Melithiazol Biosynthesis: Further Insights into Myxobacterial PKS/NRPS Systems and Evidence for a New Subclass of Methyl Transferases Original Research Article

A DNA region of 41.847 base pairs from Melittangium lichenicola Me l46 is shown to be responsible for the biosynthesis of the potent electron transport inhibitor melithiazol. Melithiazol is formed by a combined polyketide synthase/peptide synthetase system resembling the myxothiazol megasynthetase from Stigmatella aurantiaca DW4/3-1. Both natural products share an almost identical core region but employ different starter molecules. Additionally, melithiazol contains a terminal methyl ester instead of the amide moiety found in myxothiazol. Similar to myxothiazol formation, the methyl ester is formed via an amide intermediate, which is converted by a hydrolase and an unusual type of SAM (S-adenosyl-L-methionine)-dependent methyltransferase into the methyl ester. When transferred into the myxothiazol A (amide) producer, these two genes lead to the formation of the methyl ester of myxothiazol. The methyl transferase described is a member of a protein subfamily of a previously unknown function lacking a typical SAM binding motif.