Folates, Vitamin B12, Vitamin B6, Frataxin, and Iron-Sulfur Cluster Biosynthesis

The authors of this article [Tan et al., 2003: (http://hmg.oxfordjournals.org/cgi/content/full/12/14/1699) (http://www.ncbi.nlm.nih.gov/pubmed/12837693)] discuss the role that serine hydroxymethyltransferase activity may play in iron-sulfur cluster biosynthesis. The paper is sort of theoretical, but there are other articles that lend considerable credence to the hypotheses that Tan et al. (2003) offer. Tan et al. (2003) discuss the different explanations for the function of frataxin, a mitochondrial protein whose loss of function, due to genetic mutations, produces Friedrich's ataxia. Frataxin appears to transport iron in a way that allows iron-sulfur (Fe/S) clusters, which are cube-like, "scaffolded" cofactors, containing iron bound to sulfur atoms, for mitochondrial proteins, to be synthesized normally. Tan et al. (2003) discuss the way SHMT can maintain serine availability, and serine is a substrate for more than one of the enzymatic transsulfuration reactions, which are dependent on pyridoxal-5'-phosphate, derived from vitamin B6 (pyridoxine), that produce cysteine. So maintaining cysteine availability or even, potentially, the chaperoning of cysteine, appears to be necessary for the biosynthesis of Fe/S clusters.

When Fe/S clusters are not formed properly, the result is basically mitochondrial dysfunction in the tissue that's affected. There's lactic acidosis and skeletal or cardiac muscle myopathies, etc. It's interesting that heavy-chain ferritin can increase cytosolic SHMT (cSHMT) expression. The articles that discuss iron and zinc in relation to SHMT expression discussed the phenomenon in terms of nucleotide availability and DNA replication, but it's possible that increases in the intracellular heavy-chain and light-chain ferritin contents or in the labile iron pool (mobile, exchangeable iron) increase cysteine availability for Fe/S cluster biosynthesis by increasing cSHMT expression and protein content. I know there are more articles discussing transsulfuration as basically a way of maintaining cysteine availability and as not really being "about" homocysteine "disposal." But the interactions of iron metabolism with cSHMT and mtSHMT activities is really interesting, and reduced folates, vitamin B12 (methylcobalamin), and pyridoxine are all, directly or indirectly, required for mtSHMT and cSHMT activities and for the cycling of substrates between those enzymes. It's conceivable that this role of SHMT activity in Fe/S cluster biosynthesis helps explain the relief of restless legs syndrome by high doses of folates, given that reductions in iron availability to, or "acquisition" by, the brain (in particular, different groups of dopaminergic neurons) is a major factor that is thought to underlie some cases of restless legs syndrome.