Document Detail

Acinetobacter baumannii FolD ligand complexes --potent inhibitors of folate metabolism and a re-evaluation of the structure of LY374571.
MedLine Citation:
PMID:  23050773     Owner:  NLM     Status:  MEDLINE    
The bifunctional N(5),N(10)-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 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.
Thomas C Eadsforth; Fernando V Maluf; William N Hunter
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-11-05
Journal Detail:
Title:  The FEBS journal     Volume:  279     ISSN:  1742-4658     ISO Abbreviation:  FEBS J.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-22     Completed Date:  2013-01-25     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  101229646     Medline TA:  FEBS J     Country:  England    
Other Details:
Languages:  eng     Pagination:  4350-60     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors Journal compilation © 2012 FEBS.
Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, UK.
Data Bank Information
Bank Name/Acc. No.:
PDB/4B4U;  4B4V;  4B4W
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MeSH Terms
Acinetobacter baumannii / enzymology*,  metabolism*
Bacterial Proteins / chemistry,  metabolism*
Crystallography, X-Ray
Folic Acid / chemistry,  metabolism*
Methylenetetrahydrofolate Dehydrogenase (NADP) / chemistry,  metabolism*
Protein Structure, Secondary
Grant Support
082596//Wellcome Trust; 082596//Wellcome Trust; 083481//Wellcome Trust; 083481//Wellcome Trust
Reg. No./Substance:
0/Bacterial Proteins; 59-30-3/Folic Acid; EC Dehydrogenase (NADP)

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