Vitamin B12 (Cyanocobalamin).

Methionine synthase transfers a methyl group from 5-methyltetrahydrofolate through cobalamin to homocysteine, so both cofactors act in one reaction. When B12 is short the folate pool stalls in its methyl form.

Folate carries the one-carbon unit and cobalamin accepts it, so the cycle needs both. The pairing is standard for normal red cell formation and normal homocysteine metabolism.

B12 and folate return homocysteine to methionine, while pyridoxal-5-phosphate lets it leave down the cysteine branch. Covering both arms keeps flux from backing up in either.

Methionine synthase reductase and MTHFR are flavoenzymes, so riboflavin keeps cobalamin reduced and keeps methylfolate available. Low riboflavin slows the B12 reaction from both sides.

Betaine remethylates homocysteine through BHMT without folate or cobalamin, giving the cycle a second lane. It eases load on the B12-dependent route.

Cyanocobalamin must be converted into methylcobalamin for the cytosolic reaction and adenosylcobalamin for the mitochondrial mutase. Supplying the adenosyl form covers that arm without relying on conversion.

The cyanide ligand has to be removed reductively, a step that draws on cellular thiols including glutathione, before the active coenzyme forms can be built. This applies to the cyano form specifically.

The intrinsic factor and B12 complex binds its ileal cubilin receptor in a calcium-dependent manner. Adequate calcium serves the absorption step.

High ascorbate concentrations degrade cobalamins in aqueous solution into inactive analogues. Separating a large vitamin C dose in time avoids the interaction.

Iron supplies the haem while B12 and folate supply one-carbon units for DNA synthesis in dividing precursors. Any one of the three running low limits the same process.

When a marked B12 shortfall is corrected quickly, red cell production restarts and dividing cells pull potassium out of the extracellular space, so serum potassium can fall in the first days of repletion. This is a well-recognised effect that clinicians monitor for during aggressive repletion, not something that happens at ordinary maintenance intakes. It is included because the direction of the interaction is worth knowing, and it is a plasma electrolyte measure rather than a clinical outcome.

Cobalamin is named for the cobalt ion held at the centre of its corrin ring, and that cobalt is where the chemistry happens: it cycles through three oxidation states and carries the methyl or adenosyl group in the upper axial position. Cobalt appears in the co-study record with B12 for this structural reason. Supplemental inorganic cobalt is not a B12 substitute, because only microorganisms can build the corrin ring around it.

Methionine synthase uses methylcobalamin to move a methyl group from folate onto homocysteine, producing methionine. B12 status therefore sets the rate at which methionine is regenerated, and a B12 shortfall traps folate in its methyl form. This is settled one-carbon biochemistry; the readouts used to detect it, plasma homocysteine and methylmalonic acid, are markers.

Food-bound B12 has to be freed from its protein carriers by gastric acid and pepsin before intrinsic factor can bind it in the small intestine. Where gastric acid output is low, that release step is the bottleneck rather than the amount of B12 eaten. Crystalline cyanocobalamin in a supplement is already free, which is why the acid dependence applies mainly to B12 from food.

Pepsin, working at low gastric pH, is the protease that cleaves B12 free of the food proteins holding it. Without that proteolysis the vitamin never reaches intrinsic factor. The relationship is established digestive physiology and applies to dietary B12 rather than to the free crystalline form used in supplements.

Adenosylcobalamin is the cofactor for methylmalonyl-CoA mutase, the step that lets propionyl-CoA from odd-chain fatty acids and branched-chain amino acids enter the citric acid cycle. Carnitine handles the transport side of the same fatty acid traffic and buffers acyl-CoA build-up as acylcarnitines. The two sit on the same route, and acylcarnitine and methylmalonic acid profiles are the markers used to read it.

Homocysteine can be remethylated either by the B12-dependent methionine synthase route or by betaine, which comes from choline oxidation, through betaine-homocysteine methyltransferase. The betaine route needs no B12. Adequate choline therefore provides a parallel path for methyl group transfer, which is established one-carbon wiring rather than a substitute for B12's other role in methylmalonyl-CoA mutase.

Glycine N-methyltransferase consumes excess S-adenosylmethionine by methylating glycine to sarcosine, which is how a cell dumps surplus methyl capacity. That sits directly downstream of the methionine that B12-dependent methionine synthase regenerates. The link is a pathway relationship read from established biochemistry, not a tested pairing.

The final step of endogenous creatine synthesis is a methyl transfer from S-adenosylmethionine, and it is one of the larger single consumers of methyl groups in the body. Supplying creatine directly reduces that demand, which is the mechanistic basis for the observation that creatine intake and one-carbon markers move together. What has been measured is plasma homocysteine and related markers, not an outcome.