Document Detail


Staphylococcus aureus FabI: inhibition, substrate recognition, and potential implications for in vivo essentiality.
MedLine Citation:
PMID:  22579249     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Methicillin-resistant Staphylococcus aureus (MRSA) infections constitute a serious health threat worldwide, and novel antibiotics are therefore urgently needed. The enoyl-ACP reductase (saFabI) is essential for the S. aureus fatty acid biosynthesis and, hence, serves as an attractive drug target. We have obtained a series of snapshots of this enzyme that provide a mechanistic picture of ligand and inhibitor binding, including a dimer-tetramer transition combined with extensive conformational changes. Significantly, our results reveal key differences in ligand binding and recognition compared to orthologous proteins. The remarkable observed protein flexibility rationalizes our finding that saFabI is capable of efficiently reducing branched-chain fatty acid precursors. Importantly, branched-chain fatty acids represent a major fraction of the S. aureus cell membrane and are crucial for its in vivo fitness. Our discovery thus addresses a long-standing controversy regarding the essentiality of the fatty acid biosynthesis pathway in S. aureus rationalizing saFabI as a drug target.
Authors:
Johannes Schiebel; Andrew Chang; Hao Lu; Michael V Baxter; Peter J Tonge; Caroline Kisker
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Structure (London, England : 1993)     Volume:  20     ISSN:  1878-4186     ISO Abbreviation:  Structure     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-05-14     Completed Date:  2012-09-10     Revised Date:  2013-07-16    
Medline Journal Info:
Nlm Unique ID:  101087697     Medline TA:  Structure     Country:  United States    
Other Details:
Languages:  eng     Pagination:  802-13     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Ltd. All rights reserved.
Affiliation:
Rudolf Virchow Center for Experimental Biomedicine, Institute for Structural Biology, University of Würzburg, D-97080 Würzburg, Germany.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Bacterial Proteins / antagonists & inhibitors,  chemistry*,  metabolism
Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / antagonists & inhibitors*,  chemistry*,  metabolism
Fatty Acids / metabolism
Kinetics
Ligands
Molecular Sequence Data
Protein Conformation
Staphylococcus aureus / enzymology*,  metabolism
Structure-Activity Relationship
Substrate Specificity
Grant Support
ID/Acronym/Agency:
R01 AI044639/AI/NIAID NIH HHS; R01 GM102864/GM/NIGMS NIH HHS; T32 GM008444/GM/NIGMS NIH HHS; T32 GM092714/GM/NIGMS NIH HHS; T32GM008444/GM/NIGMS NIH HHS; T32GM092714/GM/NIGMS NIH HHS; U01 AI070383/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Bacterial Proteins; 0/Fatty Acids; 0/Ligands; EC 1.3.1.9/Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
Comments/Corrections

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