期刊
CHEMISTRY & BIOLOGY
卷 15, 期 10, 页码 1079-1090出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2008.08.011
关键词
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资金
- Office of Naval Research [N00014-02-1-0725]
- NIGMS
- National Institutes of Health Cell and Molecular Biology Training Grant Program
- National Science Foundation Graduate Research Fellowship Program
- National Science Foundation [DBI-0100085]
The fungal type III polyketide synthase 2'-oxoalkylresorcylic acid synthase (ORAS) primes with a range of acyl-Coenzyme A thioesters (C-4-C-20) and extends using malonyl-Coenzyme A to produce pyrones, resorcinols, and resorcylic acids. To gain insight into this unusual substrate specificity and product profile, we have determined the crystal structures of ORAS to 1.75 angstrom resolution, the Phe-252 -> Gly site-directed mutant to 2.1 angstrom resolution, and a binary complex of ORAS with eicosanoic acid to 2.0 angstrom resolution. The structures reveal a distinct rearrangement of structural elements near the active site that allows accommodation of long-chain fatty acid esters and a reorientation of the gating mechanism that controls cyclization and polyketide chain length. The roles of these structural elements are further elucidated by characterization of various structure-based site-directed variants. These studies establish an unexpected plasticity to the PKS fold, unanticipate from structural studies of other members of this enzyme family.
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