Vitamins & Coenzymes

Vitamins are organic micronutrients required in small amounts for normal metabolism. Most function as coenzymes or precursors to coenzymes — non-protein molecules that participate directly in enzymatic reactions, often serving as carriers of electrons, acyl groups, or one-carbon units.

Fat-Soluble Vitamins

Vitamin A (retinol and derivatives — retinal, retinoic acid): absorbed from diet as retinol or beta-carotene (provitamin A, cleaved by intestinal beta-carotene dioxygenase). Stored in liver as retinyl esters. Functions: (1) Retinal (11-cis retinal) is the chromophore of rhodopsin in rod photoreceptors — photoisomerisation to all-trans retinal triggers the visual signal cascade; (2) Retinoic acid is a ligand for nuclear receptors (RAR, RXR) that regulate transcription of genes for cell differentiation, proliferation, and morphogenesis; (3) Important for integrity of epithelial surfaces and immune function. Deficiency: night blindness (earliest sign), xerophthalmia, Bitot's spots, keratomalacia, increased susceptibility to respiratory and gastrointestinal infections. Toxicity: hypervitaminosis A causes hepatotoxicity, pseudotumour cerebri, teratogenicity (avoid in pregnancy).

Vitamin D (cholecalciferol D3, ergocalciferol D2): synthesised in skin from 7-dehydrocholesterol by UV-B irradiation. Activated by two hydroxylation steps: 25-hydroxylation in liver (25-OH-D, calcidiol — the major circulating form, measured clinically) → 1-alpha-hydroxylation in kidney (1,25-(OH)2-D, calcitriol — the active hormone). 1-alpha-hydroxylase is activated by PTH and low phosphate; inhibited by FGF-23. Calcitriol acts via VDR nuclear receptor: upregulates intestinal calcium and phosphate absorption (TRPV6, calbindin), promotes renal calcium reabsorption, and with PTH promotes bone resorption (osteoclast activation). Deficiency: rickets (children — softening and bowing of long bones, Harrison's sulcus, rachitic rosary), osteomalacia (adults — bone pain, proximal myopathy, pseudofractures). Causes: inadequate sunlight, dark skin, malabsorption, chronic kidney disease.

Vitamin E (tocopherols, especially alpha-tocopherol): major lipid-soluble antioxidant. Donates a hydrogen atom to lipid peroxyl radicals (ROO•), terminating chain reactions in membrane phospholipids. Regenerated by vitamin C. Transported in lipoproteins. Deficiency: rare — associated with fat malabsorption (abetalipoproteinaemia); causes haemolytic anaemia, peripheral neuropathy, and ataxia (spinocerebellar degeneration).

Vitamin K (phylloquinone K1 from plants, menaquinones K2 from bacteria): essential cofactor for gamma-glutamyl carboxylase, which carboxylates glutamate residues to gamma-carboxyglutamate (Gla) on coagulation factors II (prothrombin), VII, IX, X, protein C and protein S. Gla residues chelate Ca2+ and allow membrane binding essential for coagulation. Warfarin inhibits vitamin K epoxide reductase (VKOR), depleting active vitamin K and impairing coagulation factor synthesis. Deficiency causes bleeding; neonates receive prophylactic vitamin K to prevent haemorrhagic disease of the newborn (VKOR immature, gut bacteria not yet established).

Water-Soluble B Vitamins as Coenzymes

Vitamin B1 — Thiamine → Thiamine pyrophosphate (TPP): cofactor for pyruvate dehydrogenase complex (oxidative decarboxylation of pyruvate → acetyl-CoA), alpha-ketoglutarate dehydrogenase (TCA cycle), and transketolase (pentose phosphate pathway). Deficiency causes Wernicke encephalopathy (ophthalmoplegia, ataxia, confusion — due to impaired glucose metabolism in brain) progressing to Korsakoff psychosis; wet beriberi (high-output cardiac failure, peripheral oedema) and dry beriberi (peripheral polyneuropathy). Common in chronic alcoholism and malnutrition.

Vitamin B2 — Riboflavin → FAD and FMN: electron carriers accepting 2 electrons and 2 protons. FAD is the prosthetic group of Complex I (NADH dehydrogenase, actually FMN), succinate dehydrogenase (Complex II), acyl-CoA dehydrogenase (beta-oxidation), and many other oxidoreductases. FMN is the first electron acceptor in Complex I.

