Overview Examples B1 (thiamine: TPP) B2 (riboflavin: FAD and FMN) B3 (niacin: NAD+) B5 (pantothenic acid: CoA) B6 (pyridoxine: PLP) B12 (cobalamin) C (ascorbic acid) biotin folate Characteristics when consumed in excess are eliminated in the urine exceptions are B12 and folate (stored in liver) B-complex deficiencies often result in dermatitis, glossitis, diarrhea Vitamin B1 (Thiamine) Function a cofactor for several enzymes such as thiamine pyrophosphate (TPP) pyruvate dehydrogenase (glycolysis) α-ketoglutarate dehydrogenase (TCA cycle) transketolase (HMP shunt) branched-chain AA dehydrogenase (metabolism of Val, Leu, Ile) Deficiency causes alcoholism most common cause in US EtOH interferes with thiamine absorption in small intestine malnutrition non-enriched rice symptoms impaired glucose breakdown due to decreased activity of pyruvate dehydrogenase leads to ATP depletion highly aerobic tissues are affected first Wernicke's syndrome ataxia, confusion, nystagmus, ophthalmoplegia Korsakoff's syndrome confabulation, psychosis, and mammillary body hemorrhage beriberi dry beriberi peripheral neuropathy due to demyelination symmetrical muscle wasting no fluid retention wet beriberi high-output cardiac failure (dilated cardiomyopathy) edema diagnosis can be made by measuring increased transketolase activity after thiamine administration mechanism thiamine is a cofactor necessary for the function of transketolase diagnosis of thiamine deficiency is made by history management patients that present with thiamine deficienty should be treated with thiamine first after thiamine has been administered, can then administer glucose in IV fluids mechanism thiamine is a cofactor for enzymatic steps in glycolysis administering glucose before thiamine could further decrease thiamine levels for enzymes like transketolase which could exacerbate Wernicke-Korsakoff syndrome Vitamin B2 (Riboflavin) Function cofactor for oxidation and reduction (e.g., FADH2) succinate dehydrogenase precursor to FAD and FMN involved with many dehydrogenase enzymes Deficiency causes severe malnourishment symptoms cheilosis (inflammation of the lips and scaling and fissures at the corners of the mouth) corneal vascularization dry skin magenta-colored tongue Vitamin B3 (Niacin) Function constituent of NAD+and NADP+ (used in redox reactions) derived from tryptophan involved with many dehydrogenase enzymes synthesis requires vitamin B2 and B6 Deficiency causes diets low in tryptophan or niacin corn staple diets Hartnup disease ↓ tryptophan absorption in kidneys and small intestine malignant carcinoid syndrome ↑ tryptophan metabolism in production of serotonin INH therapy ↓ vitamin B6 leading to ↓ niacin synthesis symptoms glossitis severe deficiency leads to pellagra (3 D's) diarrhea, dermatitis, dementia Excess causes nicotinic acid given at high doses as hyperlipidemic treatment (raised HDL) symptoms facial flushing mediated by prostaglandins, treated with aspirin intrahepatic cholestasis hyperglycemia hyperuricemia Vitamin B5 (Pantothenate) Function component of coenzyme A required for many enzymatic processes fatty acid synthase (fatty acid metabolism) acyl transferases pyruvate dehydrogenase (PDH) α-ketoglutarate dehydrogenase (TCA cycle) Deficiency rare symptoms dermatitis, enteritis, alopecia, and adrenal insufficiency Vitamin B6 (Pyridoxine) Function converted to pyridoxal phosphate, a cofactor used in transamination (e.g., ALT and AST in protein catabolism) decarboxylation reactions glycogen phosphorylase cystathionine synthesis heme synthesis required for the synthesis of niacin from tryptophan Deficiency causes INH (isoniazid) oral contraceptives goat milk chronic alcoholism symptoms convulsions, hyperirritability, peripheral neuropathy, sideroblastic anemias, cheilosis or stomatitis Vitamin B12 (Cobalamin) Function cofactor for homocysteine methyltransferase transfers CH3 groups as methylcobalamin cofactor for homocysteine + N-methyl THF → methionine + THF cofactor for methylmalonyl-CoA mutase metabolism of propionate (odd-chain fatty acid degradation) at the conversion of methylmalonyl CoA → succinyl CoA folate not directly involved in this pathway megaloblastic anemia with an elevated methylmalonyl CoA indicates B12 deficiency