spacer
spacer

PDBsum entry 1nhd

Go to PDB code: 
protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
1nhd
Jmol
Contents
Protein chains
229 a.a.
60 a.a.
Ligands
NAD ×2
Superseded by: 1vrw 1vrw
PDB id:
1nhd
Name: Oxidoreductase
Title: Crystal structure analysis of plasmodium falciparum enoyl- acyl-carrier-protein reductase with nadh
Structure: Enoyl-acyl carrier reductase. Chain: a, b. Synonym: enoyl-acp-reductase. Engineered: yes. Enoyl-acyl carrier reductase. Chain: c, d. Synonym: enoyl-acp-reductase. Engineered: yes
Source: Plasmodium falciparum. Malaria parasite p. Falciparum. Expressed in: escherichia coli.
Biol. unit: Octamer (from PQS)
Resolution:
2.40Å     R-factor:   0.176     R-free:   0.224
Authors: R.Perozzo,M.Kuo,A.S.Sidhu,J.T.Valiyaveettil,R.Bittman, W.R.Jacobs Jr.,D.A.Fidock,J.C.Sacchettini
Key ref:
R.Perozzo et al. (2002). Structural elucidation of the specificity of the antibacterial agent triclosan for malarial enoyl acyl carrier protein reductase. J Biol Chem, 277, 13106-13114. PubMed id: 11792710 DOI: 10.1074/jbc.M112000200
Date:
19-Dec-02     Release date:   25-Feb-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
No UniProt id for this chain
Struc: 229 a.a.
Protein chains
No UniProt id for this chain
Struc: 60 a.a.
Key:    Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, B, C, D: 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(+)
= trans-2,3-dehydroacyl-[acyl- carrier protein]
+ NADH
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1074/jbc.M112000200 J Biol Chem 277:13106-13114 (2002)
PubMed id: 11792710  
 
 
Structural elucidation of the specificity of the antibacterial agent triclosan for malarial enoyl acyl carrier protein reductase.
R.Perozzo, M.Kuo, A.S.Sidhu, J.T.Valiyaveettil, R.Bittman, W.R.Jacobs, D.A.Fidock, J.C.Sacchettini.
 
  ABSTRACT  
 
The human malaria parasite Plasmodium falciparum synthesizes fatty acids using a type II pathway that is absent in humans. The final step in fatty acid elongation is catalyzed by enoyl acyl carrier protein reductase, a validated antimicrobial drug target. Here, we report the cloning and expression of the P. falciparum enoyl acyl carrier protein reductase gene, which encodes a 50-kDa protein (PfENR) predicted to target to the unique parasite apicoplast. Purified PfENR was crystallized, and its structure resolved as a binary complex with NADH, a ternary complex with triclosan and NAD(+), and as ternary complexes bound to the triclosan analogs 1 and 2 with NADH. Novel structural features were identified in the PfENR binding loop region that most closely resembled bacterial homologs; elsewhere the protein was similar to ENR from the plant Brassica napus (root mean square for Calphas, 0.30 A). Triclosan and its analogs 1 and 2 killed multidrug-resistant strains of intra-erythrocytic P. falciparum parasites at sub to low micromolar concentrations in vitro. These data define the structural basis of triclosan binding to PfENR and will facilitate structure-based optimization of PfENR inhibitors.
 
  Selected figure(s)  
 
