Studies of lincosamide formation complete the biosynthetic pathway for lincomycin A

Abstract

Significance Lincomycin A is an antibiotic used clinically in the treatment of Gram-positive bacterial infections. Its biosynthesis has attracted much attention due to its unique sulfur-containing thiooctose core. Despite significant progress in our understanding of lincomycin biosynthesis, the mechanism by which GDP-ᴅ- erythro -α-ᴅ- gluco -octose maturates to GDP-ᴅ-α-ᴅ-lincosamide remains obscure. Herein, the long-sought missing link is established to consist of two epimerizations: a 6,8-dehydration and a transamination reaction catalyzed by four enzymes. Furthermore, unlike other epimerases that function regiospecifically, a single enzyme is found to catalyze epimerization at two different loci. Also, the dehydration is shown to be an α,γ-dehydration catalyzed by two enzymes. This study thus completes the description of the lincomycin biosynthetic pathway and highlights the complex mechanistic subtleties of unusual sugar biosynthesis.