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. The mechanism by which sulfur is incorporated into the furanose ring in albomycins—a group of natural nucleoside antibiotics—remains unclear. Now, this work explains how twitch radical S-adenosyl-l-methionine enzyme AbmM catalyses sulfur-for-oxygen replacement in the biosynthesis of albomycin δ2.