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FA-2017

Biochem FA-2017

QuestionAnswer
Purines Pure As Gold- Arginine + Guanine
Pyrimidines CUT the py- Cytosine + Uracil + Thyamine
Differences between carbamoyl phospatase synthetase I and II? CPS1- location: mitochondria. Pathway: urea. Source of N: ammonia CPS2- location: cytosol. Pathway: de novo synthesis of pyrimidines. Source of N: glutamine
Rate limiting enzyme for pyrimidine de novo synthesis Carbamoyl phosphatase synthethase II
Leflunomide MOA Inhibits dihydroorotate deshydrogenase
Enzyme impaired in orotic aciduria? Symptoms UMP synthase. Hyperamonemia + megaloblastic anemia
Hydroxyurea MOA Ribonucleotide reductase inhibitor
5-FU MOA Thymidylate synthase inhibitor
MTX,TMP, pyrimethamine MOA Dihydrofolate reductase inhibitor
6-mercaptopurine and azathioprine MOA Inhibits glutamine PPRP amidotransferase
Mycophenolate + rivabirin MOA Inhibit inosine monophosphate deshydrogenase (IMP)
Drugs that inhibit de novo pyrimidin synthesis? 1. Leflunomide 2. Hydroxyurea 3. 5-FU 4. MTX 5. TMP 6. Pyrimethamine
Drugs that inhibit de novo purine synthesis 1. 6-MP 2. Azathioprine 3. Rivabirin 4. Mycophenolate
What enzyme is deficient in SCID? Adenosine deaminase. Required for purine salvage pathway.
Enzyme deficient in Lesch-Nyhan Sx? HGPRT- defective purine salvage, can't convert guanine/hypoxanthine back into GMP -> all transformed into uric acid
Lesch Nyhan Sx findings HGPRT-hyperuricemia, gout, pissed off (aggression, self- mutilation), retardation, dysTonia + orange "sand" (Na urate crystals) in diaper
Helicase Unwinds DNA template at replication fork
DNA topoisomerases Remove supercoils
Primases Makes an RNA primer
DNA polymerase III Elongates lagging strand. Exonuclease activity proofreading nucleotides
DNA polymerase I Degrades RNA primer, replaces it with DNA
DNA ligase Joins okazaki fragments
Telomerase Eukaryotes only. Avoids loss of genetic material.
Inhibit eukaryotic topoisomerase I Irinotecan/ topotecan
Inhibit eukaryotic topoisomerase II Etoposide/ teniposide
Inhibit prokaryotic topoisomerase II + IV Fluorquinolones
Differences between etoposide and fluorquinolones? Etoposide inhibits eukaryotic topoisomerase II, fluorquinolones inhibit this enzyme in prokaryotes
Silent mutation Nucleotide substitution but codes for same amino acid. Nothing happens
Missense mutation Nucleotide substitution resulting in changed aminoacid. Protein misfunction
Nonsense mutation Nucleotide substitution resulting in early stop codon. Protein doesn't function
Stop codons UAA, UAG, UGA
DNA mutation in sickle cell disease? Missense mutation
Frameshift mutation Deletion or insertion of nucleotides resulting in misreading of all nucleotides downstream.
Splice site mutation Mutation at the splice site results in retained intron in mRNA.
DNA mutation in Duchenne musuclar dysthrophy? Frameshift mutation
DNA mutation in Tay Sachs disease? Frameshift mutation
Lac operon Example of a genetic response to an enviromental change. If glucose is present, E. Coli will use it and transcription of B- galactosidase to metabolize lactose will not take place
Conditions for transcription of B-galactosidase to take place in lac operon CAP present (in situations with low glucose) and repressor absent (in situations with high lactose)
Nucleotide excision repair Endonucleases. Dna polymerase and ligase fill and reseal gaps. Repairs bulky lesions. Occurs in G1
Base excision repair 1. Glycosylase removes altered base 2. Endonucleases remove nucleotides at 5' end 3. Lyase cleaves 3'end 4. Dna polymerase fills gap 5. Dna ligase seals it. Occurs throughout cell cycle
Mismatch repair Mismatchrd nucleotides are removed. Occurs in G2
Defective nonhomologous end joining results in what diseases Ataxia telangectasia, fanconi anemia, breast/ovarian ca with BRCA1 mutation
DNA repair mechanism defective in xeroderma pigmentosum Nucleotide excision repair
DNA repair mechanism defective in Lynch sx? Mismatch repair
RNA polymerase I Makes rRNA
RNA polymerase II Makes mRNA
RNA polymerase III Makes tRNA
Inhibits RNA polymerase II Alpha- amanitin found in amanita phalloides. Can cause severe hepatotoxicity
Inhibits RNA polymerase in both eukaryotes and prokaryotes Actinomycin D
DNA- dependent RNA polymerase in prokaryotes inhibitor Rifampin
Exons They contain the actual genetic information coding for protein
Introns Intervening noncoding segments of DNA
Steps in protein synthesis 1. Initiation 2. Elongation 3. Termination
What happens in initiation? Initiation factors help assemble the 40s and 60s subunits
What happens in elongation? 1. Aminoacyl-tRNA binds to A site (if it has methionine it binds directly to P site) 2. rRNA transfers polypeptide to amino acid in A site 3. Ribosome advances moving tRNA to P site. This keeps going until stop codon is reached
What happens in termination? Stop codon is recognized and completed polypeptide is released.
