Crystal structure and biochemical studies of the trans-acting polyketide enoyl reductase LovC from lovastatin biosynthesis.
Lovastatin is an important statin prescribed for the treatment and prevention of cardiovascular diseases. Biosynthesis of lovastatin uses an iterative type I polyketide synthase (PKS). LovC is a trans-acting enoyl reductase (ER) that specifically reduces three out of eight possible polyketide intermediates during lovastatin biosynthesis. Such trans-acting ERs have been reported across a variety of other fungal PKS enzymes as a strategy in nature to diversify polyketides. How LovC achieves such specificity is unknown. The 1.9-Å structure of LovC reveals that LovC possesses a medium-chain dehydrogenase/reductase (MDR) fold with a unique monomeric assembly. Two LovC cocrystal structures and enzymological studies help elucidate the molecular basis of LovC specificity, define stereochemistry, and identify active-site residues. Sequence alignment indicates a general applicability to trans-acting ERs of fungal PKSs, as well as their potential application to directing biosynthesis.
Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA.
Brian D
BD
Ames
Chi
C
Nguyen
Joel
J
Bruegger
Peter
P
Smith
Wei
W
Xu
Suzanne
S
Ma
Emily
E
Wong
Steven
S
Wong
Xinkai
X
Xie
Jesse W-H
JW
Li
John C
JC
Vederas
Yi
Y
Tang
Shiou-Chuan
SC
Tsai
D001230:Aspergillus / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy; D041022:Candida tropicalis / Q000378:metabolism; D020134:Catalytic Domain; D002850:Chromatography, Gel; D018360:Crystallography, X-Ray / Q000379:methods; D006801:Humans; D008148:Lovastatin / Q000096:biosynthesis* / Q000737:chemistry; D008968:Molecular Conformation; D009154:Mutation; D009249:NADP / Q000737:chemistry; D048630:Polyketide Synthases / Q000737:chemistry*; D011487:Protein Conformation; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D055672:Static Electricity; D013237:Stereoisomerism; D013379:Substrate Specificity; D015533:Transcriptional Activation
D009249:NADP; D048630:Polyketide Synthases; D008148:Lovastatin