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PDBsum entry 1lx6

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protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
1lx6
Jmol
Contents
Protein chains
243 a.a. *
Ligands
NAD ×2
ZAM ×2
Waters ×247
* Residue conservation analysis
PDB id:
1lx6
Name: Oxidoreductase
Title: Crystal structure of e. Coli enoyl reductase-NAD+ with a bou benzamide inhibitor
Structure: Enoyl-[acyl-carrier-protein] reductase [nadh]. Chain: a, b. Synonym: nadh-dependent enoyl-acp reductase. Engineered: yes
Source: Escherichia coli. Organism_taxid: 562. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Tetramer (from PDB file)
Resolution:
2.40Å     R-factor:   0.188     R-free:   0.250
Authors: W.W.Smith,X.Qiu,C.A.Janson
Key ref: W.H.Miller et al. (2002). Discovery of aminopyridine-based inhibitors of bacterial enoyl-ACP reductase (FabI). J Med Chem, 45, 3246-3256. PubMed id: 12109908 DOI: 10.1021/jm020050+
Date:
04-Jun-02     Release date:   04-Sep-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P0AEK4  (FABI_ECOLI) -  Enoyl-[acyl-carrier-protein] reductase [NADH] FabI
Seq:
Struc:
262 a.a.
243 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.1.3.1.9  - Enoyl-[acyl-carrier-protein] reductase (NADH).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: An acyl-[acyl-carrier protein] + NAD+ = a trans-2,3-dehydroacyl-[acyl- carrier protein] + NADH
acyl-[acyl-carrier protein]
+
NAD(+)
Bound ligand (Het Group name = NAD)
corresponds exactly
= trans-2,3-dehydroacyl-[acyl- carrier protein]
+ NADH
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   1 term 
  Biological process     metabolic process   10 terms 
  Biochemical function     oxidoreductase activity     3 terms  

 

 
    reference    
 
 
DOI no: 10.1021/jm020050+ J Med Chem 45:3246-3256 (2002)
PubMed id: 12109908  
 
 
Discovery of aminopyridine-based inhibitors of bacterial enoyl-ACP reductase (FabI).
W.H.Miller, M.A.Seefeld, K.A.Newlander, I.N.Uzinskas, W.J.Burgess, D.A.Heerding, C.C.Yuan, M.S.Head, D.J.Payne, S.F.Rittenhouse, T.D.Moore, S.C.Pearson, V.Berry, W.E.DeWolf, P.M.Keller, B.J.Polizzi, X.Qiu, C.A.Janson, W.F.Huffman.
 