Functions of A,P,E sites A- holds upcoming tRNA P- accommodates growing peptide E- holds empty tRNA as it exits
Cells that remain in G0 Neurons, skeletal and cardiac muscle, RBCs
Smooth endoplasmic reticulum function Steroid synthesis and detoxification
Golgi function Distribution center for proteins and lipids from the ER to the vesicles and plasma membrane. Adds mannose-6-P to proteins for trafficking to lysosomes
Enzyme deficient in I-cell disease N-acetylglucosaminyl-1-Ptransferase. Failure of Golgi to phosphorylate mannose residues. Proteins are secreted extracellularly
I-cell disease findings Coarse facial features, clouded corneas, restricted joint movement, high plasma levels of lysosomal enzymes. Fatal
Vesicular trafficking proteins COP1: retrograde -> Golgi to ER. COP2: anterograde -> ER to Golgi. Clathrin: Golgi to lysosomes
Peroxisomal diseases Zellweger Sx and Refsum disease
Zellweger Hypotonia, seizures, hepatomegaly, early death
Refsum disease Scaly skin, ataxia, cataracts/night blindness, shortening of 4th toe, epiphyseal dysplasia
Vimentin- cell type and tumors Mesenchymal tissue. Sarcomas, endometrial ca, meningioma, renal cell ca
Desmin- cell type and tumors Muscle- rhabdomyosarcoma
Cytokeratin- cell type and tumors Epithelial cells- squamous cell ca
GFAP-cell type and tumors Neuroglia- astrocytoma and glioblastoma
Neurofilaments Neurons- neuroblastoma
Drugs that act on microtubles 1.Mebendazole 2.Griseofulvin 3. Colchicine 4. Vincristine/Vinblastine 5. Paclitaxel
Dynein Retrograde to microtubule
Kinesin Anterograde to microtubule
Kartagener sx Dynein arm defect. Decreased fertility, bronchiectasis, recurrent sinusitis, chronic ear infections, conductive hearing loss, situs inversus
Collagen type 1 Bone, skin, tendon, dentin, fascia, cornea, late wound repair
Collagen type 2 Cartilage, vitreous body, nucleus pulposus
Collagen type 3 Reticulin, blood vessels, uterus, fetal tissue, granulation tissue
Collagen type 4 Basement membrane, basal lamina, lens
Collagen defective in Alport Sx Collageb type 4
Autoantibodies against what type of collagen in Goodpasture Type 4
Collagen deficient in vascular Ehlers-Danlos Sx Type 3
Decreased production of what collagen in Osteogenesis Imperfecta Type 1
Steps in collagen synthesis 1. Synthesis 2. Hydroxylation 3. Glycosylation 4. Exocytosis 5. Proteolytic processing 6. Cross linking
Synthesis- collagen synthesis Translation of collagen alpha chains (preprocollagen). Uses glycine and proline/lysine
Hydroxylation- collagen synthesis Hydroxylation of proline and lysine. Uses vit C
Glycosylation- collagen synthesis Formation of procollagen, a triple helix
Exocytosis-collagen synthesis Exocytosis of procollagen into extracellular space
Proteolytic processing-collagen synthesis Cleavage of terminal refions of procollagen-> insoluble tropocollagen
Disease originating from impaired collagen hydroxylation Scurvy
Disease originating from impaired glycosylation of collagen Osteogenesis Imperfecta
Disease originating from impaired proteolytic processing Ehlers-Danlos
Cross linking-collagen synthesis Reinforcement of tropocollagen molecules to make collagen fibrils
Diseases that originate from impaired cross linking collagen Ehlers-Danlos and Menkes
Osteogenesis Imperfecta- defective genes COL1A1 and COL1A2
Modes of inheritance- OI Type I: AD. Type 2: AR
Symptoms of OI 1. Multiple fractures. 2. Blue sclerae 3. Tooth abnornalities (opalescent teeth that wear easily) 4. Hearing loss
Types of Ehlers Danlos- can be associated with berry + aortic aneurysm Hypermobility (most common), classical type (joint +skin- type 5 collagen), vascular type (vascular and organ rupture-type 3 collagen)
Menkes disease XR. Impaired Cu+ absorption due to defective Menkes protein. Decreases activity of lysyl oxidase
Symptoms of Menkes Brittle, kinky hair, growth retardation and hypotonia
Where is elastin found Skin, lungs, large arteries, elastic ligaments, vocal cords, ligamenta flava.
What is elastin made of NONhydroxylated proline, glycine and lysine.
What enzyme inhibits elastase Alpha 1 antitrypsin
Gene mutated in Marfans? Defective protein? FBN1 gene on chromosome 15. Defective fibrillin-forms sheath around elastin
Marfan syndrome- symptoms Tall long extremities, pectus carinatum or excavatum, hypermobile joints, arachnodactyly, cystic medial necrosis of aorta, aortic incompetence, dissecting aortic aneurysms, floppy mitral valve. Subluxation of lenses- upward and temporally.
