Molybdenum is an essential trace mineral that is the cofactor for four enzymes in the human body — sulfite oxidase (which oxidises the sulfite to sulfate, the final step in the metabolism of the sulfur-containing amino acids cysteine and methionine), xanthine oxidase (which oxidises the hypoxanthine and the xanthine to uric acid, the final step in the purine metabolism), aldehyde oxidase (which oxidises the aldehydes to carboxylic acids), and mitochondrial amidoxime reducing component (mARC, whose substrate is not yet characterised but which is thought to be involved in the metabolism of the N-oxides and of the nitrosylated compounds). Of these four molybdenum-dependent enzymes, the sulfite oxidase is the most clinically significant — it is the only known user of the sulfite in the human body, and it is the enzyme that is responsible for the detoxification of the sulfite that is generated as a byproduct of the metabolism of the sulfur-containing amino acids. Without adequate molybdenum and functional sulfite oxidase, the sulfite accumulates in the tissues, the sulfite toxicity develops, and the neurological damage, the cataracts, and the developmental delay occur — the hallmark of the molybdenum deficiency. The typical dietary molybdenum intake is 50-100mcg daily (from legumes, grains, nuts, and dark leafy vegetables), and the estimated safe and adequate intake is 45-75mcg daily for adults — the molybdenum deficiency is extremely rare in the general population, but it can occur in people with the severe malnutrition, with the malabsorption syndromes, and with the genetic disorders of the molybdenum cofactor synthesis.
Sulfite Oxidase and the Sulfite Metabolism
The sulfite oxidase (SO) is the enzyme that catalyses the oxidation of the sulfite (SO3(2-)) to the sulfate (SO4(2-)) in the final step of the metabolism of the sulfur-containing amino acids — the sulfite is generated as a byproduct of the catabolism of the cysteine (via the cysteine sulfinic acid pathway) and of the methionine (via the S-adenosylmethionine pathway), and it must be rapidly oxidised to the sulfate to prevent the accumulation of the toxic sulfite. The SO is a homodimeric enzyme that is located in the intermembrane space of the mitochondria, and it contains a molybdenum cofactor (MoCo) and a heme group — the MoCo is the site of the sulfite oxidation, and the heme group is involved in the electron transfer to the cytochrome c. Without adequate molybdenum and functional SO, the sulfite accumulates in the tissues (particularly in the brain, the eyes, and the liver), and it produces the neurotoxicity (by inhibiting the glutamate transporters and by promoting the oxidative stress), the lens opacification (by reacting with the lens proteins to form the sulfite-protein adducts that disrupt the lens transparency), and the hepatotoxicity (by inhibiting the cytochrome P450 enzymes and by promoting the oxidative stress in the liver) that are the hallmark of the sulfite toxicity.
The clinical importance of the molybdenum for the SO function is underscored by the observation that the molybdenum cofactor deficiency (Moco deficiency) produces a severe clinical syndrome that includes the intractable seizures, the developmental delay, the ectopia lentis (lens dislocation), the encephalopathy, and the early death — all of which are the direct result of the sulfite accumulation and the sulfite toxicity. The Moco deficiency is one of the most severe inborn errors of metabolism — it is caused by the genetic mutations in the genes that are required for the synthesis of the molybdenum cofactor (the MOCS1, MOCS2, and GPRN genes) and it is characterised by the complete absence of the activity of all four molybdenum-dependent enzymes. The treatment of the Moco deficiency is the dietary restriction of the sulfur-containing amino acids (to reduce the sulfite production) and the supplementation with the high-dose molybdenum (to maximise the residual SO activity) — but the prognosis remains poor, and most affected children do not survive beyond early childhood.
Practical Application
For general molybdenum supplementation, the evidence-based approach is to supplement with 45-100mcg of molybdenum daily (as molybdenum picolinate or sodium molybdate — the forms that are well absorbed and well tolerated). Most people achieve adequate molybdenum from a varied diet — molybdenum is found in legumes (especially lentils and chickpeas), grains, nuts, and dark leafy vegetables. The RDA of molybdenum has not been established (because the molybdenum deficiency is so rare), but the estimated safe and adequate intake is 45mcg daily for adults (which is easily achieved from a typical diet). For comprehensive sulfur amino acid metabolism support, molybdenum pairs well with the vitamin B6 (which is required for the transsulfuration pathway that converts the homocysteine to cysteine), with the folate (which is required for the remethylation of the homocysteine to methionine), with the vitamin B12 (which is required for the methionine synthase reaction), and with the magnesium (which is a cofactor for many of the enzymes of the sulfur amino acid metabolism).
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