The living world contains a very large number of sulfur-containing molecules. In addition to the abundant cysteine and glutathione, there are secondary metabolites and cofactors such as biotin and lipoic acid, as well as nucleotides and acids modified within nucleic acids and proteins respectively. In fact, very little is known about the biosynthesis of these compounds, the players involved and the mechanisms for inserting sulfur atoms into their precursors. This is a highly controversial research topic.
In this lesson, the question is addressed on the basis of recent results obtained with the methylthio-transferases: MiaB and MtaB, which catalyze the selective incorporation of a SCH3 group in position 2 of the adenosine of transfer RNAs, and RimO, which catalyzes the incorporation of a SCH3 group on the side chain of an aspartate of a ribosomal protein, through the chemically difficult conversion of a C-H bond into a C-S bond. This enzyme family is characterized by the existence of two [4Fe-4S] clusters, one of which is typical of " Radical-SAM " proteins, serving to initiate reactions through the formation of a 5'-deoxyadenosyl radical used to activate substrates into radicals. The role of the second cluster is controversial, but recent observations, both mechanistic and structural, suggest that the sulfur co-substrate, of the sulfide or methyl-sulfide type, binds to one of the iron atoms of this cluster to better react with the intermediate radicals. It has also been shown that an MtaB homologue is present in humans. This is the product of the CDKAL1 gene, which is a susceptibility gene for type 2 diabetes. The discovery that CDKAL1 is involved in a modification of transfer RNAs, notably through the study of a KO mouse, has led to an understanding of the mechanisms by which diabetics with an inactive CDKAL1 enzyme suffer from a defect in insulin secretion.
