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PDBsum entry 2c07

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Oxidoreductase PDB id
2c07
Jmol
Contents
Protein chain
246 a.a. *
Ligands
SO4
Waters ×184
* Residue conservation analysis
PDB id:
2c07
Name: Oxidoreductase
Title: Oxoacyl-acp reductase of plasmodium falciparum
Structure: 3-oxoacyl-(acyl-carrier protein) reductase. Chain: a. Fragment: 54-c terminus, residues 54-304. Synonym: oxoacyl-acp reductase. Engineered: yes
Source: Plasmodium falciparum. Malaria parasite. Organism_taxid: 36329. Strain: 3d7. Expressed in: escherichia coli. Expression_system_taxid: 511693. Expression_system_variant: codon plus ril.
Biol. unit: Tetramer (from PDB file)
Resolution:
1.50Å     R-factor:   0.202     R-free:   0.223
Authors: J.E.Urch,S.R.Wickramasinghe,K.A.Inglis,S.Muller, A.H.Fairlamb,D.M.F.Van Aalten
Key ref: S.R.Wickramasinghe et al. (2006). Kinetic, inhibition and structural studies on 3-oxoacyl-ACP reductase from Plasmodium falciparum, a key enzyme in fatty acid biosynthesis. Biochem J, 393, 447-457. PubMed id: 16225460 DOI: 10.1042/BJ20050832
Date:
26-Aug-05     Release date:   20-Oct-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q8I2S7  (Q8I2S7_PLAF7) -  3-oxoacyl-(Acyl-carrier protein) reductase
Seq:
Struc:
301 a.a.
246 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.1.1.1.100  - 3-oxoacyl-[acyl-carrier-protein] reductase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: (3R)-3-hydroxyacyl-[acyl-carrier-protein] + NADP+ = 3-oxoacyl-[acyl- carrier-protein] + NADPH
(3R)-3-hydroxyacyl-[acyl-carrier-protein]
+ NADP(+)
= 3-oxoacyl-[acyl- carrier-protein]
+ NADPH
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     metabolic process   3 terms 
  Biochemical function     oxidoreductase activity     3 terms  

 

 
    reference    
 
 
DOI no: 10.1042/BJ20050832 Biochem J 393:447-457 (2006)
PubMed id: 16225460  
 
 
Kinetic, inhibition and structural studies on 3-oxoacyl-ACP reductase from Plasmodium falciparum, a key enzyme in fatty acid biosynthesis.
S.R.Wickramasinghe, K.A.Inglis, J.E.Urch, S.Müller, D.M.van Aalten, A.H.Fairlamb.
 
  ABSTRACT  
 
Type II fatty acid biosynthesis represents an attractive target for the discovery of new antimalarial drugs. Previous studies have identified malarial ENR (enoyl acyl-carrier-protein reductase, or FabI) as the target for the antiseptic triclosan. In the present paper, we report the biochemical properties and 1.5 A (1 A=0.1 nm) crystal structure of OAR (3-oxoacyl acyl-carrier-protein reductase, or FabG), the second reductive step in fatty acid biosynthesis and its inhibition by hexachlorophene. Under optimal conditions of pH and ionic strength, Plasmodium falciparum OAR displays kinetic properties similar to those of OAR from bacteria or plants. Activity with NADH is <3% of that with NADPH. Fluorescence enhancement studies indicate that NADPH can bind to the free enzyme, consistent with kinetic and product inhibition studies suggesting a steady-state ordered mechanism. The crystal structure reveals a tetramer with a sulphate ion bound in the cofactor-binding site such that the side chains of the catalytic triad of serine, tyrosine and lysine are aligned in an active conformation, as previously observed in the Escherichia coli OAR-NADP+ complex. A cluster of positively charged residues is positioned at the entrance to the active site, consistent with the proposed recognition site for the physiological substrate (3-oxoacyl-acyl-carrier protein) in E. coli OAR. The antibacterial and anthelminthic agent hexachlorophene is a potent inhibitor of OAR (IC50 2.05 microM) displaying non-linear competitive inhibition with respect to NADPH. Hexachlorophene (EC50 6.2 microM) and analogues such as bithionol also have antimalarial activity in vitro, suggesting they might be useful leads for further development.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
  20559451 C.Ben Mamoun, S.T.Prigge, and H.Vial (2010).
Targeting the Lipid Metabolic Pathways for the Treatment of Malaria.
  Drug Dev Res, 71, 44-55.  
19746209 A.Gurvitz (2009).
Caenorhabditis elegans F09E10.3 encodes a putative 3-oxoacyl-thioester reductase of mitochondrial type 2 fatty acid synthase FASII that is functional in yeast.
  J Biomed Biotechnol, 2009, 235868.  
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.  
18172196 A.S.Tarun, X.Peng, R.F.Dumpit, Y.Ogata, H.Silva-Rivera, N.Camargo, T.M.Daly, L.W.Bergman, and S.H.Kappe (2008).
A combined transcriptome and proteome survey of malaria parasite liver stages.
  Proc Natl Acad Sci U S A, 105, 305-310.  
18791006 K.Hölsch, J.Havel, M.Haslbeck, and D.Weuster-Botz (2008).
Identification, cloning, and characterization of a novel ketoreductase from the cyanobacterium Synechococcus sp. strain PCC 7942.
  Appl Environ Microbiol, 74, 6697-6702.  
17715365 J.Mazumdar, and B.Striepen (2007).
Make it or take it: fatty acid metabolism of apicomplexan parasites.
  Eukaryot Cell, 6, 1727-1735.  
  17277451 Q.Mao, W.L.Duax, and T.C.Umland (2007).
Crystallization and X-ray diffraction analysis of the beta-ketoacyl-acyl carrier protein reductase FabG from Aquifex aeolicus VF5.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 106-109.  
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.