Molybdenum, Sulfite Oxidase Deficiency, and the Aldehyde Oxidase Family

This article is interesting and discusses some of the molybdopterin-cofactor-containing enzymes [Garattini et al., 2003: (http://www.biochemj.org/bj/372/0015/bj3720015.htm) (http://www.ncbi.nlm.nih.gov/pubmed/12578558?dopt=Citation)]. The most "important" molybdenum-containing enzyme is sulfite oxidase, a mitochondrial enzyme that converts sulfite into sulfate. Actually, that article mainly discusses the flavin-dependent molybdenum-containing enzymes and not so much sulfite oxidase. The phenotype of human, genetic sulfite oxidase deficiency (or generalized molybdenum cofactor deficiency) is very severe and causes all sorts of neurological problems. In humans getting total parenteral nutrition, molybdenum deficiency can cause neurological problems. A reduction in sulfite oxidase activity doesn't just cause sulfite accumulation but severely deranges sulfur-containing amino acid metabolism and can cause ahomocysteinemia (absence of homocysteine in the serum), can disrupt the sulfation of glycosaminoglycans, cause glutathione depletion by decreasing cysteine availability, etc. Some humans with genetically-based sulfite oxidase deficiency have mental retardation, and so it's a fairly vital enzyme.

Xanthine oxidoreductase also contains the molybdopterin cofactor, but that enzyme can function in a molybdopterin-depleted state (with not all subunits occupied by molybdopterin cofactors or something). Aldehyde oxidase can also act as an alternative, stopgap measure for metabolizing aldehydes that can't be disposed of by normal pathways. That's one area of intersection with the propionate pathway, with methylmalonate semaldehyde dehydrogenase. I think that aldehyde oxidases can accept a fairly wide variety of substrates, etc. I don't think there's much to be done with molybdenum, but it can theoretically deplete copper from the body. But I doubt that occurs under normal levels of intake. I think the upper range that's been tested in humans is up to like 1,000 micrograms/d, but there's very low toxicity. I think the European Union Commission did a toxicological assessment and found extremely low toxicity but assigned an upper limit of 600 micrograms/d for humans. It's much, much less toxic than something like copper or, arguably, even zinc, in terms of supplementation (if one compares the dosages in supplements and the ranges of dosages people discuss). There is a good amount of research on molybdenum in nutrition, and I have a dozen articles, or so, on it in relation to nutrition. It's clearly essential, because the molybdenum cofactor is a fairly elaborate organic structure, requiring multiple enzymatic steps to synthesize, and is like a primitive version of heme. Incidentally, one of the enzymes involved in molybdopterin biosynthesis is a radical SAM enzyme, which is a really primitive class of enzymes that uses S-adenosylmethionine as a cofactor for some kind of strange reaction and produces 5'-deoxyadenosine as a product. There are theoretically many radical SAM enzymes that haven't been identified. One article I read was discussing the fact that vast numbers of unidentified enzymes in the human genome appeared to be methyltransferases and have sequences consistent with their being methyltransferases. The numbers of enzymes that use SAM-e as a cofactor, including the radical SAM and methyltransferase family, could be very large, and the activities of radical SAM enzymes would seriously derange the computational models for homocysteine and folate metabolism. 5'-deoxyadenosine is an inhibitor of S-adenosylhomocysteine hydrolase and ribonucleotide reductase, and then you have the molybdopterin-induced increases in homocysteine production, mediated by increases in sulfite oxidase activity, etc. The current models only take into account the SAM-e/S-adenosylhomocysteine ratio, not the SAM-e/5'-deoxyadenosine ratio.