Ocular changes in marfan and homocystinuria Marfan- lens subluxation upward and temporally. Homocystinuria- downward and inward.
Polymerase chain reaction uses Used to amplify a desired fragment of DNA.
Southern blot DNA sample, DNA probe
Northern blot RNA sample, RNA probe
Western blot Protein sample, antibody probe. Confirmatory test for HIV after + ELISA
Southwestern blot Transcription factors
What is Flow cytometry Cells are tagged with antibodies and then these are tagged with a fluorescent dye
What is flow cytometry used for? Commonly in workup of hematologic abnormalities- PNH, fetal rbcs in mothers blood, immunodeficiencies
ELISA-direct Used to detect the presence of a specific antigen in pts blood sample.
ELISA- indirect Used to detect the presence of a specific antibody in pts blood sample.
ELISA used for VIH screening Direct elisa
Fluorescence in situ hybridization Fluorescent DNA or RNA probe used foe specific location of genes in chromosomes
Codominance definition and example Both alleles contribute to the phenotype of the heterozygote. Blood groups A, B, AB, alpha 1 antitrypsin deficiency
Variable expressivity- definition and example Disease with variable degree of affectation. NF1
Incomplete penetrance- definition and example Disease but no phenotype at all. BRACA1 gene mutations
Pleiotropy- definition and example One gene contributes to multiple phenotypic effects. PKU
Anticipation- definition and example Increased severity or earlier onset of disease in succeeding generations. Huntington's
Mosaicism- definition and example Genetically distinct cell lines in same individual. McCune-Albright
McCune Albright Sx- defect and symptoms Mutation in G protein signaling. 1. Cafe au lait 2. Fibrous dysplasia 3. One endocrinopathy. Lethal if affects all cells
Locus heterogeneity- definitions and example Mutations at different loci can produce a similae phenotype. Albinism
Allelic heterogeneity- definition and example Different mutations in the same locus produce the same phenotype. B-thalassemia
Hardy-Weinberg formulas 1) p + q = 1. 2) p^2 +2pq + q^2. P^2 = frequency of A. Q^2 = frequency of a
Imprinting- definition and examples At the same loci, only one allele is active; the other is inactive. Deletion of the active allele is disease. Prader-Willi, Angelman.
Prader-Willi- symptoms Paternal gene deleted. Hyperphagia, obesity, intellectual disability, hypogonadism, hypotonia and osteoporosis
Angelman syndrome- symptoms Maternal gene is deleted. Inappropriate laughter, seizures, ataxia and severe intellectual disability
X linked dominant- examples Hypophosphatemic rickets, fragile x, alport sx.
Mitochondrial inheritance Offspring of females may show signs of disease. MELAS- mitochondrial encephalopathy, lactic acidosis and strokes. Biopsy: ragged red fibers.
CF- defective gene and chromosome CFTR that encodes ATP gated Cl channel that secretes Cl in lungs and GI and reabsorbes Cl in sweat glands. Chromosome 15
Dx of CF >60mEql of CL in sweat. Can have alkalosis + hypokalemia
CF symptoms: pulm, GI, newborns, GU Recurrent pulm infections (aureus-infancy, pseudo-adolescence),chronic bronchitis + bronchiectasis, pancreatic insufficiency, malabsorption, meconium ileus, infertility in men.
X linked recessive disorders 1. Ornithine transcarbamylase deficiency, ocular albinism 2. Fabry 3. Wiskot-Aldrich 4. Hemophilia A/B 5. Lesch Nyhan 6. Duchenne/Becker, 7. Bruton's 8. Hunter Sx. 9. G6PD def
Duchenne- absent protein? symptoms? MCC of death? Dystrophin. Pseudohypertrophy of calf muscles due to fibrofatty replacement of muscle. Dilated cardiomyopathy
Duchenne- protein function? Labs? Dystrophin: anchors actin to transmembrane proteins. Elevated CK and aldolase.
How are duchenne and becker different? Dystrophin is absent in becker while is its partially functional in becker. Becker has onset in adolescence
Myotonic type 1 muscular dystrophy- cause + symptoms CTG trinucleotide repeat. Myotonia, muscle wasting, cataracts, tersticular atrophy, frontal balding, arrhythmia.
Fragile X syndrome- gene involved + symptoms FMR1 gene. Intellectual disability, macroorchidism, large jaw, large everted ears, autism, mitral valve prolapse.
Trinucleotide repeats expansion diseases: Huntingtons (CAG), Myotonic dystrophy (CTG), Friederich Ataxia (GAA) Fragile X Sx (CGG)
What are the 3 main causes of Downs? 1. maternal age: meiotic nondisjunction 2. Robertosnian translocation 3. Mosaicism
Downs- quad screen 1. Decreased AFP 2. Increased BhCG 3. Decreased estriol 4. Increased inhibin A
Downs- first trimester US Increased nuchal translucency, hypoplastic nasal bone, decreased serum PAPP-A
Downs- associated pathologies 1. Duodenal atresia 2. ASD 3. Hirschsprung 4. Alzheimer 5. ALL
Edwards Sx- chromosome + symptoms 18. PRINCE- Prominent occiput, Rocker-bottom feet, Intellectual disability, Nondisjunction, Clenched fists, low set Ears, micrognatia.
