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USMLE: Biochemistry
Heterochromatin Highly Condensed DNA Transcriptionally inactive Ex. Barr bodies (inactivated X chromosomes) Euchromatin Less condensed DNA Transcriptionally active DNA Methylation Occurs at CpG Islands to repress transcription 'CpG Methylation Makes DNA MUTE' Template strand cytosine and adenine are methylated, which allow mismatch repair enzymes to distinguish between old and new strands. Histone Methylation Represses DNA transcription Histone Acetylation Relaxes DNA coiling and allows for transcription 'Histone acetylation makes DNA ACTIVE' Histones Nucleosome (8):
- H2A x
- H2B x
- H3 x
- H4 x Linker Histone
- H Histones rich in arginine and lysine Purines vs Pyrimidines Purines: A, G (2 rings) Pyrimidines: T, C (1 ring)
G-C bond has 3 H bonds (higher melting temperature) A-T bond has 2 H bonds Pyrimidine Synthesis Rate Limiting Step Carbamoyl Phosphate Synthetase II Combines Glutamine, CO2, ATP to make Carbamoyl Phosphate Purine Synthesis Rate Limiting Step Glutamine PRPP Aminotransferase Converts PRPP to IMP Lesch-Nyhan Syndrome Defective purine salvage due to absent HGPRT Unable to recycle Guanine and Hypoxanthine to GMP and IMP respectively. Excess Uric acid and de novo purine synthesis HGPRT: hyperuricemia. gout, pissed off (aggression, self mutilation), retardation, dysTonia Helicase Unwinds DNA template at replication fork Single Stranded binding proteins prevent strands from reannealing DNA Topoisomerases Creates single or double stranded break in helix to remove supercoils T1: No ATP required T2: ATP required Primase Makes RNA primer for DNA polymerase III to initiate transcription DNA Polymerase III Prokaryotes ONLY
Codes for N-formylmethionine in prokaryotes Stop Codons UGA, UAG, UAA Mismatch Repair Repairs G/T or A/C Pairings Mismatched nucleotides are removed, gap is filled and resealed. Occurs during G2 phase of cell cycle Ex. Defective in hereditary nonpolyposis colorectal cancer Base Excision Repair Specific endonucleases ( glycosylase ) removes the altered base and creates an apurinic/apyrimidinic (AP) site Gap filled by DNA polymerase and ligation of strand nick by DNA ligase III Nucleotide Excision Repair Removes thymidine dimers caused by UV Light DNA polymerase and ligase fill and reseal the gap respectively. Repairs bulky helix-distorting lesions Ex. this process is defective in Xeroderma pigmentosa caused by UV light exposure Nonhomologous End Joining Brings together 2 ends of DNA fragments to repair double-stranded breaks No requirement for homology, some DNA may be lost Mutated in ataxia telangiectasia and fanconi anemia RNA polymerase I Makes rRNA the most numeous RNA polymerase II Makes mRNA the most massive
RNA polymerase III Makes tRNA the most tiny α-amanitin Found in Amanita phalloides (deadly mushrooms) inhibits RNA polymerase II Causes severe hepatotoxicity RNA polymerase (prokaryotes) 1 RNA polyermase (multisubunit complex) makes all 3 kinds of RNA snRNP Binds to primary transcript and helps to form a spliceosome allowing the removal of introns between exons. 5'-CCA-3' Amino acid acceptor site on tRNA molecule tRNA T-arm Necessary for tRNA-ribosome binding tRNA D-arm Necessary for tRNA recognition by correct aminoacyl-tRNA synthetase Aminoacyl-tRNA Synthetase Utilizes ATP to attach AA to tRNA tRNA + ATP + AA --> aa-tRNA + AMP + PPi Wobble Codons differing in the 3rd 'wobble' position may code for the same tRNA/amino acid Eukaryotic Ribosome 40S + 60S = 80S Eukaryotes = EVEN NUMBERS Prokaryotic Ribosome 30S + 50S = 70S prOkaryotes = ODD NUMBERS
