PDBsum entry 1bvr

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Oxidoreductase PDB id
Protein chains
(+ 0 more) 268 a.a. *
NAD ×6
THT ×4
Waters ×663
* Residue conservation analysis
PDB id:
Name: Oxidoreductase
Title: M.Tb. Enoyl-acp reductase (inha) in complex with NAD+ and c1 acyl-substrate
Structure: Protein (enoyl-acyl carrier protein (acp) reducta chain: a, b, c, d, e, f. Synonym: inha. Engineered: yes
Source: Mycobacterium tuberculosis. Organism_taxid: 1773. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Tetramer (from PQS)
2.80Å     R-factor:   0.217     R-free:   0.344
Authors: D.A.Rozwarski,C.Vilcheze,M.Sugantino,R.Bittman,W.Jacobs,Tb S Genomics Consortium (Tbsgc)
Key ref:
D.A.Rozwarski et al. (1999). Crystal structure of the Mycobacterium tuberculosis enoyl-ACP reductase, InhA, in complex with NAD+ and a C16 fatty acyl substrate. J Biol Chem, 274, 15582-15589. PubMed id: 10336454 DOI: 10.1074/jbc.274.22.15582
17-Sep-98     Release date:   17-Sep-99    
Go to PROCHECK summary

Protein chains
P9WGR1  (INHA_MYCTU) -  Enoyl-[acyl-carrier-protein] reductase [NADH]
269 a.a.
268 a.a.
Key:    Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - 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]
Bound ligand (Het Group name = NAD)
corresponds exactly
= trans-2,3-dehydroacyl-[acyl- carrier protein]
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     oxidation-reduction process   5 terms 
  Biochemical function     oxidoreductase activity     2 terms  


DOI no: 10.1074/jbc.274.22.15582 J Biol Chem 274:15582-15589 (1999)
PubMed id: 10336454  
Crystal structure of the Mycobacterium tuberculosis enoyl-ACP reductase, InhA, in complex with NAD+ and a C16 fatty acyl substrate.
D.A.Rozwarski, C.Vilchèze, M.Sugantino, R.Bittman, J.C.Sacchettini.
Enoyl-ACP reductases participate in fatty acid biosynthesis by utilizing NADH to reduce the trans double bond between positions C2 and C3 of a fatty acyl chain linked to the acyl carrier protein. The enoyl-ACP reductase from Mycobacterium tuberculosis, known as InhA, is a member of an unusual FAS-II system that prefers longer chain fatty acyl substrates for the purpose of synthesizing mycolic acids, a major component of mycobacterial cell walls. The crystal structure of InhA in complex with NAD+ and a C16 fatty acyl substrate, trans-2-hexadecenoyl-(N-acetylcysteamine)-thioester, reveals that the substrate binds in a general "U-shaped" conformation, with the trans double bond positioned directly adjacent to the nicotinamide ring of NAD+. The side chain of Tyr158 directly interacts with the thioester carbonyl oxygen of the C16 fatty acyl substrate and therefore could help stabilize the enolate intermediate, proposed to form during substrate catalysis. Hydrophobic residues, primarily from the substrate binding loop (residues 196-219), engulf the fatty acyl chain portion of the substrate. The substrate binding loop of InhA is longer than that of other enoyl-ACP reductases and creates a deeper substrate binding crevice, consistent with the ability of InhA to recognize longer chain fatty acyl substrates.
  Selected figure(s)  
Figure 2.
