deoxyadenosylcobalamin

**Structure and forms:** Cobalamin has a corrin ring with a central cobalt atom. The two active coenzyme forms are (1) adenosylcobalamin (deoxyadenosylcobalamin), found in mitochondria, and (2) methylcobalamin, found in the cytosol. Dietary B12 comes from animal products. It is released from food by gastric acid and pepsin, bound by haptocorrin (R-binder) from saliva, then freed by pancreatic proteases and bound to intrinsic factor (from gastric parietal cells). The B12-intrinsic factor complex is absorbed in the terminal ileum. In blood, transcobalamin II carries B12 to tissues, and the liver stores it (several years' supply).

**Reaction (mitochondrial):** Odd-chain fatty acids, valine, isoleucine, methionine and threonine, and cholesterol side chain → propionyl-CoA → (propionyl-CoA carboxylase, needs biotin) → D-methylmalonyl-CoA → (methylmalonyl-CoA epimerase) → L-methylmalonyl-CoA → (**methylmalonyl-CoA mutase, needs adenosylcobalamin**) → succinyl-CoA → TCA cycle.

**Cytosolic counterpart:** Methylcobalamin is the cofactor for homocysteine methyltransferase (methionine synthase). It converts homocysteine + N5-methyl-THF to methionine + THF. Without it, folate is "trapped" as N5-methyl-THF (the methyl-folate trap), which impairs DNA synthesis and causes megaloblastic anemia.

**Clinical consequences of B12 deficiency:** - Megaloblastic (macrocytic) anemia with hypersegmented neutrophils, from impaired DNA synthesis (methyl-folate trap). - Neurologic findings, thought to come from the methylmalonyl-CoA mutase block. Abnormal (odd-chain) fatty acids accumulate and are incorporated into myelin. These include subacute combined degeneration (demyelination of the dorsal columns and lateral corticospinal tracts), with paresthesias, loss of vibration and proprioception, spastic paralysis, ataxia, and dementia. Neuropathy can occur without anemia, and folate supplementation can correct the anemia while the neurologic damage progresses. - Labs: ↑ homocysteine and ↑ methylmalonic acid (MMA). In folate deficiency, homocysteine is ↑ but MMA is normal. - Causes: pernicious anemia (autoimmune destruction of parietal cells or anti-intrinsic factor antibodies), strict veganism, *Diphyllobothrium latum* (fish tapeworm), terminal ileum disease (Crohn disease) or resection, gastrectomy, chronic pancreatic insufficiency, and metformin or PPI/H2-blocker use. - Treatment: IM or high-dose oral B12. Treat neurologic involvement promptly.

**Inherited disorders:** Methylmalonic acidemia is caused by a defect in methylmalonyl-CoA mutase or in adenosylcobalamin synthesis (cblA, cblB). It presents in infancy with vomiting, lethargy, metabolic acidosis, hyperammonemia, and failure to thrive. Treatment is a protein-restricted diet, and some patients respond to hydroxocobalamin.

**High-yield pearls:** - Adenosylcobalamin is used by one mammalian mutase (methylmalonyl-CoA mutase). Methylcobalamin is used by methionine synthase. - Both mammalian B12-dependent enzymes are tested: methylmalonyl-CoA mutase and homocysteine methyltransferase. - The Schilling test historically evaluated the cause of B12 malabsorption. - B12 is the only vitamin stored for years, so deficiency develops slowly (about 2–5 years).