Vitamin B3 — Niacin (nicotinic acid) → NAD+ and NADP+: the most important electron carriers in metabolism. NAD+ accepts 2 electrons (as H−) to become NADH — function in catabolism (glycolysis, PDC, TCA cycle, beta-oxidation). NADP+/NADPH — function in anabolic reactions (fatty acid synthesis, cholesterol synthesis) and antioxidant defence (glutathione reductase, cytochrome P450 reactions). Each NADH yields ~2.5 ATP via oxidative phosphorylation. Can be synthesised from tryptophan (60 mg tryptophan → 1 mg niacin). Deficiency causes pellagra: dermatitis (photosensitive), diarrhoea, dementia (3 Ds) — classically in populations subsisting on maize without alkali treatment (niacin in maize is bound and unavailable). High-dose niacin inhibits hepatic VLDL secretion and raises HDL (used pharmacologically).

Vitamin B5 — Pantothenate → Coenzyme A (CoA-SH): CoA is the universal acyl group carrier, forming high-energy thioester bonds. Central to: pyruvate dehydrogenase (acetyl-CoA product), TCA cycle (acetyl-CoA entry, succinyl-CoA production), fatty acid synthesis (malonyl-CoA, acetyl-CoA), beta-oxidation (acyl-CoA intermediates), cholesterol synthesis, and acetylcholine synthesis. Deficiency is rare.

Vitamin B6 — Pyridoxine → Pyridoxal phosphate (PLP): cofactor for over 100 enzymes, primarily aminotransferases (transaminases) and decarboxylases. Functions: transamination (PLP forms Schiff bases with amino acid alpha-amino groups, transferring the amino group to alpha-ketoacids — critical for amino acid catabolism and gluconeogenesis), decarboxylation (DOPA decarboxylase: DOPA → dopamine; aromatic amino acid decarboxylase: 5-HTP → serotonin), glycogen phosphorylase (PLP is tightly bound prosthetic group). Deficiency: sideroblastic anaemia (impaired haem synthesis — ALA synthase requires PLP), peripheral neuropathy, seborrhoeic dermatitis. Isoniazid (TB treatment) is a PLP antagonist.

Vitamin B9 — Folate → Tetrahydrofolate (THF): one-carbon carrier in the forms methyl-THF, methylene-THF, formyl-THF, etc. Essential for: (1) Purine synthesis (C2 and C8 of the purine ring derived from formyl-THF); (2) Thymidylate synthesis (dUMP → dTMP via thymidylate synthase, using methylene-THF as one-carbon donor and reducing agent — methylene-THF is oxidised to DHF, regenerated to THF by dihydrofolate reductase, DHFR); (3) Methionine cycle (methyl-THF donates methyl group to homocysteine → methionine, catalysed by methionine synthase with B12 as cofactor). Methotrexate inhibits DHFR. Deficiency: megaloblastic (macrocytic) anaemia, neural tube defects (NTDs — spina bifida, anencephaly) in early pregnancy. Periconceptional folate supplementation (400 μg/day) reduces NTD risk by ~70%.

Vitamin B12 — Cobalamin → Adenosylcobalamin and Methylcobalamin: two active forms. (1) Methylcobalamin is cofactor for methionine synthase (methyl-THF + homocysteine → THF + methionine). B12 deficiency causes folate trap — methyl-THF cannot donate its methyl group without B12, so THF is not regenerated, impairing all one-carbon reactions including thymidylate synthesis. (2) Adenosylcobalamin is cofactor for methylmalonyl-CoA mutase (methylmalonyl-CoA → succinyl-CoA — essential for odd-chain fatty acid and branched-chain amino acid catabolism). B12 deficiency: megaloblastic anaemia (indistinguishable from folate deficiency), subacute combined degeneration of the spinal cord (posterior columns: proprioception and vibration; lateral corticospinal tracts: upper motor neurone signs), glossitis. Causes: pernicious anaemia (autoimmune loss of gastric parietal cells → no intrinsic factor (IF) → B12 not absorbed in terminal ileum), strict veganism, terminal ileal disease (Crohn's), gastrectomy. Biotin (B7): cofactor for carboxylase enzymes (pyruvate carboxylase, ACC, propionyl-CoA carboxylase) — biotin is covalently attached to the enzyme and carries CO2. Deficiency: raw egg white contains avidin (tight biotin binder); causes dermatitis and alopecia. Vitamin C (ascorbic acid): reducing agent — cofactor for prolyl and lysyl hydroxylases (collagen proline and lysine hydroxylation, essential for triple-helix stability and cross-linking), dopamine beta-hydroxylase (dopamine → norepinephrine). Regenerates vitamin E. Deficiency: scurvy — perifollicular haemorrhage, bleeding gums, corkscrew hairs, impaired wound healing, anaemia.