Vitamin B12 (Cobalamin)

Mechanism

1. Synthesis of Methionine (Cytosol)

The enzyme methionine synthase requires methylcobalamin as a cofactor to transfer a methyl group from N5-methyl-THF to homocysteine, regenerating cellular methionine. If B12 decreases, folate becomes trapped as inactive N5-methyl-THF (the "folate trap"), preventing DNA synthesis:

2. Isomerization of Methylmalonyl-CoA to Succinyl-CoA (Mitochondria)

The mitochondrial enzyme methylmalonyl-CoA mutase requires 5-deoxyadenylcobalamin to convert methylmalonyl-CoA derived from the catabolism of odd-chain fatty acids and amino acids into succinyl-CoA, a direct substrate of the Krebs cycle. In its absence, accumulated methylmalonic acid (MMA) alters the myelin sheath of neuronal axons:

Subacute Combined Degeneration of the Spinal Cord

Severe and prolonged deficiency of vitamin B12 induces progressive demyelination of the posterior and lateral cords of the spinal cord. Clinically it is manifested by loss of vibratory sensitivity, distal paresthesias, progressive sensory ataxia and bilateral Babinski sign. Alert: Correcting megaloblastic deficiency using only folic acid may mask hematological B12 deficiency, but catastrophically accelerates irreversible neurological degeneration.

Pharmacokinetics

Gastrointestinal absorption mechanism

Due to its large molecular volume and water solubility, cobalamin requires a multiphase gastrointestinal transport system:

ACID GASTRIC MEDIUM Release and Binding to Haptocorrin

The ingested cobalamin binds to the proteins of the bolus. In the stomach, acid secretion (HCl) and pepsin release cobalamin, which associates with haptocorrin (R protein) secreted by the salivary glands to protect the vitamin from the corrosive stomach environment.

DUODENAL FRONT Emergence of the Complex with the Intrinsic Factor (IF)

In the alkaline duodenum, pancreatic proteases hydrolyze haptocorrin, releasing cobalamin. This immediately binds to Intrinsic Factor (IF), a glycoprotein secreted by the gastric parietal cells of the gastric body and fundus.

TERMINAL ILEUM Cubilin Receptor-Mediated Absorption

The cobalamin-FI dimer travels intact to the terminal ileum, where the soluble domain binds to cubilin, a specific cell membrane receptor that mediates endocytosis of the complex. In the enterocyte, the vitamin is released and binds to Transcobalamin II (TC-II) to be exported to the bloodstream.

Metabolic functions of cobalamin

Cobalamin acts as a coenzyme only in two fundamental metabolic reactions within the human body:

Indicators and dose

Clinical Indications and Dosage

Treatment of Pernicious Anemia (autoimmune destruction of parietal cells with absence of IF), post-gastrectomy states, ileal resection or strict non-supplemented vegetarian diet.

In the absence of intrinsic factor, the oral route is ineffective at standard doses. 1000 µg of deep intramuscular cyanocobalamin is prescribed in an induction regimen (daily for a week, then weekly for a month) and a maintenance dose of 1000 µg monthly for life indefinitely.