Document Detail


Identification and substrate specificity of beta -ketoacyl (acyl carrier protein) synthase III (mtFabH) from Mycobacterium tuberculosis.
MedLine Citation:
PMID:  10840036     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The long-chain alpha-alkyl-beta-hydroxy fatty acids, termed mycolic acids, which are characteristic components of the mycobacterial cell wall are produced by successive rounds of elongation catalyzed by a multifunctional (type I) fatty acid synthase complex followed by a dissociated (type II) fatty acid synthase. In bacterial type II systems, the first initiation step in elongation is the condensation of acetyl-CoA with malonyl-acyl carrier protein (ACP) catalyzed by beta-ketoacyl-ACP III (FabH). An open reading frame in the Mycobacterium tuberculosis genome (Rv0533c), now termed mtfabH, was 37.3% identical to Escherichia coli ecFabH and contained the Cys-His-Asn catalytic triad signature. However, the purified recombinant mtFabH clearly preferred long-chain acyl-CoA substrates rather than acyl-ACP primers and did not utilize acetyl-CoA as a primer in comparison to ecFabH. In addition, purified mtFabH was sensitive to thiolactomycin and resistant to cerulenin in an in vitro assay. However, mtFabH overexpression in Mycobacterium bovis BCG did not confer thiolactomycin resistance, suggesting that mtFabH may not be the primary target of thiolactomycin inhibition in vivo and led to several changes in the lipid composition of the bacilli. The data presented is consistent with a role for mtFabH as the pivotal link between the type I and type II fatty acid elongation systems in M. tuberculosis. This study opens up new avenues for the development of selective and novel anti-mycobacterial agents targeted against mtFabH.
Authors:
K H Choi; L Kremer; G S Besra; C O Rock
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  275     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2000 Sep 
Date Detail:
Created Date:  2000-10-13     Completed Date:  2000-10-13     Revised Date:  2010-10-07    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  28201-7     Citation Subset:  IM    
Affiliation:
Department of Biochemistry, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
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MeSH Terms
Descriptor/Qualifier:
3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / chemistry,  genetics*,  metabolism*
Acyl Coenzyme A / metabolism
Amino Acid Sequence
Bacillus subtilis / enzymology,  genetics
Catalytic Domain
Cloning, Molecular
Escherichia coli / enzymology,  genetics
Genome, Bacterial
Molecular Sequence Data
Mycobacterium tuberculosis / enzymology*,  genetics*
Open Reading Frames
Recombinant Proteins / chemistry,  metabolism
Sequence Alignment
Sequence Homology, Amino Acid
Substrate Specificity
Grant Support
ID/Acronym/Agency:
AI-38087/AI/NIAID NIH HHS; CA 21765/CA/NCI NIH HHS; GM 34496/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Acyl Coenzyme A; 0/Recombinant Proteins; EC 2.3.1.180/3-ketoacyl-acyl carrier protein synthase III; EC 2.3.1.41/3-Oxoacyl-(Acyl-Carrier-Protein) Synthase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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