Bifunctional acyltransferase/decarboxylase LnmK as the missing link for beta-alkylation in polyketide biosynthesis.
Beta-alkylations contribute to the vast structural diversity displayed by polyketide natural products. A unified pathway has been proposed for introduction of both beta-methyl and beta-ethyl branches catalyzed by hydroxymethylglutaryl-CoA synthase homologues that utilize acetyl- or propionyl-S-acyl carrier protein (ACP) as a substrate. While the origin of acetyl-S-ACP has been established, that of propionyl-S-ACP remains unknown. Here we report the characterization of LnmK from the leinamycin biosynthetic machinery as a bifunctional acyltransferase/decarboxylase (AT/DC) that derives propionyl-S-ACP from methylmalonyl-CoA, accounting for the missing link of the beta-ethyl or propionyl branch in polyketide biosynthesis. LnmK represents an emerging family of novel AT/DC enzymes and could be exploited by combinatorial biosynthesis methods to engineer novel polyketides, especially those with beta-alkyl branches.
Liu
Tao
T
Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53705-2222, USA.
Huang
Yong
Y
Shen
Ben
B
D000217:Acyltransferases / Q000378:metabolism*; D000478:Alkylation; D002262:Carboxy-Lyases / Q000378:metabolism*; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000378:metabolism; D007769:Lactams / Q000378:metabolism*; D018942:Macrolides / Q000378:metabolism*; D013844:Thiazoles / Q000378:metabolism*; D013871:Thiones / Q000378:metabolism*
D007769:Lactams; D018942:Macrolides; D013844:Thiazoles; D013871:Thiones; C059000:leinamycin; D000217:Acyltransferases; D006904:Hydroxymethylglutaryl-CoA Synthase; D002262:Carboxy-Lyases