Edwards Sx- quad screen 1. Decreased AFP 2. Decreased BhCG 3. Decreased estriol 4. Decreased or normal inhibin A
Patau Sx- chromosome + symptoms 13. Intellectual disability, microphthalmia, microcephaly, cleft lip + palate, holoprosencephaly, polydactyly, cutis aplasia.
What diseases have nuchal translucency on US? 1. Downs 2. Patau 3. Turner
Robertsonian translocation-definition Long arms of 2 acrocentric chromosomes fuse at the centromere and the 2 short arms are lost.
Cri-du-chat Sx- chromosome + symptoms Deletion chr 5. Microcephaly, intellectual disability, high pitch crying, VSD.
Williams Sx- chromosome + symptoms Deletion chr 7. Elfin facies, intellectual disability, hyperCa (increased sensitivity to Vit D), extreme friendliness with strangers
22q11 deletion sx: aberrant development of 3rd and 4th pouches DiGeorge + Velocardiofacial sx
Vit A-functions Antioxidant, differentiation of epithelial cells into specialized tissue, prevents squamous metaplasia
Vit A- uses Measles, APL (all-trans retinoic acid), Cystic acne (isotretinoin)
Vit A- deficiency Night blindness, xerosis cutis, keratomalacia- Bitot spots.
Vit A- excess Acute- nausea + vertigo + blurred vision. Chronic- alopecia, dry skin, hepatotoxicity, arthralgias, pseudotumor cerebri, teratogenic- cleft palate + CV anomalies
Vit D- D2? D3? storage form? active form? D2-ergocalciferol (plants) D3-cholecalficerol (milk, skin). Storage-25-OH D3 (calcidiol) Active- 1,25 (OH2) D3 (calcitriol)
Enzyme used to convert calcidiol to calcitriol? 1-alpha-hydroxylase
Vit D- deficiency Children-rickets: genu varum. Adults- osteomalacia: bone pain + muscle weakness
Vit D- excess HyperCa, loss of appeptite, stupor.
Why does sarcoidosis increase Ca? Granulomas produce 25- hydroxylase
Vit E- function, deficiency Antioxidant. Hemolytic anemia, acanthocytosis, posterior column + spinocerebellar demyelination.
Vit K- function Activated by epoxide reductase, cofactor for gamma carboxylation of glutamic acid -> Necessary for maturation of clotting factors II, VII, IX, X and proteins C + S.
Lab changes in Vit K deficiency Increased PT + PTT, normal bleeding time.
Zinc- function Important in formation of zinc fingers, essential for carbonic anhydrase
Zinc deficiency Senses: anosmia, dysgeusia, acrodermatitis enterophatica, delayed wound healing. Sexual: hypogonadism, decreased adult hair. May predispose to alcoholic cirrhosis
Kwashiorkor- symptoms Protein malnutrition- MEALS: Malnutrition, Edema, Anemia, Liver (fatty), Skin lesions (hyperkeratosis/hyperpigmentation)
Marasmus- symptoms Caloric malnutrition. Muscle wasting.
Vit B1- name + function Thiamine. Thiamine pyrophosphate (TPP) is a cofactor for: 1. Pyruvate DHNase 2. alpha ketoglutarate DHNase 3. Transketolase 4. Branched-chain ketoacid DHNase.
Vit B1 deficiency Wernicke encephalopathy (ACO(u)te) Ataxia, Confusion, Ophtalmoplegia. Korsakoff (chronic)- Confabulation, personality change, permanent memory loss.
What structures are damaged in Wernicke-Korsakoff Sx? Medial dorsal nucleus of thalamus + mamillary bodies.
Dry beriberi (B1 def) Polyneuritis, symmetrical muscle wasting
Wet beriberi (B1 def) High output cardiac failure (dilated cardiomyopathy), edema.
Vit B2- name + function RiboFlavin. Component of FAD + FMN used as cofactors in redox reactions. (TLC 4 N)
Vit B2- deficiency Cheilosis + Corneal Vascularization (The 2 Cs of B2)
Vit B3- name + function Niacin, constituent of NAD, NADP (TLC 4 N). Used lower levels of VLDL and increase HDL.
What vitamin is derived from tryptophan? B3-niacin
Hartup Disease- cause + symptoms AR. Deficiency of tryptophan transporters in kidney and enterocytes -> no B3 (niacin)- Pellagra (Diarrhea, Dermatitis, Dementia, Death)
Vit B3- deficiency Glossitis. Severe deficiency leads to pellagra: diarrhea, dermatitis, dementia, death)
Causes of B3 deficiency Hartnup disease (low tryptophan), Malignant carcinoid sx (increased tryp metabolism), Isonazid (decreased Vit B6 needed for synthesis of B3).