Fig. 2. Conformation of bound substrate and shape of binding crevice. A, atomic coordinates of the InhA-bound NAD^+ and C16 fatty acyl substrate, trans-2-hexadecenoyl-(N-acetylcysteamine)-thioester, superimposed onto the final NCS-averaged simulated annealing "omit" electron density (44) map contoured at 0.8 . The different atom types are represented by unique colors: carbon (gray), oxygen (red), nitrogen (blue), sulfur (yellow), and phosphorus (magenta). The C16 fatty acyl substrate folds into a general U-shaped conformation, with the trans double bond located directly over the nicotinamide ring of NAD^+. B, solvent-accessible surface of the M. tuberculosis long chain substrate enoyl-ACP reductase (InhA) binding crevice shown in black dots. A portion of the bound NAD^+ (nicotinamide, nicotinamide ribose, and phosphates) is shown in green, and the bound C16 fatty acyl substrate is shown in red. C, solvent-accessible surface of the E. coli short chain substrate enoyl-ACP reductase (FabI) binding crevice shown in black dots. A portion of the bound NAD^+ (nicotinamide, nicotinamide ribose, and phosphates) is shown in green, and the bound benzodiazaborine drug is shown in cyan (Protein Data Bank entry 1dfg). The C16 fatty acyl substrate from the InhA ternary complex is superimposed onto the FabI surface. This figure was produced using the SPOCK program (57).
Figure 6.
Fig. 6. SDR family catalytic triad. A, schematic representation of the active site of the E. coli 7 -HSDH in complex with a bile acid product (7-oxo group) and NADH product (Protein Data Bank entry 1fmc). The SDR family catalytic triad is Ser^146-Tyr^159-Lys^163. The dashed lines represent hydrogen bonds, and the numeric values are their distances in angstroms. B, M. tuberculosis enoyl-ACP reductase (InhA) in complex with a C16 fatty acyl substrate and NAD^+. The structurally analogous SDR family catalytic triad of InhA is Phe^149-Tyr^158-Lys^165. This figure was produced using Chemistry 4-D Draw© (ChemInnovation Software, San Diego, CA, 1995).
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (1999, 274, 15582-15589) copyright 1999.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20055482 H.Lu, and P.J.Tonge (2010).
Mechanism and inhibition of the FabV enoyl-ACP reductase from Burkholderia mallei.
  Biochemistry, 49, 1281-1289.  
20028393 X.Y.Lu, Y.D.Chen, and Q.D.You (2010).
3D-QSAR studies of arylcarboxamides with inhibitory activity on InhA using pharmacophore-based alignment.
  Chem Biol Drug Des, 75, 195-203.  
19136596 A.Gurvitz, J.K.Hiltunen, and A.J.Kastaniotis (2009).
Heterologous expression of mycobacterial proteins in Saccharomyces cerevisiae reveals two physiologically functional 3-hydroxyacyl-thioester dehydratases, HtdX and HtdY, in addition to HadABC and HtdZ.
  J Bacteriol, 191, 2683-2690.  
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
19151923 R.P.Massengo-Tiassé, and J.E.Cronan (2009).
Diversity in enoyl-acyl carrier protein reductases.
  Cell Mol Life Sci, 66, 1507-1517.  
19429621 R.Reich-Slotky, C.A.Kabbash, P.Della-Latta, J.S.Blanchard, S.J.Feinmark, S.Freeman, G.Kaplan, H.A.Shuman, and S.C.Silverstein (2009).
Gemfibrozil inhibits Legionella pneumophila and Mycobacterium tuberculosis enoyl coenzyme A reductases and blocks intracellular growth of these bacteria in macrophages.
  J Bacteriol, 191, 5262-5271.  
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.  
18552191 A.Gurvitz, J.K.Hiltunen, and A.J.Kastaniotis (2008).
Function of heterologous Mycobacterium tuberculosis InhA, a type 2 fatty acid synthase enzyme involved in extending C20 fatty acids to C60-to-C90 mycolic acids, during de novo lipoic acid synthesis in Saccharomyces cerevisiae.
  Appl Environ Microbiol, 74, 5078-5085.  
18079742 J.C.Sacchettini, E.J.Rubin, and J.S.Freundlich (2008).
Drugs versus bugs: in pursuit of the persistent predator Mycobacterium tuberculosis.
  Nat Rev Microbiol, 6, 41-52.  
19011750 K.L.Kavanagh, H.Jörnvall, B.Persson, and U.Oppermann (2008).
Medium- and short-chain dehydrogenase/reductase gene and protein families : the SDR superfamily: functional and structural diversity within a family of metabolic and regulatory enzymes.
  Cell Mol Life Sci, 65, 3895-3906.  