  ABSTRACT  
 
Bacterial enoyl-ACP reductase (FabI) catalyzes the final step in each cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. Our efforts to identify potent, selective FabI inhibitors began with screening of the GlaxoSmithKline proprietary compound collection, which identified several small-molecule inhibitors of Staphylococcus aureus FabI. Through a combination of iterative medicinal chemistry and X-ray crystal structure based design, one of these leads was developed into the novel aminopyridine derivative 9, a low micromolar inhibitor of FabI from S. aureus (IC(50) = 2.4 microM) and Haemophilus influenzae (IC(50) = 4.2 microM). Compound 9 has good in vitro antibacterial activity against several organisms, including S. aureus (MIC = 0.5 microg/mL), and is effective in vivo in a S. aureus groin abscess infection model in rats. Through FabI overexpressor and macromolecular synthesis studies, the mode of action of 9 has been confirmed to be inhibition of fatty acid biosynthesis via inhibition of FabI. Taken together, these results support FabI as a valid antibacterial target and demonstrate the potential of small-molecule FabI inhibitors for the treatment of bacterial infections.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21175675 A.K.Agarwal, and C.W.Fishwick (2010).
Structure-based design of anti-infectives.
  Ann N Y Acad Sci, 1213, 20-45.  
20131353 G.Kumar, T.Banerjee, N.Kapoor, N.Surolia, and A.Surolia (2010).
SAR and pharmacophore models for the rhodanine inhibitors of Plasmodium falciparum enoyl-acyl carrier protein reductase.
  IUBMB Life, 62, 204-213.  
19282328 C.J.Zheng, M.J.Sohn, and W.G.Kim (2009).
Vinaxanthone, a new FabI inhibitor from Penicillium sp.
  J Antimicrob Chemother, 63, 949-953.  
19734171 K.England, C.am Ende, H.Lu, T.J.Sullivan, N.L.Marlenee, R.A.Bowen, S.E.Knudson, D.L.Knudson, P.J.Tonge, and R.A.Slayden (2009).
Substituted diphenyl ethers as a broad-spectrum platform for the development of chemotherapeutics for the treatment of tularaemia.
  J Antimicrob Chemother, 64, 1052-1061.  
19578428 S.L.Kinnings, N.Liu, N.Buchmeier, P.J.Tonge, L.Xie, and P.E.Bourne (2009).
Drug discovery using chemical systems biology: repositioning the safe medicine Comtan to treat multi-drug and extensively drug resistant tuberculosis.
  PLoS Comput Biol, 5, e1000423.  
19952429 Y.J.Kwon, Y.Fang, G.H.Xu, and W.G.Kim (2009).
Aquastatin A, a new inhibitor of enoyl-acyl carrier protein reductase from Sporothrix sp. FN611.
  Biol Pharm Bull, 32, 2061-2064.  
18663709 S.K.Tipparaju, D.C.Mulhearn, G.M.Klein, Y.Chen, S.Tapadar, M.H.Bishop, S.Yang, J.Chen, M.Ghassemi, B.D.Santarsiero, J.L.Cook, M.Johlfs, A.D.Mesecar, M.E.Johnson, and A.P.Kozikowski (2008).
Design and synthesis of aryl ether inhibitors of the Bacillus anthracis enoyl-ACP reductase.
  ChemMedChem, 3, 1250-1268.
PDB code: 2qio
17327670 S.P.Muench, S.T.Prigge, R.McLeod, J.B.Rafferty, M.J.Kirisits, C.W.Roberts, E.J.Mui, and D.W.Rice (2007).
Studies of Toxoplasma gondii and Plasmodium falciparum enoyl acyl carrier protein reductase and implications for the development of antiparasitic agents.
  Acta Crystallogr D Biol Crystallogr, 63, 328-338.
PDB codes: 2o2s 2o2y 2o50
17323650 C.J.Zheng, M.J.Sohn, and W.G.Kim (2006).
Atromentin and leucomelone, the first inhibitors specific to enoyl-ACP reductase (FabK) of Streptococcus pneumoniae.
  J Antibiot (Tokyo), 59, 808-812.  
16980474 G.Gerlach, and J.Reidl (2006).
NAD+ utilization in Pasteurellaceae: simplification of a complex pathway.
  J Bacteriol, 188, 6719-6727.  
15066985 C.Freiberg, N.A.Brunner, G.Schiffer, T.Lampe, J.Pohlmann, M.Brands, M.Raabe, D.Häbich, and K.Ziegelbauer (2004).
Identification and characterization of the first class of potent bacterial acetyl-CoA carboxylase inhibitors with antibacterial activity.
  J Biol Chem, 279, 26066-26073.  
15105103 L.L.Ling, J.Xian, S.Ali, B.Geng, J.Fan, D.M.Mills, A.C.Arvanites, H.Orgueira, M.A.Ashwell, G.Carmel, Y.Xiang, and D.T.Moir (2004).
Identification and characterization of inhibitors of bacterial enoyl-acyl carrier protein reductase.
  Antimicrob Agents Chemother, 48, 1541-1547.  
  15043388 R.J.Heath, and C.O.Rock (2004).
Fatty acid biosynthesis as a target for novel antibacterials.
  Curr Opin Investig Drugs, 5, 146-153.  
14987762 Y.Ji, D.Yin, B.Fox, D.J.Holmes, D.Payne, and M.Rosenberg (2004).
Validation of antibacterial mechanism of action using regulated antisense RNA expression in Staphylococcus aureus.
  FEMS Microbiol Lett, 231, 177-184.  
15726819 Y.M.Zhang, Y.J.Lu, and C.O.Rock (2004).
The reductase steps of the type II fatty acid synthase as antimicrobial targets.
  Lipids, 39, 1055-1060.  
12776214 L.Miesel, J.Greene, and T.A.Black (2003).
Genetic strategies for antibacterial drug discovery.
  Nat Rev Genet, 4, 442-456.  
12606558 M.R.Kuo, H.R.Morbidoni, D.Alland, S.F.Sneddon, B.B.Gourlie, M.M.Staveski, M.Leonard, J.S.Gregory, A.D.Janjigian, C.Yee, J.M.Musser, B.Kreiswirth, H.Iwamoto, R.Perozzo, W.R.Jacobs, J.C.Sacchettini, and D.A.Fidock (2003).
Targeting tuberculosis and malaria through inhibition of Enoyl reductase: compound activity and structural data.
  J Biol Chem, 278, 20851-20859.
PDB codes: 1p44 1p45
12556209 N.Woodford (2003).
Novel agents for the treatment of resistant Gram-positive infections.
  Expert Opin Investig Drugs, 12, 117-137.  
12377565 M.B.Schmid (2002).
Structural proteomics: the potential of high-throughput structure determination.
  Trends Microbiol, 10, S27-S31.  
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.