Vit B3- excess symptoms 1. Facial flushing (induced by prostaglandin, can avoid by taking aspirin 2. HyperGlu 3. HyperUricemia
Vitamin B5- name + function Pantothenic acid, essential component of coenzyme A (used to form Acetyl-Coa)
Vit B5 deficiency Dermatitis, Enteritis, Alopecia, Adrenal insuffiency
Vit B6- name + function Pyridoxine. Converted to pyridoxal phosphate, 1. Used in transamination - ALT + AST 2. Synthesis of heme, niacin, histamine, serotonin, EPI, Nore, Dopa, GABA.
Vit B6 deficieny (Think loss of GABA) Convulsions, hyperirritability, peripheral neuropathy, sideroblastic anemias.
Vit B7- name + function Biotin. Cofactor for carboxylation
Vit B7 deficiency + causes Dermatitis, alopecia, enteritis (like B5). Caused by antibiotic excess or raw egg whites
Vit deficiency leading to alopecia + enteritis + dermatitis Vit B5 + Vit B7.
Vit B9- name + function Folate. Converted to THF, important for synthesis of nitrogenous bases
Vit B9 deficiency symptoms + causes Megaloblastic anemia, PMNs, glossitis, NO neurological symptoms. Caused by phenytoin, sulfas, methotrexate
Vit B9 deficiency labs Increased homocysteine, normal methylmalonic acid.
Vit B12- name + function Cobalamin (uses cobalt). Cofactor for methionine synthase- DNA synthesis
What type of patients are prone to Vit B12 def? Vegans, B12 is found in animal products.
Vit B12 deficiency causes Malarbsorption (sprue, enteritis, diphyllobothrium latum), no intrinsic factor (pernicious anemia, gastric bypass qx), absence of terminal ileum (qx, chrons), vegans.
Vit B12 deficiency symptoms Megaloblastic anemia, PMNs, paresthesias, subactute COMBINED degeneration (dorsal columns + corticospinal + spinocerebellar).
Vit B12 deficiency labs Increased homocysteine and methymalonic acid.
Vit C- function 1. Hydroxylation of proline + lysine 2. Conversion of Dopa-> NE (B-hydroxylase) 3. Antioxidant
Vit C deficiency Scurvy- swollen gums, bruising, petechiae, hemarthrosis, anemia, poor wound healing, corscrew hair.
Vit C + Fe association? Vit C reduces Fe3 to Fe2. Increasing Fe absorption decreases lead absorption.
Fomepizole MOA, uses Inhibits alcohol dehydrogenase. Antidote for methanol + ethylene glycol poisoning.
Antidote for methanol + ethylene glycol poisoning Fomepizole
Disulfiram MOA, uses Inhibits acetaldehyde dehydrogenase. Discouraging drinking
End product of ethanol metabolism Ethanol -> acetaldehyde -> acetate
End product of methanol metabolism Methanol-> formaldehyde -> formic acid
End product of ethylenglycol metabolism Oxalic acid
Triad of formaldehyde intoxication (methanol) 1. CNS depression 2. Acidosis 3. Blindness
Triad of oxalic acid intoxication (EG) 1. CNS depression 2. Acidosis 3. Kidney damage
Limiting reagent in ethanol metabolism NAD+
Ethanol metabolism increases NADH/NAD+ ratio in liver causing? 1. Pyruvate-> lactic acidosis. 2. Oxalacetate -> fasting hypoGlu 3. Hepatoesteatosis
What 3 processes occur in both mitochondria and cytoplasm? 1. Heme synthesis 2. Urea cycle 3. Gluconeogenesis
Glycolysis- rate limiting enzyme PKF-1 (Phosphofructokinase-1)
Gluconeogenesis- rate limiting enzyme Fructose 1,6 Biphosphatase
TCA cycle- rate limiting enzyme Isocitrate deshydrogenase
Glycogenesis- rate limiting enzyme Glycogen synthase
Glycogenolysis- rate limiting enzyme Glycogen phosphorylase
HMP shunt - rate limiting enzyme Glucose -6-Phosphate deshydrogenase
De novo pyrimide synthesis - rate limiting enzyme Carbamoyl phosphate synthase II
De novo purine synthesis - rate limiting enzyme Glutamine-phosphoribosylpyrophosphate (PRPP) amidotransferase
Urea cycle- rate limiting enzyme Carbamoyl phosphate synthase I
Fatty acid synthesis- rate limiting enzyme Acetyl-CoA carboxylase
Fatty acid oxidation- rate limiting enzyme Carnitine acyltransferase I
Ketogenesis - rate limiting enzyme HMG-CoA Synthase
Cholesterol synthesis - rate limiting enzyme HMG-CoA reductase
Glycolysis- regulators (+) AMP, fructose 2,6BP. (-) ATP, citrate
Gluconeogenesis - regulators (+) ATP, citrate (-) AMP, fructose 2,6 BP
Glycogenesis- regulators (+) Insulin, cortisol (-) Glucagon, Epi
Glycogenolysis- regulators (+) Glucagon, Epi, AMP (-) Insulin, ATP
How many ATPs are produced via the malate-aspartate shuttle? and where 32, liver + heart
How many ATPs are produced via the glycerol-3-P shuttle?, where? 30, muscle
How many ATPs does anaerobic glycolysis produce? 2
What pathway produces NADPH? Vit? HMP-Shunt, Vit 3
4 NADPH uses 1. FA + chol synthesis 2. Oxygen reactive species 3. Cytochrome P-450 system 4. Glutathione reductase to degrade free radicals in RBCs
Hexokinase + Glucokinase function Convert Glu into Glu-6-P to trap it inside cells for glycolysis/glycogenesis
Hexokinase vs Glucokinase [Location: G-liver + pancreas, H-other tissues] [Km + Vmax:G-High, H-Low] [Induced by insulin: G-yes, H-no]
End product of glycolysis? Pyruvate.
