoproteinemia
Chronic pancreatitis => lipase deficiency => poor fat absorption & steatorrhea (foul smelling bulky stools containing undigested fat)
Discuss the key clinical features of sphingolipidoses: Fabry, Tay-Sachs, Gaucher, Niemann-Pick, Krabbe, Metachromatic leukodystrophy
- Fabry- X linked rec- deficiency of alpha-galactosidase => accumulates globotriaosylceramide [accumulation of ceramide trihexoside]
*key features: angiokeratomas, peripheral neuropathy, glomerulopathy
Early triad: angiokeratomas, peripheral neuropathy, hypohidrosis [absence of sweating to normal stimuli]
Late: Progressive renal failure, cardiovascular disease - Tay-Sachs- Aut rec- beta-hexosaminidase A deficiency => accumulates GM2 ganglioside
*macular cherry-red spot, progressive neurodegeneration, lysosomes with onion skin, NO HEPATOSPLENOMEGALY, developmental delay - Gaucher- aut rec- beta-glucocerebrosidase def => accumulation of glucocerebroside
*hepatosplenomegaly, pancytopenia, bone pain/osteopenia, osteoporosis, aseptic necrosis of femur, bone crises, Gaucher cells [lipid-laden macrophages resembling crumpled tissue paper]
*treat with recombinant glucocerebroside
*most common - Niemann-Pick- aut rec- sphingomyelinase def => accum of sphingomyelin
*macular cherry red spot, progressive neurodegeneration, hepatosplenomegaly, foam cells [lipid-laden macrophages] - Krabbe- aut rec- galactocerebrosidase def => galactocerebroside and psychosine accum
*progressive neurodegeneration, peripheral neuropathy, optic atrophy, globoid cells, developmental delay - Metachromatic leukodystrophy- aut rec- def of arylsulfatase A => accum of cerebroside sulfate
*Progressive neurodegeneration, peripheral neuropathy
*central & peripheral demyelination with ataxia, dementia
Discuss clinical features of Hurler and Bloom syndromes
Hurler- mucopolysaccharidosis => dysostosis multiplex = enlarged skull, abnormally shaped ribs and vertebrae, corneal clouding (blindness), developmental delay, gargoylism [physical features typical of Hurler syndrome: clawed hands and thick, coarse facial features with a low nasal bridge] accumulation of heparan sulfate, dermatan sulfate due to DEFICIENCY IN alpha-L-iduronidase
Bloom- small stature, infertility, predisposing to malignancy and classic sun-sensitive facial rash => chromosomal instability
Discuss the structure of tRNA
The tRNA 74-93 nucleotides, non coding RNA
Secondary structure:
1. Acceptor stem- base pairing of 5’ terminal nucleotides with 3’ terminal nucleotides; 3’ CCA with amino acid, 5’ terminal phosphate
2. 3’ CCA- added to 3’ end as posttranscriptional modification in eukaryotes & prokaryotes
3. D loop- dihydrouridine residues; facilitate correct tRNA recognition by proper aminoaciduria tRNA synthetase
4. Anticodon loop- sequences complementary to mRNA codon
5. T loop- T psi C sequence necessary for binding of tRNA to ribosomes = robot humidity, pseudo uridine, cytosine residues
34 yo severe headache & blurry vision. Symptoms began after having lunch with lots of fancy meats & cheeses, PMH severe atypical depression; BP 210/130mmHg, HR 110/min; appears tremulous and diaphoretic
What kind of medication was used, what steps of mono amine neuro transmission were affected?
Hypertensive emergency (severe HTN, headache, blurry vision), excessive sympathetic activity (tachycardia, diaphoretic, tremors) Try amine usually metabolized by MAO in gut; mitochondrial enzyme, responsible for degradation of MAO neurotransmitters in pre synaptic nerve terminal *MAO inhibitors- tranylcypromine, phenelzine => block breakdown of tyramine
