Radical S-adenosyl-l-methionine FeS cluster implicated as the sulfur donor during albomycin biosynthesis

Carbon-sulfur bond-forming reactions in natural product biosynthesis largely involve Lewis acid/base chemistry with relatively few examples catalysed by radical S-adenosyl-l-methionine (SAM) enzymes. The latter have been limited to radical-mediated sulfur insertion into carbon-hydrogen bonds with the sulfur atom originating from a sacrificial auxiliary iron-sulfur cluster. Here we show that the radical SAM enzyme AbmM encoded in the albomycin biosynthetic gene cluster catalyses a sulfur-for-oxygen swapping reaction, transforming the furanose ring of cytidine 5'-diphosphate to a thiofuranose moiety that is essential for the antibacterial activity of albomycin δ₂. Thus, in addition to its canonical function of mediating the reductive cleavage of SAM, the radical SAM catalytic cluster of AbmM appears to play a role in providing the sulfur introduced during the AbmM-catalysed reaction. These discoveries not only establish the origin of the thiofuranose core in albomycin δ₂ but, more importantly, also emphasize the functional diversity of radical SAM catalysis.