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PDBsum entry 1u6s

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protein ligands Protein-protein interface(s) links
Transferase PDB id
1u6s
Jmol
Contents
Protein chains
334 a.a. *
Ligands
DCC ×2
Waters ×193
* Residue conservation analysis
PDB id:
1u6s
Name: Transferase
Title: Crystal structure of the complex between mycobacterium tuber beta-ketoacyl-acyl carrier protein synthase iii and lauroyl a
Structure: 3-oxoacyl-[acyl-carrier-protein] synthase iii. Chain: a, b. Synonym: beta-ketoacyl-acp synthase iii, kas iii, mtfabh. Engineered: yes. Mutation: yes
Source: Mycobacterium tuberculosis. Organism_taxid: 1773. Gene: fabh. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Dimer (from PQS)
Resolution:
2.30Å     R-factor:   0.208     R-free:   0.247
Authors: F.Musayev,S.Sachdeva,J.N.Scarsdale,K.A.Reynolds,H.T.Wright
Key ref:
F.Musayev et al. (2005). Crystal structure of a substrate complex of Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III (FabH) with lauroyl-coenzyme A. J Mol Biol, 346, 1313-1321. PubMed id: 15713483 DOI: 10.1016/j.jmb.2004.12.044
Date:
30-Jul-04     Release date:   22-Mar-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam  
P9WNG3  (FABH_MYCTU) -  3-oxoacyl-[acyl-carrier-protein] synthase 3
Seq:
Struc:
335 a.a.
334 a.a.*
Key:    Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 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
Bound ligand (Het Group name = DCC)
matches with 83.61% similarity
+ malonyl-[acyl-carrier-protein]
= acetoacetyl-[acyl-carrier- protein]
+ CoA
+ 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   7 terms 
  Biochemical function     catalytic activity     8 terms  

 

 
    reference    
 
 
DOI no: 10.1016/j.jmb.2004.12.044 J Mol Biol 346:1313-1321 (2005)
PubMed id: 15713483  
 
 
Crystal structure of a substrate complex of Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III (FabH) with lauroyl-coenzyme A.
F.Musayev, S.Sachdeva, J.N.Scarsdale, K.A.Reynolds, H.T.Wright.
 
  ABSTRACT  
 
Beta-ketoacyl-acyl carrier protein synthase III (FabH) catalyzes a two step reaction that initiates the pathway of fatty acid biosynthesis in plants and bacteria. In Mycobacterium tuberculosis, FabH catalyzes extension of lauroyl, myristoyl and palmitoyl groups from which cell wall mycolic acids of the bacterium are formed. The first step of the reaction is an acyl group transfer from acyl-coenzyme A to the active-site cysteine of the enzyme; the second step is acyl chain extension by two carbon atoms through Claisen condensation with malonyl-acyl carrier protein. We have previously determined the crystal structure of a type II, dissociated M.tuberculosis FabH, which catalyzes extension of lauroyl, myristoyl and palmitoyl groups. Here we describe the first long-chain Michaelis substrate complex of a FabH, that of lauroyl-coenzyme A with a catalytically disabled Cys-->Ala mutant of M.tuberculosis FabH. An elongated channel extending from the mutated active-site cysteine defines the acyl group binding locus that confers unique acyl substrate specificity on M.tuberculosis FabH. CoA lies in a second channel, bound primarily through interactions of its nucleotide group at the enzyme surface. The apparent weak association of CoA in this complex may play a role in the binding and dissociation of long chain acyl-CoA substrates and products and poses questions pertinent to the mechanism of this enzyme.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Mechanism for the FabH catalyzed initiation of fatty acid biosynthesis. The intermediate enclosed in a box represents the Michaelis complex whose structure for the C112A mutant is described here.
Figure 2.
Figure 2. Composite omit map electron density for lauroyl-CoA bound to subunit A of mtFabH homodimer. Electron density is contoured at 1s.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2005, 346, 1313-1321) copyright 2005.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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.  
20534558 E.Okamura, T.Tomita, R.Sawa, M.Nishiyama, and T.Kuzuyama (2010).
Unprecedented acetoacetyl-coenzyme A synthesizing enzyme of the thiolase superfamily involved in the mevalonate pathway.
  Proc Natl Acad Sci U S A, 107, 11265-11270.  
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.  
  18453702 B.Bagautdinov, Y.Ukita, M.Miyano, and N.Kunishima (2008).
Structure of 3-oxoacyl-(acyl-carrier protein) synthase II from Thermus thermophilus HB8.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 64, 358-366.
PDB code: 1j3n
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.  
19099550 K.Raman, Y.Kalidas, and N.Chandra (2008).
targetTB: A target identification pipeline for Mycobacterium tuberculosis through an interactome, reactome and genome-scale structural analysis.
  BMC Syst Biol, 2, 109.  
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
18264115 Y.M.Zhang, and C.O.Rock (2008).
Membrane lipid homeostasis in bacteria.
  Nat Rev Microbiol, 6, 222-233.  
17524982 M.M.Alhamadsheh, F.Musayev, A.A.Komissarov, S.Sachdeva, H.T.Wright, N.Scarsdale, G.Florova, and K.A.Reynolds (2007).
Alkyl-CoA disulfides as inhibitors and mechanistic probes for FabH enzymes.
  Chem Biol, 14, 513-524.
PDB codes: 2eft 2gyo
16356722 A.M.Haapalainen, G.Meriläinen, and R.K.Wierenga (2006).
The thiolase superfamily: condensing enzymes with diverse reaction specificities.
  Trends Biochem Sci, 31, 64-71.  
15987898 X.Qiu, A.E.Choudhry, C.A.Janson, M.Grooms, R.A.Daines, J.T.Lonsdale, and S.S.Khandekar (2005).
Crystal structure and substrate specificity of the beta-ketoacyl-acyl carrier protein synthase III (FabH) from Staphylococcus aureus.
  Protein Sci, 14, 2087-2094.
PDB code: 1zow
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.