Proteasome Barrel shaped protein that degrades damaged or ubiquitin-tagged proteins Defects linked in some cases of Parkinson's disease Carbamoyl Phosphate Synthetase II Converts Glutamine, CO2 and ATP into Carbamoyl Phosphate - rate limiting step of pyrimidine synthesis Orotic Acid Made from the combination of Carbamoyl phosphate and Aspartate in Pyrimidine synthesis pathway. When UMP synthase (downstream) is deficient, Orotic acid accumulates aka Orotic Aciduria Hydroxyurea Inhibits Ribonucleotide Reductase This enzyme converts UDP to dUDP in pyrimidine synthesis Ribonucleotide Reductase Converts UDP to dUDP in pyrimidine synthesis. Inhibited by hydroxyurea Orotic Acidura When UMP synthase is deficient, orotic acid accumulates. Type of Megaloblastic anemia
- Does not improve with Vit. B12 or folate administration
- NO HYPERAMMONEMIA
- Presents as Orotic Acid in the urine and Failure to thrive Supplement with dietary Uridine to bypass the enzyme PRPP Amidotransferase Rate limiting step that converts PRPP to IMP in Purine synthesis. Indirectly inhibited by 6-MP Indirectly inhibited by Allopurinol Adenosine Deaminase Enzyme in purine salvage pathway that converts adenosine to inosine (recycling of adenine)
Deficiency causes excess ATP and dATP to build up thus causing negative feedback inhibition of ribonucleotide reductase and prevents DNA synthesis and thus decreases lymphocyte cound. Major cause of SCID (severe combined immunodeficiency) HGPRT Responsible for recycling guanine and hypoxanthine to GMP and IMP in purine salvage pathway. Deficiency leads to excess Xanthine production and therefore uric acid. Lesch-Nyhan Syndrome SRP Signal Recognition Particle Cytosolic protein that traffics translated peptides from ribosome and helps them get to the RER for modification. Absent or dysfunctional SRP results in protein accumulating in cytosol. Vimentin Immunohistochemical stain for Connective Tissue Desmin Immunohistochemical stain for Muscle Cytokeratin Immunohistochemical stain for Epithelial cells GFAP Immunohistochemical stain for Neuroglia Dynein Microtubule motor protein Retrograde to microtubule ( + --> - ) Kinesin Microtubule motor protein Anterograde to microtubule ( - --> + )
Uniparental Disomy Offspring received 2 copies of a chromosome from 1 parents and no copies from the other parents. Vitamin B Thiamine Remember: ATP Cofactor needed for these Enzymes:
- alpha-ketoglutorate dehydrogenase
- transketolase
- pyruvate dehydrogenase Deficiency results in impaired glucose breakdown and ATP depletion. Worsened by glucose infusion. Results in Wernicke-Korsakoff Syndrome: W - confusion, opthalmoplegia, ataxia K - personality change, memory loss Dry beriberi - polyneuritis, symmetrical muscle wasting (muscle) Wet beriberi - dilated cardiomyopathy (cardiac) Wernicke-Korsakoff Syndrome Results from Vitamin B1 (thiamine) deficiency W - confusion, opthalmoplegia, ataxia K - personality change, memory loss Dry Beriberi Results from Vitamin B1 (thiamine) deficiency polyneuritis, symmetrical muscle wasting (muscle issues) Wet Beriberi Results from Vitamin B1 (thiamine) deficiency Wet beriberi - dilated cardiomyopathy (cardiac issues) Vitamin B Riboflavin
Components of FAD and FMN (cofactors used in redox reactions - ex. TCA cycle) Needed for enzymes that end in dehydrogenase Deficiency results in Cheilosis : inflammation of the lips, scaling fissures at the corner of the mouth. and Corneal Vascularization Vitamin B Niacin Component of NAD+ and NADP+ (used in redox reactions) Derived from tryptophan. Synthesis requires B2 and B Used to treat dyslipidemia - lowers levels of VLDL and raises levels of HDL Deficiency from Hartnup disease (impaired tryptophan absorption) Presents at Glossitis and Pellagra : dementia, diarrhea, dermatitis Vitamin B Pyridoxine Converted to PLP, a cofactor in transamination (ALT, AST), decarboxylation, glycogen phosphorylase, Needed for heme, vitamin B3, 5-HT, NE, dopamine, GABA Deficiency results in convulsions (GABA) or sideroblastic anemia (heme) Vitamin B Penthotenic Acid (pento = 5) Component of coenzyme A Deficiencies: dermatitis, enteritis, alopecia, adrenal insufficiency Vitamin B Biotin Cofactor for carboxylation enzymes (adding carbon)