Figure 2.
Fig. 2. Tertiary structure of PfENR. a, representation of subunit B of the PfENR tetramer with the cofactor NADH and inhibitor triclosan bound to their active sites. Helices are shown in gold, the -strands in green, NADH and triclosan are colored by atom type. The tertiary structure shows the Rossmann fold typical of dinucleotide-binding enzymes (43). The chain break visible at the top of the inhibitor binding site is due to the PfENR substrate binding loop that was not resolved in the crystal structures. b, front view of the PfENR tetramer, in which each subunit is represented as a differently colored tube. The bound NADH is colored by atom type. Three perpendicular 2-fold symmetry axes intersect in the center, creating a molecule of internal 222 symmetry.
Figure 4.
Fig. 4. Structural details of the substrate/inhibitor binding site. a, stereo view of the 2F[o] F[c] electron density map contoured at 1 for bound analog 2 and NADH cofactor. Shown are residues 277 and 216-221. b, stereo view of the three superimposed PfENR·inhibitor complexes. Residues involved in the formation of the binding pocket are shown. The most important amino acids for interactions are labeled. Triclosan is shown in red, 1 in blue, and 2 in green. The corresponding cofactor of each inhibitor complex is colored accordingly. Hydrogen bonds with Tyr277 and the 2'-hydroxyl group of the nicotinamide ribose, as well as three additional hydrogen bonds mediated through the hydroxyl group of the naphthalene ring of 2 are shown as yellow dotted lines. The binding mode of triclosan, 1, and 2 showed the same stacking interactions to the nicotinamide ring of the cofactor with respect to ring A. Inhibitor 2 also exhibited three additional hydrogen bonds mediated through the hydroxyl group of the naphthalene ring that could interact with the side-chain nitrogen of Asn218 and the main-chain oxygen and nitrogen of Ala^219.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2002, 277, 13106-13114) copyright 2002.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21280175 K.Maity, T.Banerjee, N.Prabakaran, N.Surolia, A.Surolia, and K.Suguna (2011).
Effect of substrate binding loop mutations on the structure, kinetics, and inhibition of enoyl acyl carrier protein reductase from plasmodium falciparum.
  IUBMB Life, 63, 30-41.
PDB codes: 3am3 3am4 3am5
  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.  
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.  
20055482 H.Lu, and P.J.Tonge (2010).
Mechanism and inhibition of the FabV enoyl-ACP reductase from Burkholderia mallei.
  Biochemistry, 49, 1281-1289.  
20821705 J.Lyndall, P.Fuchsman, M.Bock, T.Barber, D.Lauren, K.Leigh, E.Perruchon, and M.Capdevielle (2010).
Probabilistic risk evaluation for triclosan in surface water, sediments, and aquatic biota tissues.
  Integr Environ Assess Manag, 6, 419-440.  
20821704 P.Fuchsman, J.Lyndall, M.Bock, D.Lauren, T.Barber, K.Leigh, E.Perruchon, and M.Capdevielle (2010).
Terrestrial ecological risk evaluation for triclosan in land-applied biosolids.
  Integr Environ Assess Manag, 6, 405-418.  
19701949 A.P.Singh, N.Surolia, and A.Surolia (2009).
Triclosan inhibit the growth of the late liver-stage of Plasmodium.
  IUBMB Life, 61, 923-928.  
  19206187 H.Lu, K.England, C.am Ende, J.J.Truglio, S.Luckner, B.G.Reddy, N.L.Marlenee, S.E.Knudson, D.L.Knudson, R.A.Bowen, C.Kisker, R.A.Slayden, and P.J.Tonge (2009).
Slow-onset inhibition of the FabI enoyl reductase from francisella tularensis: residence time and in vivo activity.
  ACS Chem Biol, 4, 221-231.
PDB code: 2jjy
19130456 J.S.Freundlich, F.Wang, C.Vilchèze, G.Gulten, R.Langley, G.A.Schiehser, D.P.Jacobus, W.R.Jacobs, and J.C.Sacchettini (2009).
Triclosan derivatives: towards potent inhibitors of drug-sensitive and drug-resistant Mycobacterium tuberculosis.
  ChemMedChem, 4, 241-248.
PDB codes: 3fne 3fnf 3fng 3fnh
19424997 K.Gademann, and J.Kobylinska (2009).
Antimalarial natural products of marine and freshwater origin.
  Chem Rec, 9, 187-198.  
19859979 N.Kapoor, T.Banerjee, P.Babu, K.Maity, N.Surolia, and A.Surolia (2009).
Design, development, synthesis, and docking analysis of 2'-substituted triclosan analogs as inhibitors for Plasmodium falciparum Enoyl-ACP reductase.
  IUBMB Life, 61, 1083-1091.  
19347595 V.A.Morde, M.S.Shaikh, R.R.Pissurlenkar, and E.C.Coutinho (2009).
Molecular modeling studies, synthesis, and biological evaluation of Plasmodium falciparum enoyl-acyl carrier protein reductase (PfENR) inhibitors.
  Mol Divers, 13, 501-517.  
18457948 C.W.am Ende, S.E.Knudson, N.Liu, J.Childs, T.J.Sullivan, M.Boyne, H.Xu, Y.Gegina, D.L.Knudson, F.Johnson, C.A.Peloquin, R.A.Slayden, and P.J.Tonge (2008).
Synthesis and in vitro antimycobacterial activity of B-ring modified diaryl ether InhA inhibitors.
  Bioorg Med Chem Lett, 18, 3029-3033.  
