期刊
SCIENCE
卷 343, 期 6175, 页码 1140-1144出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1248000
关键词
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资金
- National Institutes of Health [GM 058518, GM 100011, GM 069657]
- U.S. DOE [DE-AC02-06CH11357]
- Michigan Economic Development Corporation
- Michigan Technology Tri-Corridor [085P1000817]
The bicyclic beta-lactam/2-pyrrolidine precursor to all carbapenem antibiotics is biosynthesized by attachment of a carboxymethylene unit to C5 of L-proline followed by beta-lactam ring closure. Carbapenem synthase (CarC), an Fe(II) and 2-(oxo)glutarate (Fe/2OG)-dependent oxygenase, then inverts the C5 configuration. Here we report the structure of CarC in complex with its substrate and biophysical dissection of its reaction to reveal the stereoinversion mechanism. An Fe(IV)-oxo intermediate abstracts the hydrogen (H center dot) from C5, and tyrosine 165, a residue not visualized in the published structures of CarC lacking bound substrate, donates H center dot to the opposite face of the resultant radical. The reaction oxidizes the Fe(II) cofactor to Fe(III), limiting wild-type CarC to one turnover, but substitution of the H center dot-donating tyrosine disables stereoinversion and confers to CarC the capacity for catalytic substrate oxidation.
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