Deficiency results in scurvy (collagen defect) and weakened immune system. Excess can increase the risk of iron toxicity. Vitamin E Tocopherol / Tocotrienol Antioxidant (protects RED BLOOD CELLS and membranes from free radical damage) Deficiency can cause hemolytic anemia or neurologic symptoms (can be confused with B deficiency) but does not have megaloblastic anemia, or hypersegmented neutrophils. Vitamin K Phytomenadione, Phylooquinone, Phytonadione Cofactor needed for gamma-carboxylation of glutamic acid residues for blood clotting. Synthesized by intestinal flora and needed for clotting factors II, VII, IX, X, Protein C, S (diSCo
Neonatal hemorrhage can occur from deficiency because sterile intestines unable to synthesize vitamin K. Vitamin A Retinol Antioxidant and component of visual pigments Used to treat measles and AML (M3) Deficiency can cause night blindness, corneal degeneration, bitot spots. Used for Acne with Isotretinoin and used for wrinkles Excess can cause pseudotumor cerebri (intracranial pressure) and it's Teratogenic!!!! Hexokinase Phosphorylates glucose to yield glucose- 6 - phosphate (G6P). Found in most tissues Low Km Low Vmax
Down regulated by presence of G6P Glucokinase Phosphorylates glucose to yield glucose- 6 - phosphate (G6P). Found in liver and beta cells of pancreas. High Km High Vmax Induced by insulin Down regulated by presence of Fructose- 6 - phosphate Phosphofructokinase- 1 Rate limiting enzyme of Glycolysis Converts Fructose- 6 - Phosphate to Fructose-1,6- Bisphosphate Down regulated by ATP and citrate (energy not needed) Pyruvate Kinase Catalyzes conversion of Phosphoenolpyruvate (PEP) to pyruvate in Glycolysis. FBPase- 2 Fructose Bisphosphatase- 2 During fasting state, increased glucagon causes increased cAMP and protein kinase A therefore increasing FBPase-2 activity and decreasing PFK-2 activity to cause more gluconeogenesis and less glycolysis PFK- 2 Phosphofructokinase- 2 During well fed state, increased insulin causes decreased cAMP and protein kinase A therefore increasing PFK-2 activity and decreasing FBPase-2 activity to cause more glycolysis and less gluconeogenesis. Glycogen Branches Have alpha-(1,6 bonds) Glycogen Linkages
Refers to the 1 to 4 residues remaining on a branch after glycogen phosphorylase has already shortened it. Glycogen Synthase Rate Limiting Step of glycogen synthesis where UDP-glucose is attached via α-(1,4) glycosidic bonds to the growing polymer of glycogen. Note: Branching enzyme creates branches off the linkages via α-(1,6) glycosidic bonds. Von Gierke Disease Type I Glycogen Storage disease Deficiency in Glucose- 6 - phosphatase (responsible for converting G6P to glucose Results in severe fasting hypoglycemia , increased blood lactate, triglycerides and uric acid. Treat with frequent oral glucose / cornstarch Pompe Disease Type II Glycogen Storage disease Deficiency in lysosomal α-1,4-glucosidase Remember: pump = 4 chambers = 1,4 glucosidase "Pompe trashes the pump" - results in cardiomegaly, hypertrophic cardiomyopathy Pyruvate Carboxylase Gluconeogenesis: Converts Pyruvate to Oxaloacetate Requires biotin as a cofactor and you can replenish TCA cycle or use Oxaloacetate in gluconeogenesis. Occurs in mitochondria Pyruvate Dehydrogenase Converts Pyruvate to Acetyl-CoA Allows for the transition between glycolysis and TCA cycle Requires Vitamins B1 (thiamine), B2 (FAD), B3 (NAD+), B5 (coenzyme A), Lipoic acid as cofactors.
