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PDBsum entry 2gyo

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protein ligands Protein-protein interface(s) links
Transferase PDB id
2gyo
Jmol
Contents
Protein chains
317 a.a. *
Ligands
COA
MEE
SO4 ×2
Waters ×224
* Residue conservation analysis
PDB id:
2gyo
Name: Transferase
Title: Methanethiol-cys 112 inhibition complex of e. Coli ketoacyl iii (fabh) and coenzyme a
Structure: 3-oxoacyl-[acyl-carrier-protein] synthase 3. Chain: a, b. Synonym: 3-oxoacyl- [acyl-carrier-protein] synthase iii, be ketoacyl-acp synthase iii, kas iii, ecfabh. Engineered: yes
Source: Escherichia coli. Organism_taxid: 562. Gene: fabh. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.00Å     R-factor:   0.213     R-free:   0.268
Authors: M.M.Alhamadsheh,F.Musayev,A.A.Komissarov,S.Sachdeva,H.T.Wrig N.Scarsdale,G.Florova,K.A.Reynolds
Key ref:
M.M.Alhamadsheh et al. (2007). Alkyl-CoA Disulfides as Inhibitors and Mechanistic Probes for FabH Enzymes. Chem Biol, 14, 513-524. PubMed id: 17524982 DOI: 10.1016/j.chembiol.2007.03.013
Date:
09-May-06     Release date:   05-Jun-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P0A6R0  (FABH_ECOLI) -  3-oxoacyl-[acyl-carrier-protein] synthase 3
Seq:
Struc:
317 a.a.
317 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.3.1.180  - Beta-ketoacyl-[acyl-carrier-protein] synthase Iii.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Acetyl-CoA + malonyl-[acyl-carrier-protein] = acetoacetyl-[acyl-carrier- protein] + CoA + CO2
Acetyl-CoA
+ malonyl-[acyl-carrier-protein]
= acetoacetyl-[acyl-carrier- protein]
+
CoA
Bound ligand (Het Group name = COA)
corresponds exactly
+ CO(2)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   1 term 
  Biological process     metabolic process   5 terms 
  Biochemical function     catalytic activity     6 terms  

 

 
    reference    
 
 
DOI no: 10.1016/j.chembiol.2007.03.013 Chem Biol 14:513-524 (2007)
PubMed id: 17524982  
 
 
Alkyl-CoA Disulfides as Inhibitors and Mechanistic Probes for FabH Enzymes.
M.M.Alhamadsheh, F.Musayev, A.A.Komissarov, S.Sachdeva, H.T.Wright, N.Scarsdale, G.Florova, K.A.Reynolds.
 
  ABSTRACT  
 
The first step of the reaction catalyzed by the homodimeric FabH from a dissociated fatty acid synthase is acyl transfer from acyl-CoA to an active site cysteine. We report that C(1) to C(10) alkyl-CoA disulfides irreversibly inhibit Escherichia coli FabH (ecFabH) and Mycobacterium tuberculosis FabH with relative efficiencies that reflect these enzymes' differential acyl-group specificity. Crystallographic and kinetic studies with MeSSCoA show rapid inhibition of one monomer of ecFabH through formation of a methyl disulfide conjugate with this cysteine. Reaction of the second subunit with either MeSSCoA or acetyl-CoA is much slower. In the presence of malonyl-ACP, the acylation rate of the second subunit is restored to that of the native ecFabH. These observations suggest a catalytic model in which a structurally disordered apo-ecFabH dimer orders on binding either the first substrate, acetyl-CoA, or the inhibitor MeSSCoA, and is restored to a disordered state on binding of malonyl-ACP.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. FabH Inhibition by Alkyl-CoA Disulfides
(A) Chemical structures of alkyl-CoA disulfides 1–5.
(B) Proposed mechanism of ecFabH inactivation by MeSSCoA (1). Cys112 of ecFabH forms a methyl disulfide conjugate upon incubation with MeSSCoA (1). The released CoA in the CoA binding channel may be retained or dissociated.
Figure 5.
Figure 5. Crystal Structure of the ecFabH-MeSSCoA Soaked Complex
Stereo figure showing electron density for (A) the CoA and MeS-Cys112 in the A subunit of the ecFabH-MeSSCoA (1) complex (0.16 mM) contoured at a level of 0.9σ, and (B) electron density of the corresponding site in the B subunit. Electron density of nearby groups is omitted for clarity.
 
  The above figures are reprinted by permission from Cell Press: Chem Biol (2007, 14, 513-524) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21322068 J.Wang, and H.O.Sintim (2011).
Dialkylamino-2,4-dihydroxybenzoic Acids as Easily Synthesized Analogues of Platensimycin and Platencin with Comparable Antibacterial Properties.
  Chemistry, 17, 3352-3357.  
21516317 Y.Pérez-Castillo, M.Froeyen, M.A.Cabrera-Pérez, and A.Nowé (2011).
Molecular dynamics and docking simulations as a proof of high flexibility in E. coli FabH and its relevance for accurate inhibitor modeling.
  J Comput Aided Mol Des, 25, 371-393.  
19191586 P.J.Lee, J.B.Bhonsle, H.W.Gaona, D.P.Huddler, T.N.Heady, M.Kreishman-Deitrick, A.Bhattacharjee, W.F.McCalmont, L.Gerena, M.Lopez-Sanchez, N.E.Roncal, T.H.Hudson, J.D.Johnson, S.T.Prigge, and N.C.Waters (2009).
Targeting the fatty acid biosynthesis enzyme, beta-ketoacyl-acyl carrier protein synthase III (PfKASIII), in the identification of novel antimalarial agents.
  J Med Chem, 52, 952-963.  
19074144 R.Veyron-Churlet, V.Molle, R.C.Taylor, A.K.Brown, G.S.Besra, I.Zanella-Cléon, K.Fütterer, and L.Kremer (2009).
The Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III activity is inhibited by phosphorylation on a single threonine residue.
  J Biol Chem, 284, 6414-6424.  
19721072 Y.Zeng, H.Roy, P.B.Patil, M.Ibba, and S.Chen (2009).
Characterization of two seryl-tRNA synthetases in albomycin-producing Streptomyces sp. strain ATCC 700974.
  Antimicrob Agents Chemother, 53, 4619-4627.  
18524602 E.Turos, K.D.Revell, P.Ramaraju, D.A.Gergeres, K.Greenhalgh, A.Young, N.Sathyanarayan, S.Dickey, D.Lim, M.M.Alhamadsheh, and K.Reynolds (2008).
Unsymmetric aryl-alkyl disulfide growth inhibitors of methicillin-resistant Staphylococcus aureus and Bacillus anthracis.
  Bioorg Med Chem, 16, 6501-6508.  
18096200 S.Sachdeva, F.Musayev, M.M.Alhamadsheh, J.Neel Scarsdale, H.Tonie Wright, and K.A.Reynolds (2008).
Probing reactivity and substrate specificity of both subunits of the dimeric Mycobacterium tuberculosis FabH using alkyl-CoA disulfide inhibitors and acyl-CoA substrates.
  Bioorg Chem, 36, 85-90.
PDB code: 2qx1
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.