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PDBsum entry 2ccd

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Oxidoreductase PDB id
2ccd
Jmol
Contents
Protein chains
715 a.a. *
Ligands
HEM ×2
Waters ×595
* Residue conservation analysis
PDB id:
2ccd
Name: Oxidoreductase
Title: Crystal structure of the catalase-peroxidase (katg) and s315t mutant from mycobacterium tuberculosis
Structure: Peroxidase/catalase t. Chain: a, b. Synonym: katg s315t, catalase-peroxidase t. Engineered: yes. Mutation: yes. Other_details: heme protorphyrin ix fe(iii)
Source: Mycobacterium tuberculosis. Organism_taxid: 1773. Strain: mtb h37rv. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Dimer (from PDB file)
Resolution:
2.10Å     R-factor:   0.232     R-free:   0.276
Authors: H.Yu,J.C.Sacchettini
Key ref: X.Zhao et al. (2006). Hydrogen peroxide-mediated isoniazid activation catalyzed by Mycobacterium tuberculosis catalase-peroxidase (KatG) and its S315T mutant. Biochemistry, 45, 4131-4140. PubMed id: 16566587 DOI: 10.1021/bi051967o
Date:
16-Jan-06     Release date:   19-Jan-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam  
P9WIE4  (KATG_MYCTO) -  Catalase-peroxidase
Seq:
Struc:
 
Seq:
Struc:
740 a.a.
715 a.a.*
Key:    Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.1.11.1.21  - Catalase peroxidase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction:
1. Donor + H2O2 = oxidized donor + 2 H2O
2. 2 H2O2 = O2 + 2 H2O
Donor
+ H(2)O(2)
= oxidized donor
+ 2 × H(2)O
2 × H(2)O(2)
= O(2)
+ 2 × H(2)O
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     oxidation-reduction process   4 terms 
  Biochemical function     oxidoreductase activity     5 terms  

 

 
    reference    
 
 
DOI no: 10.1021/bi051967o Biochemistry 45:4131-4140 (2006)
PubMed id: 16566587  
 
 
Hydrogen peroxide-mediated isoniazid activation catalyzed by Mycobacterium tuberculosis catalase-peroxidase (KatG) and its S315T mutant.
X.Zhao, H.Yu, S.Yu, F.Wang, J.C.Sacchettini, R.S.Magliozzo.
 