What enzyme makes fructose 2,6BP in glycolysis? PKF-2 induced by insulin
How does glucagon turn off glycolysis and drive gluconeogenesis? It activates FBPase-1 which converts Fructose 1,6-BP back to fructose-6-P to be used in gluconeogenesis and also activates Fructose 2,6 BPase to convert fructose 2,6 BP back to fructose-6-P
What are the 4 end products of pyruvate? 1. Acetyl-Coa to be used in TCA cycle 2. Lactate to be used in Cori cycle 3. Oxaloacetate to be used in gluconeogenesis 4. Alanine to transport N
What enzyme converts Pyruvate to Acetyl CoA Pyruvate DHnase
What are the cofactors used by pyruvate Dhnase and alpha ketoglutarate Dhnase? Tender Loving Care For Nancy: 1. Thiamine pyrophosphate (B1). Lipoic acid (inhibited by arsenic) 3. Coenzyme A (B5) 4. FAD (B2) 5. NAD (B3)
What cofactor does arsenic inhibit? Characteristic manifestations of arsenic intoxication? Lipoic Acid. Garlic breath and rice water stools
Pyruvate Dhnase deficiency- inheritance mode + symptoms XR. Acetyl-Coa can't be made, pyruvate gets shunted to other pathways leading to lactic acidosis + neurologic symptoms, increased serum alanine.
Pyruvate Dhnase deficiency- treatment Increase intake of ketogenic nutrients like high fat diet or increased lysine and leucine
What is NADH used for from the TCA cycle? It's used in the ETC to transfer electrons and make ATP
What is the electron transport chain? It's a pathway that uses electrons from the NADH generated by the TCA cycle to move H across the inner mitochondrial membrane to the intermembrane space to create a chemical gradient and then use it to power an ATPase and create ATP.
Cofactors used in Complex I? Inhibitors? NADH. Rotenone, MPP (a derivate from mepiridine), amytal
Cofactors used in Complex II? FADH2.
Cofactors used in Complex III? Inhibitors? Cytochrome c. Antimycin A
Inhibitors of Complex IV? CN, H2S, Azide, CO
Inhibitors of ATPase in ETC? Olygomicin
Uncoupling agents- definition + examples Agents that increase permeability of membrane causing H to move back into the inner mitochondrial membrane, decreasing the chemical gradient and stopping ATP production producing heat. 2,4 DNP, aspirin overdose, thermogenin.
Irreversible enzymes in Gluconeogenesis 1. Pyruvate to Oxalacetate using Pyruvate carboxylase, uses acetyl-Coa 2. Oxalacetate to PEP using PEP carboxykinase 3. Fructose 1,6 BP to Fructose 6 P using Fructose 1,6BPase
HMP shunt function Provides a source of NADPH from glucose 6 P.
Sites where the HMP shunt occurs Lactating mammary glands, liver, adrenal cortex (sites of FA or chol synthesis) and RBCs
G6PD deficiency- inheritance + symptoms + histology XR. Hemolytic anemia (RBCs can't be protected from free radicals. Heinz bodies (denatured Hb) and bite cells (phagocytic removal of heinz bodies)
Heinz bodies + bite cells Seen in G6PD deficiency. Heinz bodies- denatured Hb. Bite cells: phagocytic removal of Heinz bodies
Agents that precipitate hemolytic anemia in G6PD deficiency? (6) 1. Sulfas 2. Primaquine 3. Chloroquine 4. Fava beans 5. Nitrofurantoine 6. Isoniacid
Essential fructosuria- enzyme defective + symptoms AR. Fructokinase. Fructose in blood and urine
Fructose intolerance- enzyme deficient + pathogenesis +symptoms AR. Aldolase B. Fructose 1 P accumulates, most of the P is used to create it so it's lacking in other pathways like gluconeogenesis and glycogenolysis. Hypoglycemia, jaundice, cirrhosis, vomiting. Urine dipstick for glu is -
Galactokinase deficiency- symptoms AR. Infantile cataracts, galactose accumulates and is converted to galactitol
Classic galactosemia- enzyme deficient + symptoms AR. Galactose-1-P-uridyltransferase. Symptoms present when child beings feeding. Failure to thrive, jaundice, hepatomegaly, infantile cataracts, intellectual disability, can predispose to E coli.
Lactase deficiency-causes + symptoms + changes in stool and breath 1. Primary: age dependent decline after childhood 2. Secondary: loss of brush border 3. Congenital deficiency. Stool: decreased pH. Breath: increased H. Osmotic diarrhea, bloating, cramps, flatulence.
