PMID- 16492739
OWN - NLM
STAT- MEDLINE
DCOM- 20060410
LR  - 20190108
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 103
IP  - 9
DP  - 2006 Feb 28
TI  - Structure-based inhibitor design of AccD5, an essential acyl-CoA carboxylase 
      carboxyltransferase domain of Mycobacterium tuberculosis.
PG  - 3072-7
AB  - Mycolic acids and multimethyl-branched fatty acids are found uniquely in the cell 
      envelope of pathogenic mycobacteria. These unusually long fatty acids are 
      essential for the survival, virulence, and antibiotic resistance of Mycobacterium 
      tuberculosis. Acyl-CoA carboxylases (ACCases) commit acyl-CoAs to the 
      biosynthesis of these unique fatty acids. Unlike other organisms such as 
      Escherichia coli or humans that have only one or two ACCases, M. tuberculosis 
      contains six ACCase carboxyltransferase domains, AccD1-6, whose specific roles in 
      the pathogen are not well defined. Previous studies indicate that AccD4, AccD5, 
      and AccD6 are important for cell envelope lipid biosynthesis and that its 
      disruption leads to pathogen death. We have determined the 2.9-Angstroms crystal 
      structure of AccD5, whose sequence, structure, and active site are highly 
      conserved with respect to the carboxyltransferase domain of the Streptomyces 
      coelicolor propionyl-CoA carboxylase. Contrary to the previous proposal that 
      AccD4-5 accept long-chain acyl-CoAs as their substrates, both crystal structure 
      and kinetic assay indicate that AccD5 prefers propionyl-CoA as its substrate and 
      produces methylmalonyl-CoA, the substrate for the biosyntheses of 
      multimethyl-branched fatty acids such as mycocerosic, phthioceranic, 
      hydroxyphthioceranic, mycosanoic, and mycolipenic acids. Extensive in silico 
      screening of National Cancer Institute compounds and the University of 
      California, Irvine, ChemDB database resulted in the identification of one 
      inhibitor with a K(i) of 13.1 microM. Our results pave the way toward 
      understanding the biological roles of key ACCases that commit acyl-CoAs to the 
      biosynthesis of cell envelope fatty acids, in addition to providing a target for 
      structure-based development of antituberculosis therapeutics.
FAU - Lin, Ting-Wan
AU  - Lin TW
AD  - Department of Molecular Biology and Biochemistry, University of California, 
      Irvine, 92697, USA.
FAU - Melgar, Melrose M
AU  - Melgar MM
FAU - Kurth, Daniel
AU  - Kurth D
FAU - Swamidass, S Joshua
AU  - Swamidass SJ
FAU - Purdon, John
AU  - Purdon J
FAU - Tseng, Teresa
AU  - Tseng T
FAU - Gago, Gabriela
AU  - Gago G
FAU - Baldi, Pierre
AU  - Baldi P
FAU - Gramajo, Hugo
AU  - Gramajo H
FAU - Tsai, Shiou-Chuan
AU  - Tsai SC
LA  - eng
SI  - PDB/2A75
GR  - R03 TW005778/TW/FIC NIH HHS/United States
GR  - R01 GM100305/GM/NIGMS NIH HHS/United States
GR  - R03 TW007982/TW/FIC NIH HHS/United States
GR  - LM-07443-01/LM/NLM NIH HHS/United States
GR  - T15 LM007443/LM/NLM NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20060221
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Antitubercular Agents)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Ligands)
RN  - EC 6.4.- (Carbon-Carbon Ligases)
RN  - EC 6.4.1.- (acyl-CoA carboxylase)
SB  - IM
MH  - Antitubercular Agents/chemistry/pharmacology
MH  - Binding Sites
MH  - Carbon-Carbon Ligases/*antagonists & inhibitors/*chemistry/metabolism
MH  - Computational Biology
MH  - *Drug Design
MH  - Enzyme Inhibitors/*chemistry/*pharmacology
MH  - Ligands
MH  - Models, Molecular
MH  - Mycobacterium tuberculosis/*enzymology
MH  - Protein Structure, Quaternary
MH  - Substrate Specificity
PMC - PMC1413898
COIS- Conflict of interest statement: No conflicts declared.
EDAT- 2006/02/24 09:00
MHDA- 2006/04/11 09:00
PMCR- 2006/08/28
CRDT- 2006/02/24 09:00
PHST- 2006/02/24 09:00 [pubmed]
PHST- 2006/04/11 09:00 [medline]
PHST- 2006/02/24 09:00 [entrez]
PHST- 2006/08/28 00:00 [pmc-release]
AID - 0510580103 [pii]
AID - 0987 [pii]
AID - 10.1073/pnas.0510580103 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3072-7. doi: 
      10.1073/pnas.0510580103. Epub 2006 Feb 21.