as opposed to folate metabolism of Val, Met, ILe, Thr Source found only in animal products several years of reserves stored primarily in the liver Deficiency causes pernicious anemia intrinsic factor required for absorption in the terminal ileum B12 not absorbed when intrinsic factor not produced from the parietal cells of the stomach gastric bypass surgery less intrinsic factor produced resection of terminal ileum e.g., Crohn's disease malabsorption sprue, enteritis bacterial overgrowth of terminal ileum diphyllobothrium latum (parasite) competes for B12 absoroption vegan diets use Schilling test to detect etiology of the deficiency differential process of radiolabeled B12 oral B12 + IM B12 B12 + intrinsic factor B12 + antibiotics B12 + pancreatic enzymes symptoms macrocytic, megaloblastic anemia found also in folate deficiencies hypersegmented PMNs neurologic symptoms due to abnormal myelin paresthesias and subacute combined degeneration dorsal columns of spinal cord degenerate causing loss of proprioception and vibration sensation not found in folate deficiencies could be reversible with administration of B12 severe symptoms and longer term B12 deficiency = more residual neurologic damage and less function regained Folic Acid Function converted to tetrahydrofolate (THF), a coenzyme for 1-carbon transfer/methylation reactions important for the synthesis of nitrogenous bases in DNA and RNA (thymidylate synthase) recall: uridine + methyl group = thymidine Deficiency most common vitamin deficiency in the United States absorbed in the jejunum via the action of intestinal conjugase causes dietary deficiency elderly goat milk seen in alcoholism and pregnancy liver stores last three months deficiency can be caused by several drugs e.g. phenytoin, sulfonamides, methotrexate, EtOH findings macrocytic, megaloblastic anemia hypersegmented neutrophils homocysteinemia ↑ risk of DVT and atherosclerosis no neurologic symptoms + normal methylmalonic acid level (as opposed to vitamin B12 deficiency) deficiency in pregnancy causes fetal neural tube defects supplemental folic acid in early pregnancy reduces risk Biotin Function cofactor for carboxylation enzymes (adds a 1-carbon group) pyruvate carboxylase pyruvate (3C) → oxaloacetate (4C) gluconeogenesis acetyl-CoA carboxylase acetyl-CoA (2C) → malonyl-CoA (3C) fatty acid synthesis propionyl-CoA carboxylase propionyl-CoA (3C) → methylmalonyl-CoA (4C) odd-carbon fatty acids, Val, Met, Ile, Thr catabolism Deficiency relatively rare causes antibiotic use excessive ingestion of raw eggs contains avidin which binds biotin symptoms dermatitis, alopecia, enteritis, lactic acidosis Vitamin C (Ascorbic Acid) Function antioxidant regenerates vitamin E ↓ oxidation of LDL keeps iron in Fe2+ reduced state ↑ intestinal absorption collagen synthesis essential for hydroxylation of proline and lysine prolyl and lysyl hydroxylases addition of hydroxyl group allows for hydrogen bonding between fibers without cross-linking triple helix shape cannot form synthesis of norepinephrine necessary for dopamine β-hydroxylase converts dopamine to NE hepatic synthesis of bile acids keeps THF in reduced form protects against nitrosylation of amides occurs in the stomach with presence of food preservatives nitrosamines/amides are carcinogenic Source found in fruits and vegetables British sailors carried limes to prevent scurvy Deficiency causes diet lacking citrus fruits and green vegetables infants on formula that is boiled too long excessive heat destroys vitamin C cigarette smoking symptoms scurvy swollen gums, bruising, perifollicular hemorrhage, poor wound healing, glossitis, ↑ bleeding time anemia due to combined iron and folate deficiency infantile scurvy 2-10 months excessively boiling formula Excess symptoms formation of renal calculi made from calcium oxalate (vitamin excreted as oxalate) diarrhea, nausea, vomiting excess iron absorption in those predisposed (hemochromatosis, repeat blood transfusions) S-Adenosylmethionine (SAM) Not a vitamin but an important cofactor Synthesis ATP + methionine → SAM regeneration of methionine (and thus SAM) is dependent on vitamin B12 and folate Function SAM transfers methyl units similar to THF SAM is required for the conversion of NE to epinephrine