  ABSTRACT  
 
Inhibition of the enzyme Mycobacterium tuberculosis InhA (enoyl-acyl carrier protein reductase) due to formation of an isonicotinoyl-NAD adduct (IN-NAD) from isoniazid (INH) and nicotinamide adenine dinucleotide cofactor is considered central to the mode of action of INH, a first-line treatment for tuberculosis infection. INH action against mycobacteria requires catalase-peroxidase (KatG) function, and IN-NAD adduct formation is catalyzed in vitro by M. tuberculosis KatG under a variety of conditions, yet a physiologically relevant approach to the process has not emerged that allows scrutiny of the mechanism and the origins of INH resistance in the most prevalent drug-resistant strain bearing KatG[S315T]. In this report, we describe how hydrogen peroxide, delivered at very low concentrations to ferric KatG, leads to efficient inhibition of InhA due to formation of the IN-NAD adduct. The rate of adduct formation mediated by wild-type KatG was about 20-fold greater than by the isoniazid-resistant KatG[S315T] mutant under optimal conditions (H2O2 supplied along with NAD+ and INH). Slow adduct formation also occurs starting with NADH and INH, in the presence of KatG even in the absence of added peroxide, due to endogenous peroxide. The poor efficiency of the KatG[S315T] mutant can be enhanced merely by increasing the concentration of INH, consistent with this enzyme's reduced affinity for INH binding to the resting enzyme and the catalytically competent enzyme intermediate (Compound I). Origins of drug resistance in the KatG[S315T] mutant enzyme are analyzed at the structural level through examination of the three-dimensional X-ray crystal structure of the mutant enzyme.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21330112 G.Ramasubban, K.L.Therese, U.Vetrivel, M.Sivashanmugam, P.Rajan, R.Sridhar, H.N.Madhavan, and N.Meenakshi (2011).
Detection of novel coupled mutations in the katG gene (His276Met, Gln295His and Ser315Thr) in a multidrug-resistant Mycobacterium tuberculosis strain from Chennai, India, and insight into the molecular mechanism of isoniazid resistance using structural bioinformatics approaches.
  Int J Antimicrob Agents, 37, 368-372.  
20593210 R.Purohit, V.Rajendran, and R.Sethumadhavan (2011).
Relationship between mutation of serine residue at 315th position in M. tuberculosis catalase-peroxidase enzyme and Isoniazid susceptibility: An in silico analysis.
  J Mol Model, 17, 869-877.  
20054829 C.E.Cade, A.C.Dlouhy, K.F.Medzihradszky, S.P.Salas-Castillo, and R.A.Ghiladi (2010).
Isoniazid-resistance conferring mutations in Mycobacterium tuberculosis KatG: catalase, peroxidase, and INH-NADH adduct formation activities.
  Protein Sci, 19, 458-474.  
20566771 F.Wang, P.Jain, G.Gulten, Z.Liu, Y.Feng, K.Ganesula, A.S.Motiwala, T.R.Ioerger, D.Alland, C.Vilchèze, W.R.Jacobs, and J.C.Sacchettini (2010).
Mycobacterium tuberculosis dihydrofolate reductase is not a target relevant to the antitubercular activity of isoniazid.
  Antimicrob Agents Chemother, 54, 3776-3782.  
19933836 H.I.Lee, J.H.Yoon, J.S.Nam, Y.M.Kim, and Y.T.Ro (2010).
Cloning, expression and characterization of the catalase-peroxidase (KatG) gene from a fast-growing Mycobacterium sp. strain JC1 DSM 3803.
  J Biochem, 147, 511-522.  
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.  
19363028 J.Suarez, K.Ranguelova, J.P.Schelvis, and R.S.Magliozzo (2009).
Antibiotic Resistance in Mycobacterium tuberculosis: PEROXIDASE INTERMEDIATE BYPASS CAUSES POOR ISONIAZID ACTIVATION BY THE S315G MUTANT OF M. TUBERCULOSIS CATALASE-PEROXIDASE (KatG).
  J Biol Chem, 284, 16146-16155.  
19129167 M.Bernroitner, M.Zamocky, P.G.Furtmüller, G.A.Peschek, and C.Obinger (2009).
Occurrence, phylogeny, structure, and function of catalases and peroxidases in cyanobacteria.
  J Exp Bot, 60, 423-440.  
19139098 X.Zhao, S.Yu, K.Ranguelova, J.Suarez, L.Metlitsky, J.P.Schelvis, and R.S.Magliozzo (2009).
Role of the Oxyferrous Heme Intermediate and Distal Side Adduct Radical in the Catalase Activity of Mycobacterium tuberculosis KatG Revealed by the W107F Mutant.
  J Biol Chem, 284, 7030-7037.  
18831539 K.Ranguelova, J.Suarez, R.S.Magliozzo, and R.P.Mason (2008).
Spin trapping investigation of peroxide- and isoniazid-induced radicals in Mycobacterium tuberculosis catalase-peroxidase.
  Biochemistry, 47, 11377-11385.  
18498226 M.Zamocky, P.G.Furtmüller, and C.Obinger (2008).
Evolution of catalases from bacteria to humans.
  Antioxid Redox Signal, 10, 1527-1548.  
18368168 R.I.Amos, B.S.Gourlay, C.H.Schiesser, J.A.Smith, and B.F.Yates (2008).
A mechanistic study on the oxidation of hydrazides: application to the tuberculosis drug isoniazid.
  Chem Commun (Camb), (), 1695-1697.  
17636923 A.Argyrou, M.W.Vetting, and J.S.Blanchard (2007).
New insight into the mechanism of action of and resistance to isoniazid: interaction of Mycobacterium tuberculosis enoyl-ACP reductase with INH-NADP.
  J Am Chem Soc, 129, 9582-9583.
PDB code: 2pr2
17204474 K.Ranguelova, S.Girotto, G.J.Gerfen, S.Yu, J.Suarez, L.Metlitsky, and R.S.Magliozzo (2007).
Radical sites in Mycobacterium tuberculosis KatG identified using electron paramagnetic resonance spectroscopy, the three-dimensional crystal structure, and electron transfer couplings.
  J Biol Chem, 282, 6255-6264.  
17188362 S.M.Kapetanaki, X.Zhao, S.Yu, R.S.Magliozzo, and J.P.Schelvis (2007).
Modification of the active site of Mycobacterium tuberculosis KatG after disruption of the Met-Tyr-Trp cross-linked adduct.
  J Inorg Biochem, 101, 422-433.  
17074073 G.S.Timmins, and V.Deretic (2006).
Mechanisms of action of isoniazid.
  Mol Microbiol, 62, 1220-1227.  
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.