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PDBsum entry 2a7s

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protein Protein-protein interface(s) links
Ligase PDB id
2a7s
Jmol
Contents
Protein chains
(+ 0 more) 529 a.a. *
Waters ×1136
* Residue conservation analysis
PDB id:
2a7s
Name: Ligase
Title: Crystal structure of the acyl-coa carboxylase, accd5, from mycobacterium tuberculosis
Structure: Probable propionyl-coa carboxylase beta chain 5. Chain: a, b, c, d, e, f. Synonym: pccase, propanoyl-coa:carbon dioxide ligase. Engineered: yes
Source: Mycobacterium tuberculosis. Organism_taxid: 1773. Gene: accd5, pccb. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Hexamer (from PQS)
Resolution:
2.90Å     R-factor:   0.193     R-free:   0.245
Authors: T.Lin,M.Melgar,J.Purdon,T.Tseng,S.C.Tsai
Key ref:
T.W.Lin et al. (2006). Structure-based inhibitor design of AccD5, an essential acyl-CoA carboxylase carboxyltransferase domain of Mycobacterium tuberculosis. Proc Natl Acad Sci U S A, 103, 3072-3077. PubMed id: 16492739 DOI: 10.1073/pnas.0510580103
Date:
06-Jul-05     Release date:   21-Feb-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam  
P9WQH7  (PCC5_MYCTU) -  Probable propionyl-CoA carboxylase beta chain 5
Seq:
Struc:
 
Seq:
Struc:
548 a.a.
529 a.a.
Key:    Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.6.4.1.3  - Propionyl-CoA carboxylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + propanoyl-CoA + HCO3- = ADP + phosphate + (S)-methylmalonyl- CoA
ATP
+ propanoyl-CoA
+ HCO(3)(-)
= ADP
+ phosphate
+ (S)-methylmalonyl- CoA
      Cofactor: Biotin
Biotin
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     metabolic process   1 term 
  Biochemical function     nucleotide binding     4 terms  

 

 
    reference    
 
 
DOI no: 10.1073/pnas.0510580103 Proc Natl Acad Sci U S A 103:3072-3077 (2006)
PubMed id: 16492739  
 
 
Structure-based inhibitor design of AccD5, an essential acyl-CoA carboxylase carboxyltransferase domain of Mycobacterium tuberculosis.
T.W.Lin, M.M.Melgar, D.Kurth, S.J.Swamidass, J.Purdon, T.Tseng, G.Gago, P.Baldi, H.Gramajo, S.C.Tsai.
 
  ABSTRACT  
 
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.
 
  Selected figure(s)  
 