Essential aminoacids PVT TIM HLL- Phenylalanine, Valine, Threonine, Trypthophan Isoleucine, Methionine, Histidine, Leucine, Lysine
Ketogenic aminoacids Lysine + Leucine
Aminoacids required in periods of growth Arginine + Histidine
Hyperammonemia- causes + pathogenesis + symptoms Liver disease, Urea cycle enzyme deficiencies. Excess NH3 which depletes alpha ketoglutarate leading to inhibition of TCA cycle. Asterixis, slurring of speach, somnolence, vomiting, cerebral edema, blurred vision
How does lactulose improve hyperammonemia Lactulose acidifies the GI tract and trap NH4 for excretion
Hyperammonemia- treatment Lactulose, Antibiotics and benzoate, phenylacetate or phenylbutyrate.
Ornithine transcarbamlylase deficiency- inheritance + symptoms XR. Increased orotic acid in blood and urine, No megaloblastic anemia
Pathway from Ph to Epi Ph (uses BH4)-> tyrosine (uses BH4)-> Dopa (uses B6) -> Dopamine -(uses Vit C)> NE -(uses SAM)> Epi
Enzyme used to convert Ph to Tyrosine, cofactor used Phenylalanine hydroxylase. BH4
Enzyme used to convert tyrosine to DOPA, cofactor used Tyrosine hydroxylase. BH4
Enzyme used to convert DOPA to melanin Tyrosinase
PKU (disorder of aromatic amino acid met)- causes, symptoms, inheritance. AR. Phenylalanine hydroxylase deficiency, BH4 deficiency. Intellectual disability, growth retardation, seizures, eczema, musty body odor.
Maternal PKU-causes + symptoms Lack of proper dietary therapy during pregnancy. In infant: microcephaly, intellectual disability, growth retardation, congenital heart defects.
Maple syrup urine disease- causes + symptoms Decreased branched-chain alpha ketoacid dhnase causing blocked degradation of branched aminoacids (Isoleucine, leucine, valine). Cns defects, intellectual disability, death.
What vitamin is deficient in maple syrup urine disease? B1
Alkaptonuria- causes + inheritance + symptoms AR. Homogentisate oxidase deficiency in the pathway to degrade tyrosine to fumarate. Black cartilage, sclerae (ochronosis), urine tuns black on prolonged exposure to air, arthralgias.
Albinism- causes Tyrosinase deficiency, DOPA can't be converted to melanin
Homocystinuria- causes (3) 1, Cystathione synthase def 2. Decreased affinity of cystathione synthase for B6 3. Methionine synthase def
Homocystinuria- symptoms HOMOCYstenuria: 1. Increased homocysteine in urine 2. Osteoporosis 3. Marfanoid habitus 4. Ocular changes (downward and inward) 5. CV (stroke + MI) 6. kYphosis, Intellectual disability
Cystinuria- causes + symptoms Hereditary defect of renal PCT and intestinal aminoacid transporter that prevents reabsorption of COLA- cysteine, ornithine, lysine and arginine. Hexagonal cystine stones
Cystinuria treatment Urine alkalinization and chelating agents
Metabolites of Dopa, NE and Epi Dopa-> Homovalinic acid, Ne-> vanillylmandelic acid, Epi -> metanephrine
Glycogen synthase-function Attachment of UDP-Glu to the growing glycogen molecule, Adds alpha 1,4 glycosidic bonds
Branching enzyme-function Makes α1,6 glycosidic linkages which build branches in glycogen. Since glycogen tends to be gigantic, these branches help to keep it somewhat compact.
Glycogen phosphorylase- function Breaks down Alpha 1,4 linkage and cuts the Glu-1-P molecules liberating them.
Why can't muscle glycogen be used as a body source of glucose? Because muscles don't have glu-6-phosphatase to convert glu-6-p back to glucose.
Enzyme that breaks alpha 1,6 glycosidic bonds? Debranching enzyme (alpha 1,6 glucosidase)
Von Gierke- enzyme deficient + symptoms Glu-6-phosphatase. Severe fasting hypoglycemia, increased lactate, TGs, uric acid (gout) + hepatomegaly.
Pompe disease- enzyme deficient + types Lysosomal acid alpha 1,4 glucosidase. Infantile: cardiomegaly, HF, Adult: muscle weakness, diaphragm weakness, resp failure, no cardiac involvement.
Cori disease- enzyme deficient + symptoms Debranching enzyme. Milder form of von Gierke with normal lactate
McArdle disease- enzyme deficient + symptoms Glycogen phosphorylase. Painful muscle cramps, myoglobinuria with strenuous exercise and arrhythmia from electrolyte abnormalities.
Tay-Sachs- enzyme deficient + accumulation product + histology Hexosaminidase A. GM2 ganglioside. Lysosomes with onion skin
Tay-Sachs- symptoms 1. Progressive neurodegeneration 2. Cherry-red spot on macula 3. Developmental delay. No hepatomegaly
Fabry disease- enzyme deficient + acummulation product Alpha galactosidase A. Cermide trihexoside
Fabry disease- symptoms 1. Angiokeratomas 2. Hypohydrosis 3. Peripheral neuropathy
Metachromatic leukodystrophy - enzyme + accumulation product + symtomps Arylsulfatase A. Cerebroside sulfate. Central and peropheral demyelination with ataxia, dementia.