  19064257 M.Yu, T.R.Kumar, L.J.Nkrumah, A.Coppi, S.Retzlaff, C.D.Li, B.J.Kelly, P.A.Moura, V.Lakshmanan, J.S.Freundlich, J.C.Valderramos, C.Vilcheze, M.Siedner, J.H.Tsai, B.Falkard, A.B.Sidhu, L.A.Purcell, P.Gratraud, L.Kremer, A.P.Waters, G.Schiehser, D.P.Jacobus, C.J.Janse, A.Ager, W.R.Jacobs, J.C.Sacchettini, V.Heussler, P.Sinnis, and D.A.Fidock (2008).
The fatty acid biosynthesis enzyme FabI plays a key role in the development of liver-stage malarial parasites.
  Cell Host Microbe, 4, 567-578.
PDB code: 3f4b
18023422 N.M.Carballeira (2008).
New advances in fatty acids as antimalarial, antimycobacterial and antifungal agents.
  Prog Lipid Res, 47, 50-61.  
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
17509532 G.Nicola, C.A.Smith, E.Lucumi, M.R.Kuo, L.Karagyozov, D.A.Fidock, J.C.Sacchettini, and R.Abagyan (2007).
Discovery of novel inhibitors targeting enoyl-acyl carrier protein reductase in Plasmodium falciparum by structure-based virtual screening.
  Biochem Biophys Res Commun, 358, 686-691.  
17879346 H.H.Lee, J.Moon, and S.W.Suh (2007).
Crystal structure of the Helicobacter pylori enoyl-acyl carrier protein reductase in complex with hydroxydiphenyl ether compounds, triclosan and diclosan.
  Proteins, 69, 691-694.
PDB codes: 1jvf 1jw7 2pd3 2pd4
17715365 J.Mazumdar, and B.Striepen (2007).
Make it or take it: fatty acid metabolism of apicomplexan parasites.
  Eukaryot Cell, 6, 1727-1735.  
  17697396 J.Z.Lu, S.P.Muench, M.Allary, S.Campbell, C.W.Roberts, E.Mui, R.L.McLeod, D.W.Rice, and S.T.Prigge (2007).
Type I and type II fatty acid biosynthesis in Eimeria tenella: enoyl reductase activity and structure.
  Parasitology, 134, 1949-1962.
PDB code: 2ptg
17875391 P.Gayathri, H.Balaram, and M.R.Murthy (2007).
Structural biology of plasmodial proteins.
  Curr Opin Struct Biol, 17, 744-754.  
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
17559403 X.Cai, A.Lorraine Fuller, L.R.McDougald, X.Tan, J.Cai, F.Wang, J.C.Sacchettini, and G.Zhu (2007).
Biochemical characterization of enoyl reductase involved in Type II fatty acid synthesis in the intestinal coccidium Eimeria tenella (Phylum Apicomplexa).
  FEMS Microbiol Lett, 272, 238-244.  
15930004 D.Kostrewa, F.K.Winkler, G.Folkers, L.Scapozza, and R.Perozzo (2005).
The crystal structure of PfFabZ, the unique beta-hydroxyacyl-ACP dehydratase involved in fatty acid biosynthesis of Plasmodium falciparum.
  Protein Sci, 14, 1570-1580.
PDB code: 1z6b
15852483 D.Tasdemir, R.Brun, R.Perozzo, and A.A.Dönmez (2005).
Evaluation of antiprotozoal and plasmodial enoyl-ACP reductase inhibition potential of turkish medicinal plants.
  Phytother Res, 19, 162-166.  
15757480 J.Wiesner, and F.Seeber (2005).
The plastid-derived organelle of protozoan human parasites as a target of established and emerging drugs.
  Expert Opin Ther Targets, 9, 23-44.  
15727041 R.J.Wilson (2005).
Parasite plastids: approaching the endgame.
  Biol Rev Camb Philos Soc, 80, 129-153.  
15895255 S.Köhler (2005).
Multi-membrane-bound structures of Apicomplexa: I. the architecture of the Toxoplasma gondii apicoplast.
  Parasitol Res, 96, 258-272.  
15952903 S.W.White, J.Zheng, Y.M.Zhang, and Rock (2005).
The structural biology of type II fatty acid biosynthesis.
  Annu Rev Biochem, 74, 791-831.  
15173840 D.A.Fidock, P.J.Rosenthal, S.L.Croft, R.Brun, and S.Nwaka (2004).
Antimalarial drug discovery: efficacy models for compound screening.
  Nat Rev Drug Discov, 3, 509-520.  
15302818 K.S.Paul, C.J.Bacchi, and P.T.Englund (2004).
Multiple triclosan targets in Trypanosoma brucei.
  Eukaryot Cell, 3, 855-861.  
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.  
14623959 B.U.Samuel, B.Hearn, D.Mack, P.Wender, J.Rothbard, M.J.Kirisits, E.Mui, S.Wernimont, C.W.Roberts, S.P.Muench, D.W.Rice, S.T.Prigge, A.B.Law, and R.McLeod (2003).
Delivery of antimicrobials into parasites.
  Proc Natl Acad Sci U S A, 100, 14281-14286.  
12692093 P.Gilbert, and A.J.McBain (2003).
Potential impact of increased use of biocides in consumer products on prevalence of antibiotic resistance.
  Clin Microbiol Rev, 16, 189-208.  
12499205 R.F.Waller, S.A.Ralph, M.B.Reed, V.Su, J.D.Douglas, D.E.Minnikin, A.F.Cowman, G.S.Besra, and G.I.McFadden (2003).
A type II pathway for fatty acid biosynthesis presents drug targets in Plasmodium falciparum.
  Antimicrob Agents Chemother, 47, 297-301.  
12832774 S.P.Muench, J.B.Rafferty, R.McLeod, D.W.Rice, and S.T.Prigge (2003).
Expression, purification and crystallization of the Plasmodium falciparum enoyl reductase.
  Acta Crystallogr D Biol Crystallogr, 59, 1246-1248.  
12037321 H.H.Lee, J.Yun, J.Moon, B.W.Han, B.I.Lee, J.Y.Lee, and S.W.Suh (2002).
Crystallization and preliminary X-ray crystallographic analysis of enoyl-acyl carrier protein reductase from Helicobacter pylori.
  Acta Crystallogr D Biol Crystallogr, 58, 1071-1073.  
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 codes are shown on the right.