Figure 3.
Fig. 3. The AccD5 active site. (A) Structural overlap between AccD5 and PccB near the active site. Two sets of oxyanion-stabilizing residues are highly conserved, including the NH of G193 and G194 and the NH of G434' and A435'. The structural similarity strongly suggests a similar enzyme mechanism. (B) Although surfaces outside of the pocket are quite different, the size and shape of the acyl-CoA-binding pockets themselves are very similar between PccB and AccD5, whose pockets are too small to accommodate the 16-carbon palmitoyl-CoA.
Figure 4.
Fig. 4. The in silico inhibitor leads of AccD5. (A) The lead compounds from the first round of in silico inhibitor screening against the AccD5 active site, in which only NCI-65828 showed extensive enzyme inhibition. (B) The lead compounds from the second round of in silico screening of 3,000 chemical homologs that resemble NCI-65828. The IC[50] values of these analogs range from 25 to 300 µM, with >50% lacking inhibitory effect on AccD5.
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21204864 G.Gago, L.Diacovich, A.Arabolaza, S.C.Tsai, and H.Gramajo (2011).
Fatty acid biosynthesis in actinomycetes.
  FEMS Microbiol Rev, 35, 475-497.  
21129975 S.Ekins, J.S.Freundlich, I.Choi, M.Sarker, and C.Talcott (2011).
Computational databases, pathway and cheminformatics tools for tuberculosis drug discovery.
  Trends Microbiol, 19, 65-74.  
20437235 A.V.Demirev, A.Khanal, B.R.Sedai, S.K.Lim, M.K.Na, and D.H.Nam (2010).
The role of acyl-coenzyme A carboxylase complex in lipstatin biosynthesis of Streptomyces toxytricini.
  Appl Microbiol Biotechnol, 87, 1129-1139.  
20725044 C.S.Huang, K.Sadre-Bazzaz, Y.Shen, B.Deng, Z.H.Zhou, and L.Tong (2010).
Crystal structure of the alpha(6)beta(6) holoenzyme of propionyl-coenzyme A carboxylase.
  Nature, 466, 1001-1005.
PDB code: 3n6r
20551974 K.J.Simmons, I.Chopra, and C.W.Fishwick (2010).
Structure-based discovery of antibacterial drugs.
  Nat Rev Microbiol, 8, 501-510.  
19763422 A.V.Demirev, J.S.Lee, B.R.Sedai, I.G.Ivanov, and D.H.Nam (2009).
Identification and characterization of acetyl-CoA carboxylase gene cluster in Streptomyces toxytricini.
  J Microbiol, 47, 473-478.  
19423629 D.G.Kurth, G.M.Gago, A.de la Iglesia, B.Bazet Lyonnet, T.W.Lin, H.R.Morbidoni, S.C.Tsai, and H.Gramajo (2009).
ACCase 6 is the essential acetyl-CoA carboxylase involved in fatty acid and mycolic acid biosynthesis in mycobacteria.
  Microbiology, 155, 2664-2675.  
19695105 T.Xu, L.Zhang, X.Wang, D.Wei, and T.Li (2009).
Structure-based substrate screening for an enzyme.
  BMC Bioinformatics, 10, 257.  
20477209 H.Tomioka, Y.Tatano, K.Yasumoto, and T.Shimizu (2008).
Recent advances in antituberculous drug development and novel drug targets.
  Expert Rev Respir Med, 2, 455-471.  
18079742 J.C.Sacchettini, E.J.Rubin, and J.S.Freundlich (2008).
Drugs versus bugs: in pursuit of the persistent predator Mycobacterium tuberculosis.
  Nat Rev Microbiol, 6, 41-52.  
18375549 S.Savvi, D.F.Warner, B.D.Kana, J.D.McKinney, V.Mizrahi, and S.S.Dawes (2008).
Functional characterization of a vitamin B12-dependent methylmalonyl pathway in Mycobacterium tuberculosis: implications for propionate metabolism during growth on fatty acids.
  J Bacteriol, 190, 3886-3895.  
17635550 C.G.Klatt, D.A.Bryant, and D.M.Ward (2007).
Comparative genomics provides evidence for the 3-hydroxypropionate autotrophic pathway in filamentous anoxygenic phototrophic bacteria and in hot spring microbial mats.
  Environ Microbiol, 9, 2067-2078.  
17707686 H.T.Wright, and K.A.Reynolds (2007).
Antibacterial targets in fatty acid biosynthesis.
  Curr Opin Microbiol, 10, 447-453.  
17599932 J.H.Chen, E.Linstead, S.J.Swamidass, D.Wang, and P.Baldi (2007).
ChemDB update--full-text search and virtual chemical space.
  Bioinformatics, 23, 2348-2351.  
17360366 M.Jain, C.J.Petzold, M.W.Schelle, M.D.Leavell, J.D.Mougous, C.R.Bertozzi, J.A.Leary, and J.S.Cox (2007).
Lipidomics reveals control of Mycobacterium tuberculosis virulence lipids via metabolic coupling.
  Proc Natl Acad Sci U S A, 104, 5133-5138.  
  17277455 M.Yamada, R.Natsume, T.Nakamatsu, S.Horinouchi, H.Kawasaki, and T.Senda (2007).
Crystallization and preliminary crystallographic analysis of DtsR1, a carboxyltransferase subunit of acetyl-CoA carboxylase from Corynebacterium glutamicum.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 120-122.  
17483212 R.Gande, L.G.Dover, K.Krumbach, G.S.Besra, H.Sahm, T.Oikawa, and L.Eggeling (2007).
The two carboxylases of Corynebacterium glutamicum essential for fatty acid and mycolic acid synthesis.
  J Bacteriol, 189, 5257-5264.  
17389997 R.S.Gokhale, P.Saxena, T.Chopra, and D.Mohanty (2007).
Versatile polyketide enzymatic machinery for the biosynthesis of complex mycobacterial lipids.
  Nat Prod Rep, 24, 267-277.  
16793549 Y.Shen, C.Y.Chou, G.G.Chang, and L.Tong (2006).
Is dimerization required for the catalytic activity of bacterial biotin carboxylase?
  Mol Cell, 22, 807-818.
PDB codes: 2gps 2gpw
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.