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Transcript
A 38-year-old woman is brought to the physician because of frequent falls, increasing confusion, and incontinence A 29-year-old woman is brought to the physician because of thought abnormalities What is the role of vitamins in metabolic pathways? Eric Niederhoffer Medical Biochemistry Vitamins in Neuromuscular Metabolism • Names and roles for vitamins and vitamin-like substances • Deficiencies and sources for vitamins and vitaminlike substances • Vitamin A transport • Role in pathways (glycolysis, glycogenolysis, PPP) • Role in pathways (TCA cycle, gluconeogenesis) • Important neurologic amino acids • Dopamine pathway • Serotonin pathway • Folate and B12 interrelationships • Tetrahydrofolate conversions • Tetrahydrofolate examples • B12 examples • Megaloblastic anemia • Schilling test • Diagnostic testing and diseases Names and Roles for Vitamins and Vitamin-like Substances Letter Name Role (metabolism) A Retinol Phototransduction B1 Thiamin Carbohydrate/myeline B2 Riboflavin Redox/respiration B3 Niacin Redox B5 Pantothenic acid (CoA) TCA,FA,cholesterol B6 Pyridoxine Pyridoxamine Pyridoxal AA, glycogenolysis B7 Biotin Gluconeogenesis, TCA, FA, AA B9 Folic acid 1C B12 Cobalamin 1C&H C Ascorbic acid Hydroxylation p-Aminobenzoic acid Folate component Choline AC, PL Inositol PL Lipoic acid TCA, acyl group transfer Tetrahydrobiopterin (BH4) AAA hydroxylase, NO synthase Deficiencies and Sources for Vitamins and Vitamin-like Substances Vitamin Deficiency Sources A✱ Night blindness Preformed: liver, egg yolk, butter, milk β-carotene: dark green and yellow veggies B1✱ Beri beri Seeds, nuts, wheatgerm, legumes, lean meat B2 Pellagra Meats, nuts, legumes B3 Pellegra Meats, nuts, legumes B5 Non known Yeast, grains, egg yolk, liver B6 Neurologic disease Yeast, liver, wheatgerm, nuts, beans, banana B7 Widespread injury Corn, soy, egg yolk, liver, kidney, tomato B9✱ Anemia Yeast, liver, leafy veggies B12✱ Pernicious anemia Liver, kidney, egg, cheese C✱ Scurvy Citrus and soft fruits p-Aminobenzoic acid See B9 Liver rice bran, whole wheat Choline Rare Whole eggs, liver, beef steak, soy (lecithin) Lipoic acid None known Liver Inositol None known Cereal grains Tetrahydrobiopterin (BH4) Rare, PKU-like Synthesized and recycled Vitamin A Transport β-carotene (plants) retinyl ester (animals) retinal retinol retinyl ester (small intestine) Liver storage PA RBP retinol Target tissue Role in Pathways (glycolysis, glycogenolysis, PPP) Glycogenolysis Glc Glycolysis Glycogen PP a vit B6 G1P G6P G6PDH/6PGDH vit B3 R5P PPP TK vit B1 G3P G3PDH vit B3 1,3BPG Ala ALT vit B6 Pyr LDH vit B3 Lactate Role in Pathways (TCA cycle, gluconeogenesis) Pyr PDH vit B1,B2,B3, B5, lipoic acid Acetyl-CoA PC vit B7 AST vit B6 Asp OA MDH vit B3 BCAA Ile, Leu, Val Mal IC TCA cycle ICDH vit B3 Fum BCKA SDH vit B2 Suc αKG SCoA BCKADH vit B1,B2,B3, B5, lipoic acid ALT vit B6 αKGDH vit B1,B2,B3, B5, lipoic acid Glu Important Neurologic Amino acids Glutamate PLP (vit B6) γ-Aminobutyrate deCO2ase Phenylalanine BH4 Phe OHase Tyrosine Phenylketonuria (PKU) PLP (vit B6) deCO2ase Tryptophan PLP (vit B6) deCO2ase Dopamine Norepinephrine Epinephrine Serotonin Dopamine Pathway Homovanillic acid (HVA) Degradation Tyrosine BH4, O2 DOPA Tyr OHase PLP (vit B6) Dopamine AAA deCO2ase Menkes disease Epinephrine PNMT DβOHase Vit C, O2 Norepinephrine SAHC SAM Metanephrine Normetanephrine Degradation (MAO/COMT) Vanillylmandelic acid (VMA) 3-Methoxy-4-hydroxymandelic acid (HMMA) Serotonin Pathway Melatonin Tryptophan BH4, O2 5HTRP Trp OHase PLP (vit B6) Serotonin (5-HT) AAA deCO2ase 5-Hydroxyindoleacetic acid (5-HIAA) 3-Hydroxykynurenine PLP (vit B6) Kynureninase Cytosolic/mitochondrial degradation pathway Xanthurenate Folate and B12 Interrelationships Folate Folate cycle N5-formimino-THF DHF THF N10-formyl-THF N5,N10-methenyl-THF Pyrimidine/Purine synthesis R5P HCO3- GTP ATP CTP UTP dGTP dATP dCTP dTTP RNA DNA N5,N10-methylene-THF N5-methyl-THF Methionine salvage Met Vit B12 HC Odd-numbered TCA cycle fatty acids Vit B 12 Choline metabolism Neurotransmitter metabolism Serine Histidine Glycine Glutamate Folate and B12 Interrelationships