Biosynthesis of lovastatin analogs with a broadly specific acyltransferase.
The natural product lovastatin and its semisynthetic, more effective derivative, simvastatin, are important drugs for the treatment of hypercholesterolemia. Here, we report the biochemical characterization of a dedicated acyltransferase, LovD, encoded in the lovastatin biosynthetic pathway. We demonstrate that LovD has broad substrate specificity towards the acyl carrier, the acyl substrate, and the decalin acyl acceptor. LovD can efficiently catalyze the acyl transfer from coenzyme A thioesters or N-acetylcysteamine (SNAC) thioesters to monacolin J. When alpha-dimethylbutyryl-SNAC was used as the acyl donor, LovD was able to convert monacolin J and 6-hydroxyl-6-desmethylmonacolin J into simvastatin and huvastatin, respectively. Using the Escherichia coli LovD overexpression strain as a whole-cell biocatalyst, preparative amounts of simvastatin were synthesized in a single fermentation step. Our results demonstrate LovD is an attractive enzyme for engineered biosynthesis of pharmaceutically important cholesterol-lowering drugs.
Xie
Xinkai
X
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, 5531 Boelter Hall, 420 Westwood Plaza, Los Angeles, California 90095, USA.
Watanabe
Kenji
K
Wojcicki
Wladyslaw A
WA
Wang
Clay C C
CC
Tang
Yi
Y
D000214:Acyl Coenzyme A / Q000737:chemistry / Q000378:metabolism; D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism*; D000924:Anticholesteremic Agents; D001230:Aspergillus / Q000235:genetics; D002384:Catalysis; D004926:Escherichia coli / Q000378:metabolism; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D008148:Lovastatin / Q000031:analogs & derivatives / Q000096:biosynthesis*; D009154:Mutation; D019821:Simvastatin / Q000138:chemical synthesis; D013379:Substrate Specificity
D000214:Acyl Coenzyme A; D000924:Anticholesteremic Agents; D005656:Fungal Proteins; C024343:butyryl-coenzyme A; D008148:Lovastatin; D019821:Simvastatin; D000217:Acyltransferases