Cobalt is a transition metal that is the essential component of the vitamin B12 (cobalamin) molecule — every molecule of cobalamin contains one atom of cobalt at its centre, and it is this cobalt atom that gives the cobalamin its unique structure and its unique biological activity. The cobalamin is the largest and the most complex of all the vitamins — it is synthesised only by certain bacteria (not by plants or animals), and it must be obtained from the diet, primarily from the animal products (meat, fish, poultry, eggs, dairy products) that contain the cobalamin that is produced by the gut bacteria of the animals. The cobalt atom in the centre of the cobalamin molecule is coordinated to four nitrogen atoms of the porphyrin-like ring system (the corrin ring), and it is this cobalt-corrin structure that distinguishes the cobalamin from all other vitamins and that gives it its unique ability to participate in only two enzymatic reactions in the human body — the methylation of the homocysteine to the methionine by the methionine synthase (which uses methylcobalamin as a cofactor) and the isomerisation of the methylmalonyl-CoA to the succinyl-CoA by the methylmalonyl-CoA mutase (which uses adenosylcobalamin as a cofactor). These two cobalt-dependent reactions are the foundation of the one-carbon metabolism and of the propionate metabolism, and their impairment by the cobalt deficiency (which manifests as the vitamin B12 deficiency) produces the megaloblastic anaemia and the subacute combined degeneration of the spinal cord that are the clinical hallmarks of the vitamin B12 deficiency.
The Cobalamin and the Methylmalonyl-CoA Mutase Reaction
The methylmalonyl-CoA mutase (MCMut) is the only enzyme in the human body that uses adenosylcobalamin as a cofactor — it catalyses the isomerisation of the methylmalonyl-CoA to the succinyl-CoA, which is the final step in the metabolism of the odd-chain fatty acids (which generate propionyl-CoA upon beta-oxidation) and of the branch-chain amino acids (isoleucine, valine, methionine, threonine, which also generate propionyl-CoA upon catabolism). The MCMut reaction is essential for the propionate metabolism — without the adenosylcobalamin and the functional MCMut, the methylmalonyl-CoA accumulates, the propionate metabolism is disrupted, and the odd-chain fatty acids and the branch-chain amino acids cannot be fully metabolised. The neurological manifestations of the vitamin B12 deficiency (including the subacute combined degeneration of the spinal cord, the peripheral neuropathy, and the cognitive impairment) are thought to result in part from the accumulation of the methylmalonyl-CoA and from the resulting impairment of the myelin synthesis, which requires the normal fatty acid metabolism for the formation of the myelin lipid bilayer.
The clinical importance of the cobalt-dependent MCMut reaction for the neurological function is underscored by the observation that the neurological manifestations of the vitamin B12 deficiency are not corrected by the folic acid supplementation — even though the folic acid can correct the megaloblastic anaemia that is associated with the vitamin B12 deficiency, it cannot correct the neurological damage, because the cobalt-dependent MCMut reaction is impaired regardless of the folate status. This is one of the most important clinical principles in nutritional medicine — the folic acid should never be used as a substitute for the vitamin B12 in the treatment of the megaloblastic anaemia, because it corrects the anaemia but accelerates the neurological damage.
Cobalt Deficiency and the Vitamin B12 Deficiency
The cobalt deficiency is indistinguishable from the vitamin B12 deficiency in clinical practice — the body stores of cobalt are primarily in the form of the cobalamin, and the cobalt that is not incorporated into the cobalamin is present in trace amounts that are not clinically significant. The cobalt deficiency is therefore defined operationally as the vitamin B12 deficiency, and it is treated with the cobalamin supplementation. The dietary sources of cobalt (and therefore of vitamin B12) are primarily the animal products — the meat, the fish, the poultry, the eggs, and the dairy products contain the cobalamin that is synthesised by the gut bacteria of the animals and that is absorbed in the terminal ileum after binding to the intrinsic factor (IF, a glycoprotein that is secreted by the parietal cells of the stomach). The vegan diet is therefore a risk factor for the vitamin B12 deficiency (and for the cobalt deficiency), and the vegans should supplement with the cobalamin at 25-100mcg daily (as the cyanocobalamin, the methylcobalamin, or the hydroxocobalamin form) to ensure an adequate intake of this essential cobalt-containing vitamin.
Practical Application
For general cobalt and vitamin B12 supplementation, the evidence-based approach is to supplement with 25-100mcg of vitamin B12 daily (as cyanocobalamin, methylcobalamin, or hydroxocobalamin — the three most common supplemental forms), which is approximately the RDA of 2.4mcg daily for adults. The large dose of the B12 supplement (which is 10-40 times the RDA) is required because the B12 is absorbed by the passive diffusion (rather than by the IF-dependent absorption) when it is present in the high concentrations — the IF-dependent absorption accounts for only 1-2mcg of the B12 per dose, and the remainder is absorbed by the passive diffusion. For people who are at risk of the vitamin B12 deficiency (including the vegans, the older adults with the atrophic gastritis, the people with the pernicious anaemia, and the people who have had the gastric surgery), the B12 supplementation at 500-1,000mcg daily is recommended. For comprehensive haematological and neurological support, cobalt and B12 pair well with the folate (which is required for the methylation of the homocysteine to the methionine and for the synthesis of the purine nucleotides), with the iron (which is required for the haemoglobin synthesis and whose deficiency produces the microcytic anaemia that is distinct from the megaloblastic anaemia of the B12 deficiency), and with the thiamine (which is required for the normal function of the nervous system and whose deficiency produces the Wernicke-Korsakoff syndrome).
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