Folate Folate cycle DHF N5-formimino-THF THF N10-formyl-THF N5,N10-methenyl-THF N5,N10-methylene-THF N5-methyl-THF Methionine salvage Met Vit B12 HC Folate and B12 Interrelationships Folate cycle Folate DHF N5-formimino-THF THF N10-formyl-THF N5,N10-methenyl-THF N5,N10-methylene-THF N5-methyl-THF Choline metabolism Glycine Folate and B12 Interrelationships Folate cycle Folate N5-formimino-THF DHF THF N10-formyl-THF N5,N10-methenyl-THF N5,N10-methylene-THF N5-methyl-THF Neurotransmitter metabolism Serine Histidine Glycine Glutamate Folate and B12 Interrelationships Folate cycle Folate DHF N5-formimino-THF THF N10-formyl-THF N5,N10-methenyl-THF N5,N10-methylene-THF Pyrimidine/Purine synthesis R5P HCO3- GTP ATP CTP UTP dGTP dATP dCTP dTTP RNA DNA N5-methyl-THF Folate and B12 Interrelationships Folate Folate cycle N5-formimino-THF DHF THF N10-formyl-THF N5,N10-methenyl-THF Pyrimidine/Purine synthesis R5P HCO3- GTP ATP CTP UTP dGTP dATP dCTP dTTP RNA DNA N5,N10-methylene-THF N5-methyl-THF Methionine salvage Met Vit B12 HC Odd-numbered TCA cycle fatty acids Vit B 12 Choline metabolism Neurotransmitter metabolism Serine Histidine Glycine Glutamate Tetrahydrofolate Examples N5,N10THF MLTHF Choline DMG Sarcosine NAD+ THF Ser PLP N5,N10THF MLTHF N5,N10MLTHF THF NADH + H+ N5,N10MLTHF CO2 + NH4+ Gly serine hydroxymethyl transferase Gly glycine synthase THF N5-FTHF FIGLU His Glu glutamate formimino transferase dUMP dTMP thymidylate synthase N5,N10MLTHF A series of reductases 7,8-DHF THF DHF reductase B12 Examples Methyl transfers (1C metabolism) ATP + Met Ad transferase Met S-AdMet THF R Met synthase Vit B12 N5MTHF Purines dTMP CT PCoA A variety of MTs R-CH3 hydrolase HC S-AdHC Cystathionine β-synthase PLP (Vit B6) Odd-chain FA oxidation/ AA metabolism MMCoA mutase L-MMCoA SCoA Vit B12 (H exchange) TCA cycle Megaloblastic Anemia This hypersegmented neutrophil is present along with macroovalocytes in a case of pernicious anemia. Compare the size of the RBC's to the lymphocyte at the lower left center. Such anemias can be due to B9 (folate) or to B12 (cobalamin) deficiency. http://library.med.utah.edu/WebPath/HEMEHTML/HEME083.html Schilling Test 58Co-B 12 + I.M. B12 IF present IF absent 58Co-B -IF 12 58Co-B 12 GI absorption No GI absorption Liver storage (~80%) Plasma protein binding (~5%) Low 58Co-B12 in urine Excreted in urine (~15%) Stage Dose 1 Oral radioactive B12 I.M. unlabeled B12 2 ORB12/I.M.UB12/IF 3 ORB12/I.M.UB12/antibi otics 4 ORB12/I.M.UB12/pancr eatic enzymes Fecal excretion Normal Low malabsorption 8 to 40% of radioactive B12 in urine malabsorption unrelated to IF malabsorption unrelated to bacterial growth malabsorption unrelated to pancreatic insufficiency Diagnostic Testing and Diseases Vitami n Tests Disease(s) A serum/plasma (direct assay) impaired night vision, xerophthalmia, immunodeficiency B1 erythrocyte transketolase, blood thiamine, pyruvate, αketoglutarate, lactate, and glyoxylate, urine thiamin wet/dry beriberi, Wernicke encephalopathy, Korsakoff dementia B2 erythrocyte glutathione reductase, urine riboflavin B3 urine N-methylnicotinamide, N-methyl-2-pyridone-5carboximide pellagra B5 serum/plasma (direct assay) “burning feet syndrome” B6 serum/plasma (direct assay), urine xanthuremate deficiency (rare) B7 serum/plasma (direct assay) deficiency, multiple carboxylase deficiency (holocarboxylase synthetase, biotinidase) B9 serum/plasma/erythrocyte (direct assay), urine Nformiminoglutamate megaloblastic anemia, hyperhomocysteinemia, neural tube defects B12 serum/plasma (direct assay), Schilling test, urine methylmalonic acid megaloblasic anemia, homocystenemia, methylmalonic aciduria and homocystinuria C serum/plasma (direct assay) scurvy ariboflavinosis, night blindness, peripheral neuropathy, pellagra Review Questions • What are the different names for vitamins A, B1, B2, B3, B5, B6, C, and B12? • Which pathway depends on vitamin A and how is it transported? • Which pathways and enzymes depend on vitamin B1, B2, B3, B6, B9, and B12? • Which pathway and enzyme depends on p-aminobenzoic acid, choline, lipoic acid, and tetrahydrobiopterin? • What are some clinical features and tests of vitamin deficiencies?