Krabbe disease- enzyme + accumulation product + symptoms Galactocerebrosidase. Galactocerebroside, psychosine. Peripheral neuropathy, destruction of oligodendrocytes, developmental delay, optic atrophy.
Gaucher disease- enzyme + accumulation product + histology Glucocerebrosidase. Glucocerebroside. Lipid laden macrophages resembling crumpled tissue paper
Gaucher disease- symptoms Hepatosplenomegaly, pancytopenia, osteopporosis, avascular necrosis of femur, bone crises.
Most common lysosomal storage disease Gaucher disease
Niemann-Pick disease- enzyme + accumulation product + histology Sphingomyelinase, sphingomyelin. Foam cells-lipid laden macrophages
Niemann-Pick dease- symptoms Progressive neurodegeneration, cherry spot on macula, hepatosplenomegaly
Hurler Sx- enzyme + accumulation product + symptoms Alpha-L-iduronidase. Heparan sulfate, dermatan sulfate. Developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly.
Hunter Sx- enzyme + accumulation produc + symptoms Iduronate sulfatase. Heparan sulfate, dermatan sulfate. Milder Hurler + aggresive behavior and no corneal clouding.
Lysosomal diseases associated with Ashkenazi Jews? (3) 1. Gaucher 2. Niemann-Pick 3. Tay-Sachs
Systemic primary carnitine deficiency- pathogenesis + symptoms Impaired transport of LCFA into mitochondria. Hypoglycemia, weakness, hypotonia
Medium chain acyl CoA dhnase deficiency- pathogenesis + symptoms Decreased breaking down of FA to Acetyl CoA. Vomiting, lethargy, coma, seizures, liver dysfunction, sudden death in children
Ketone bodies (3) acetone, acetoacetate, B-hydroxybutyrate
What ketone bodies gives fruity odor Acetone
What ketone body is + in urine? Acetoacetate
Ketone bodies used for energy? Acetoacetate + B hydroxybutyrate
Fed state- processes + hormone Glycolysis - Insulin
Fasting state - processes + hormone Hepatic glycogenolysis (major), hepatic gluconeogenesis, adipose release of FFA (minor). Glucagon and Epi
Starvation 1-3 days. Blood glu is mantained by: Hepatic glycogenolysis, adipose release of FA, muscle and liver start using FA, hepatic glyconeogenesis
Starvation after 3 days. Blood glu is mantained by: Adopose stores (ketone bodies become the main source of energy for the brain)
Lipoprotein lipase- function Degradation of TGs in chylomicrons and VLDLs
Hormone sensitive lipase- function Degradation of TGs stored in adipocytes
LCAT- function catalyzes esterification of 2/3 plasma chol
Chol- function Cell membraine integrity, bile acid, steroids, vitamin D
Chylomicron-function + secreted by Delivers dietary TGs to peripheral tissues. Intestinal epithelial cells
VLDL- function + secreted by Delivers hepatic TGs to peripheral tissues. Liver
IDL- function Degradation product of VLDL. Delivers TGs and chol to liver
LDL- function Deliver hepatic chol to peripheral tissues.
HDL- function Mediates rever chol transport from periphery to liver.
Apolipoprotein E + A function E: mediates remnant uptake (everything except LDL) A: activates LCAT
Apolipoprotein B 48 + B 100 function B48: mediates chylomicron secretion into lymphatics. B100: binds to LDL receptor
Abetalipoproteinemia: Inheritance + pathogenesis + symptoms AR. Apo B48 + B100 deficiency. Fat malabsorption, failure to thrive, acanthocytosis, retinitis pigmentosa, spinocerebellar degeneration due to vit E def.
Hyperchylomicronemia- Inheritance + pathogenesis + symptoms AR. LPL or ApoC deficiency. Pancreatitis, hepatosplenomegaly, pruritic xanthomas.
Hyperchylomicronemia - blood level Increased chylomicrons, TG, chol
Familial hypercholesterolemia- Inheritance + pathogenesis + symptoms AD. Absent or defective LDL receptors. Atherosclerosis, may have MI <20yo, tendon xanthomas, corneal arcus.
Familial hypercholesterolemia - blood level Chol >300.
Dysbetalipoproteinemia- Inheritance, pathogenesis + symptoms AR. Defective ApoE. Atherosclerosis, tuberoeruptive xanthomas, xanthoma striatum palmare
Hypertriglyceridemia- Inheritance, pathogenesis + symptoms AD. Hepatic overproduction of VLDL. TGs >1000 can cause acute pancreatitis
Systemic primary carnitine deficiency- pathogenesis + symptoms Defect in transport of LCFAs into mitochondria. Weakness, hypotonia, hypoglycemia
Medium-chain acyl CoA dhnase deficiency- pathogenesis + symptoms Decreased ability to break down FA into acetyl-CoA. Vomiting, lethargy, seizures, coma, sudden death in infants or children
Created by: Anilita