18023422 N.M.Carballeira (2008).
New advances in fatty acids as antimalarial, antimycobacterial and antifungal agents.
  Prog Lipid Res, 47, 50-61.  
18772430 T.Maier, M.Leibundgut, and N.Ban (2008).
The crystal structure of a mammalian fatty acid synthase.
  Science, 321, 1315-1322.
PDB codes: 2vz8 2vz9
17719489 A.T.Keatinge-Clay (2007).
A tylosin ketoreductase reveals how chirality is determined in polyketides.
  Chem Biol, 14, 898-908.
PDB code: 2z5l
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
  17329825 K.H.Kim, J.K.Park, B.H.Ha, J.H.Moon, and E.E.Kim (2007).
Crystallization and preliminary X-ray crystallographic analysis of enoyl-ACP reductase III (FabL) from Bacillus subtilis.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 246-248.  
17600151 N.A.Kruh, R.Rawat, B.P.Ruzsicska, and P.J.Tonge (2007).
Probing mechanisms of resistance to the tuberculosis drug isoniazid: Conformational changes caused by inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis.
  Protein Sci, 16, 1617-1627.  
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
15908576 E.K.Schroeder, L.A.Basso, D.S.Santos, and Souza (2005).
Molecular dynamics simulation studies of the wild-type, I21V, and I16T mutants of isoniazid-resistant Mycobacterium tuberculosis enoyl reductase (InhA) in complex with NADH: toward the understanding of NADH-InhA different affinities.
  Biophys J, 89, 876-884.  
15977159 M.Cohen-Gonsaud, S.Ducasse-Cabanot, A.Quemard, and G.Labesse (2005).
Ligand-induced fit in mycobacterial MabA: the sequence-specific C-terminus locks the conformational change.
  Proteins, 60, 392-400.  
15389729 R.P.Tripathi, N.Tewari, N.Dwivedi, and V.K.Tiwari (2005).
Fighting tuberculosis: an old disease with new challenges.
  Med Res Rev, 25, 93.  
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.  
15554959 R.Veyron-Churlet, O.Guerrini, L.Mourey, M.Daffé, and D.Zerbib (2004).
Protein-protein interactions within the Fatty Acid Synthase-II system of Mycobacterium tuberculosis are essential for mycobacterial viability.
  Mol Microbiol, 54, 1161-1172.  
14623976 R.Rawat, A.Whitty, and P.J.Tonge (2003).
The isoniazid-NAD adduct is a slow, tight-binding inhibitor of InhA, the Mycobacterium tuberculosis enoyl reductase: adduct affinity and drug resistance.
  Proc Natl Acad Sci U S A, 100, 13881-13886.
PDB codes: 2x22 2x23
11870865 S.Pantano, F.Alber, D.Lamba, and P.Carloni (2002).
NADH interactions with WT- and S94A-acyl carrier protein reductase from Mycobacterium tuberculosis: an ab initio study.
  Proteins, 47, 62-68.  
12230552 Y.Kallberg, U.Oppermann, H.Jörnvall, and B.Persson (2002).
Short-chain dehydrogenases/reductases (SDRs).
  Eur J Biochem, 269, 4409-4417.  
11591436 R.J.Heath, S.W.White, and C.O.Rock (2001).
Lipid biosynthesis as a target for antibacterial agents.
  Prog Lipid Res, 40, 467-497.  
10841782 K.L.Fillgrove, and V.E.Anderson (2000).
Orientation of coenzyme A substrates, nicotinamide and active site functional groups in (Di)enoyl-coenzyme A reductases.
  Biochemistry, 39, 7001-7011.  
10801480 M.Fisher, J.T.Kroon, W.Martindale, A.R.Stuitje, A.R.Slabas, and J.B.Rafferty (2000).
The X-ray structure of Brassica napus beta-keto acyl carrier protein reductase and its implications for substrate binding and catalysis.
  Structure, 8, 339-347.
PDB code: 1edo
10869170 S.L.Parikh, G.Xiao, and P.J.Tonge (2000).
Inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis, by triclosan and isoniazid.
  Biochemistry, 39, 7645-7650.  
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.