Cobalt is an essential trace mineral that is the central atom of the vitamin B12 (cobalamin) molecule — the vitamin B12 is the only vitamin that contains a cobalt atom, and this cobalt atom is essential for the chemical reactions that B12 catalyzes as a coenzyme. The vitamin B12 is an essential cofactor for two enzymes in the human body — the methionine synthase (which catalyzes the remethylation of the homocysteine to the methionine and which is the final step in the methylation cycle) and the methylmalonyl-CoA mutase (which catalyzes the isomerisation of the methylmalonyl-CoA to the succinyl-CoA and which is the final step in the odd-chain fatty acid and the valine metabolism). Without adequate cobalt and functional B12, both of these enzymes are impaired, the methylation cycle is disrupted (producing the elevated homocysteine and the impaired methylation of the DNA, the proteins, and the neurotransmitters), the odd-chain fatty acid metabolism is impaired (producing the elevated methylmalonic acid and the odd-chain fatty acid accumulation), and the haematological, neurological, and psychiatric manifestations of the B12 deficiency develop — including the megaloblastic anaemia, the subacute combined degeneration of the spinal cord, the peripheral neuropathy, the cognitive impairment, and the depression that are the hallmark of the B12 deficiency. The typical dietary cobalt intake is 5-50mcg daily (from the animal products — meat, fish, eggs, dairy — which contain the B12 in the cobalt-containing form), and the estimated safe and adequate intake is 2.4mcg daily for adults (as B12).
Cobalt and the Methionine Synthase Reaction
The methionine synthase (MS) is the enzyme that catalyzes the remethylation of the homocysteine to the methionine — it requires the methylcobalamin (the methyl form of B12) as a cofactor, and it uses the methyl group from the 5-methyltetrahydrofolate to methylate the homocysteine, forming the methionine and the tetrahydrofolate. This reaction is the only reaction in the human body that uses the methylcobalamin as a cofactor, and it is the only pathway for the disposal of the excess homocysteine (apart from the transsulfuration pathway, which requires the vitamin B6). Without adequate B12 and functional MS, the homocysteine accumulates in the blood (hyperhomocysteinaemia), the methionine synthesis is impaired, the methylation cycle is disrupted, and the DNA methylation, the protein methylation, and the neurotransmitter methylation are all compromised. This B12-dependent disruption of the methylation cycle is one of the most important mechanisms of the neuropsychiatric manifestations of the B12 deficiency — including the cognitive impairment, the depression, the dementia, and the peripheral neuropathy.
The clinical importance of the cobalt (as B12) for the methylation cycle is underscored by the observation that the B12 deficiency is associated with the elevated homocysteine and with the neuropsychiatric disorders that are the hallmark of the methylation cycle disruption. The B12 deficiency is common (particularly in the elderly, in the vegans, and in people with the malabsorption syndromes), and it is one of the most treatable causes of the dementia and of the depression — the B12 supplementation (at 500-1000mcg of cyanocobalamin or methylcobalamin daily) can reverse the cognitive impairment and the depression in people with the B12 deficiency, particularly when the deficiency is identified and treated early, before the neurological damage becomes irreversible.
Cobalt and the Methylmalonyl-CoA Mutase Reaction
The methylmalonyl-CoA mutase (MCM) is the enzyme that catalyzes the isomerisation of the methylmalonyl-CoA to the succinyl-CoA — it requires the adenosylcobalamin (the adenosyl form of B12) as a cofactor, and it is the only enzyme in the human body that uses the adenosylcobalamin as a cofactor. This reaction is the final step in the metabolism of the odd-chain fatty acids (which yield the propionyl-CoA, which is then carboxylated to the methylmalonyl-CoA, which is then isomerised to the succinyl-CoA by the MCM), and of the branched-chain amino acid valine. Without adequate B12 and functional MCM, the methylmalonic acid accumulates in the blood and the urine (methylmalonic acidaemia), the odd-chain fatty acids accumulate in the tissues, and the neurological damage develops — particularly in the spinal cord, where the demyelination of the posterior and lateral columns (the subacute combined degeneration) produces the ataxia, the spasticity, and the peripheral neuropathy that are the most characteristic neurological manifestations of the B12 deficiency.
Practical Application
For general B12 supplementation, the evidence-based approach is to supplement with 500-1000mcg of methylcobalamin or cyanocobalamin daily (as the sublingual form, which is better absorbed than the oral form, particularly in older adults who may have impaired intrinsic factor production). The RDA of B12 is 2.4mcg daily for adults, but the therapeutic doses for the B12 deficiency are much higher (500-1000mcg daily) because the B12 absorption is inefficient (only 1-2% of the oral B12 is absorbed in the absence of the intrinsic factor). For comprehensive methylation and neurological support, B12 pairs well with the folate (as 5-MTHF at 400-800mcg daily, which provides the methyl donor for the methionine synthase reaction), with the vitamin B6 (which is required for the transsulfuration pathway that disposes of the excess homocysteine by converting it to cysteine), with the magnesium (which is a cofactor for the methionine synthase and for many of the other enzymes of the methylation cycle), and with the betaine (which is an alternative methyl donor for the remethylation of the homocysteine to methionine).
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