Journal
SCIENCE
Volume 326, Issue 5952, Pages 589-592Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1175602
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Funding
- NIH [1R21GM077264, 1R01GM085128]
- David and Lucile Packard Fellowship in Science and Engineering
- Natural Sciences and Engineering Research Council of Canada
- Canada Research Chair in Bioorganic and Medicinal Chemistry
- NSF [BES0432307]
- Kosan Biosciences
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Highly reducing iterative polyketide synthases are large, multifunctional enzymes that make important metabolites in fungi, such as lovastatin, a cholesterol-lowering drug from Aspergillus terreus. We report efficient expression of the lovastatin nonaketide synthase (LovB) from an engineered strain of Saccharomyces cerevisiae, as well as complete reconstitution of its catalytic function in the presence and absence of cofactors ( the reduced form of nicotinamide adenine dinucleotide phosphate and S-adenosylmethionine) and its partner enzyme, the enoyl reductase LovC. Our results demonstrate that LovB retains correct intermediates until completion of synthesis of dihydromonacolin L, but off-loads incorrectly processed compounds as pyrones or hydrolytic products. Experiments replacing LovC with analogous MlcG from compactin biosynthesis demonstrate a gate-keeping function for this partner enzyme. This study represents a key step in the understanding of the functions and structures of this family of enzymes.
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