Molybdenum is an essential trace element that is the cofactor for four enzymes in the human body — xanthine oxidase (XO), which catalyses the oxidation of the purines (hypoxanthine and xanthine) to uric acid; aldehyde oxidase (AO), which oxidises the aldehydes and the heterocycles; sulfite oxidase (SO), which oxidises the sulfite to sulfate in the final step of the cysteine catabolism; and the mitochondrial amidoxime reducing component (mARC), whose function is less well characterised but which is thought to be involved in the reduction of the N-oxides and of the nitroso compounds. The molybdenum cofactor (MoCo) is a complex of the molybdenum atom with a pterin molecule (called the molybdopterin), and it is synthesised by all living organisms and required for the function of all molybdenum-dependent enzymes. The molybdenum cofactor deficiency is a rare but severe genetic disorder that is characterised by the inability to synthesise the molybdenum cofactor and that produces a clinical syndrome that includes the severe neurological dysfunction (seizures, developmental delay, microcephaly), the dysmorphic features (facial dysmorphism, camptodactyly), and the elevated plasma and urine levels of the sulfur-containing amino acids (particularly the cysteine and the methionine) — because the sulfite oxidase component of the molybdenum cofactor deficiency prevents the oxidation of sulfite to sulfate in the final step of the cysteine catabolism.
Xanthine Oxidase and the Purine Catabolism
Xanthine oxidase (XO) is the enzyme that catalyses the oxidation of the hypoxanthine to xanthine and of the xanthine to uric acid — the final two steps of the purine catabolism pathway that degrades the purine nucleotides (AMP, GMP) to the uric acid that is excreted in the urine. The purine catabolism pathway is active in all tissues but is particularly important in the liver, where the majority of the uric acid is produced from the dietary purines and from the turnover of the endogenous purine nucleotides. The XO-catalysed oxidation of hypoxanthine and xanthine to uric acid generates the hydrogen peroxide (H2O2) as a byproduct, and this H2O2 is normally removed by the catalase and by the glutathione peroxidase systems. However, when the XO activity is very high (as it is in the conditions of the rapid cell turnover, the tissue injury, or the inflammatory response), the H2O2 production exceeds the capacity of the antioxidant systems, and the oxidative damage to the surrounding tissues occurs — this is the mechanism of the uric acid-induced tissue damage that is the hallmark of the gout and of the other hyperuricaemia syndromes.
The clinical importance of the XO-catalysed purine oxidation is underscored by the observation that the XO inhibitors (allopurinol and febuxostat) are the most effective treatments for the gout — they reduce the production of the uric acid by inhibiting the XO-catalysed oxidation of hypoxanthine and xanthine to uric acid, and thereby lower the blood uric acid levels, reduce the deposition of the monosodium urate crystals in the joints and the soft tissues, and prevent the acute gout attacks and the chronic tophaceous changes that are the clinical manifestations of the gout. The allopurinol and the febuxostat are among the most prescribed medications in the world (because the gout is one of the most common forms of inflammatory arthritis, affecting approximately 2-4% of the adult population in the Western world), and their efficacy is a direct reflection of the central role of the XO in the uric acid production.
Molybdenum Cofactor Deficiency
The molybdenum cofactor deficiency is a rare but severe autosomal recessive genetic disorder that is characterised by the inability to synthesise the molybdenum cofactor (MoCo) and that produces a clinical syndrome that is caused by the combined deficiency of all four molybdenum-dependent enzymes. The deficiency of the sulfite oxidase (SO) component of the MoCo deficiency is particularly severe — sulfite oxidase is the enzyme that catalyses the oxidation of sulfite (SO3 2-) to sulfate (SO4 2-) in the final step of the cysteine catabolism, and when it is deficient, the sulfite accumulates and produces severe neurological damage (including the seizures, the developmental delay, the microcephaly, and the lens dislocation) that is the hallmark of the MoCo deficiency syndrome. The treatment of the MoCo deficiency is supportive (there is no curative therapy) and includes the restriction of the sulfur-containing amino acids (cysteine and methionine) in the diet, the supplementation with the cysteine-reducing agents (such as N-acetylcysteine), and the management of the seizures with the anti-epileptic drugs.
Practical Application
For general molybdenum supplementation, the evidence-based approach is to consume a varied diet that includes the molybdenum-rich foods (whole grains, legumes, nuts, seeds, green leafy vegetables) — the RDA of molybdenum is 45mcg daily for adults, and the majority of the adult population achieves this intake from a varied diet. The supplementation of molybdenum is rarely necessary because the deficiency is extremely rare (it has only been described in a few dozen patients in the medical literature, all of whom had an underlying genetic disorder of the molybdenum cofactor synthesis). However, for people who are taking the XO inhibitors (allopurinol, febuxostat) for the management of the gout, the supplementation with the antioxidants (particularly the vitamin C, the vitamin E, and the NAC) is recommended to compensate for the reduced production of the H2O2 by the inhibited XO and to prevent the oxidative damage that is associated with the sudden reduction in the uric acid production. For comprehensive purine metabolism support, molybdenum pairs well with the vitamin C (which increases the renal excretion of the uric acid and which reduces the risk of the uric acid stone formation in the kidney), with the quercetin (which is a natural XO inhibitor that reduces the production of the uric acid and which has additional anti-inflammatory effects), and with the cherry extract (which has been shown to reduce the blood uric acid levels and to reduce the frequency of the gout attacks).
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