Pyruvate Dehydrogenase Deficiency Causes buildup of pyruvate that gets shunted to lactate and alanine Results in neurologic defects and lactic acidosis Lactic Acid Dehydrogenase Converts Pyruvate to Lactate Occurs during anaerobic respiration (Cori Cycle) Requires Vitamin B3 as a cofactor Will convert Pyruvate to Lactate in muscle.. then will travel through blood to liver where enzyme will convert it back to Pyruvate. Alanine Aminotransferase Converts Pyruvate to Alanine, which carries amino groups to the liver from muscle Requires Vitamin B6 as a cofactor. 4 Fates of Pyruvate
- Alanine (Alanine Aminotransferase)
- Oxaloacetate (Pyruvate carboxylase)
- Acetyl-CoA (Pyruvate dehydrogenase)
- Lactate (Lactic Acid dehydrogenase) Mnemonic for TCA Cycle Intemediates "Citrate Is Krebs' Starting Substance For Making Oxaloacetate" Citrate, Isocitrate, α-ketoglutarate, Succinyl-CoA, Succinate, Fumarate, Malate, Oxaloacetate Isocitrate Dehydrogenase Rate Limiting Enzyme of TCA Cycle Converts Isocitrate to α-ketoglutarate Releases CO2 and NADH α-Ketoglutarate Dehydrogenase Converts α-ketoglutarate to Succinyl-CoA Releases CO2 and NADH
Also seen with Aspirin overdose and thermogenin in brown fat (animals) Phosphoenolpyruvate (PEP) Carboxykinase Gluconeogenesis: Converts Oxaloacetate to PEP in Cytosol Requires GTP Fructose-1,6-Biphosphatase Gluconeogenesis: Converts Fructose-1,6-biphosphate to Fructose- 6 - phosphate in cytosol Rate Limiting Step Glucose- 6 - Phosphatase Gluconeogenesis: Converts Glucose- 6 - phosphate (G6P) to glucose Occurs in Endoplasmic Reticulum This enzymes is NOT FOUND in MUSCLE therefore muscles cannot participate in gluconeogenesis. Glucose- 6 - P Dehydrogenase Pentose Phosphate Pathway Converts Glucose 6 - Phosphate (G6P) to Ribulose- 5 - P and NADPH Needed for reductive reactions and R5P can be used for nucleotide synthesis. NADPH is used to convert oxidized glutathione to reduced glutathione via Glutathione Reductase Glucose- 6 - P Dehydrogenase Deficiency Unable to produce NADPH thus unable to reduce glutathione and detoxify free radicals. This causes hemolytic anemia in Red Blood Cells due to poor RBC defence. against oxidizing agents.
Ex. Fava Beans, Sulfonamides, Primaquine, Anti-TB drugs, Infection X-linked Recessive Histology: Heinz Bodies + Bite Cells Glutathione Peroxidase Converts H2O2 (hydrogen peroxide) to water Necessary to neutralize reactive oxygen species Relies on Reduced Glutathione to accomplish this. Glutathione Reductase Uses NADPH to reduce Glutathione back to Reduced Glutathione, which is needed to neutralize reactive oxygen species to water. Essential Fructosuria Defect in Fructokinase which converts Fructose to Fructose- 1 - Phosphate Benign, asymptomatic accumulation of fructose that cannot be broken down so it appears in urine and blood. Fructokinase Converts Fructose to Fructose- 1 - Phosphate Deficiency causes Essential Fructosuria Benign, asymptomatic accumulation of fructose that cannot be broken down so it appears in urine and blood. Fructose Intolerance Deficiency in Aldolase-B which breaks down Fructose- 1 - Phosphate. This causes deficiency of phosphate resulting in inhibition of glycogenolysis and gluconeogenesis. Unable to correct fasting hypoglycemia. Symptoms present following consumption of fruit, juice or honey (FRUCTOSE = FRUIT). Avoid intake of both fructose and sucrose (glucose + fructose) Galactokinase
