期刊
FEBS JOURNAL
卷 279, 期 23, 页码 4350-4360出版社
WILEY
DOI: 10.1111/febs.12025
关键词
antifolate; cyclohydrolase; dehydrogenase; enzyme inhibition; X-ray structure
资金
- Wellcome Trust [082596, 083481]
- European Commission
The bifunctional N5,N10-methylenetetrahydrofolate dehydrogenase/cyclohydrolase (DHCH or FolD), which is widely distributed in prokaryotes and eukaryotes, is involved in the biosynthesis of folate cofactors that are essential for growth and cellular development. The enzyme activities represent a potential antimicrobial drug target. We have characterized the kinetic properties of FolD from the Gram-negative pathogen Acinetobacter similar to baumanni and determined high-resolution crystal structures of complexes with a cofactor and two potent inhibitors. The data reveal new details with respect to the molecular basis of catalysis and potent inhibition. A unexpected finding was that our crystallographic data revealed a different structure for LY374571 (an inhibitor studied as an antifolate) than that previously published. The implications of this observation are discussed.
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