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PDBsum entry 2osm

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protein ligands metals links
Lyase PDB id
2osm
Jmol
Contents
Protein chain
258 a.a. *
Ligands
HTS
Metals
_ZN
Waters ×106
* Residue conservation analysis
PDB id:
2osm
Name: Lyase
Title: Inhibition of carbonic anhydrase ii by thioxolone: a mechani structural study
Structure: Carbonic anhydrase 2. Chain: a. Synonym: carbonic anhydrase ii, carbonate dehydratase ii, c carbonic anhydrasE C. Ec: 4.2.1.1
Source: Homo sapiens. Human. Organism_taxid: 9606
Resolution:
1.60Å     R-factor:   not given     R-free:   0.220
Authors: A.B.Albert,G.Caroli,L.Govindasamy,M.Agbandje-Mckenna,R.Mcken B.C.Tripp
Key ref: A.A.Barrese et al. (2008). Inhibition of carbonic anhydrase II by thioxolone: a mechanistic and structural study. Biochemistry, 47, 3174-3184. PubMed id: 18266323 DOI: 10.1021/bi702385k
Date:
06-Feb-07     Release date:   12-Feb-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00918  (CAH2_HUMAN) -  Carbonic anhydrase 2
Seq:
Struc:
260 a.a.
258 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.4.2.1.1  - Carbonate dehydratase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: H2CO3 = CO2 + H2O
H(2)CO(3)
= CO(2)
+ H(2)O
      Cofactor: Zn(2+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular space   11 terms 
  Biological process     angiotensin-mediated signaling pathway   21 terms 
  Biochemical function     protein binding     5 terms  

 

 
    Added reference    
 
 
DOI no: 10.1021/bi702385k Biochemistry 47:3174-3184 (2008)
PubMed id: 18266323  
 
 
Inhibition of carbonic anhydrase II by thioxolone: a mechanistic and structural study.
A.A.Barrese, C.Genis, S.Z.Fisher, J.N.Orwenyo, M.T.Kumara, S.K.Dutta, E.Phillips, J.J.Kiddle, C.Tu, D.N.Silverman, L.Govindasamy, M.Agbandje-McKenna, R.McKenna, B.C.Tripp.
 
  ABSTRACT  
 
This paper examines the functional mechanism of thioxolone, a compound recently identified as a weak inhibitor of human carbonic anhydrase II by Iyer et al. (2006) J. Biomol. Screening 11, 782-791 . Thioxolone lacks sulfonamide, sulfamate, or hydroxamate functional groups that are typically found in therapeutic carbonic anhydrase (CA) inhibitors, such as acetazolamide. Analytical chemistry and biochemical methods were used to investigate the fate of thioxolone upon binding to CA II, including Michaelis-Menten kinetics of 4-nitrophenyl acetate esterase cleavage, liquid chromatography-mass spectrometry (LC-MS), oxygen-18 isotope exchange studies, and X-ray crystallography. Thioxolone is proposed to be a prodrug inhibitor that is cleaved via a CA II zinc-hydroxide mechanism known to catalyze the hydrolysis of esters. When thioxolone binds in the active site of CA II, it is cleaved and forms 4-mercaptobenzene-1,3-diol via the intermediate S-(2,4-thiophenyl)hydrogen thiocarbonate. The esterase cleavage product binds to the zinc active site via the thiol group and is therefore the active CA inhibitor, while the intermediate is located at the rim of the active-site cavity. The time-dependence of this inhibition reaction was investigated in detail. Because this type of prodrug inhibitor mechanism depends on cleavage of ester bonds, this class of inhibitors may have advantages over sulfonamides in determining isozyme specificity. A preliminary structure-activity relationship study with a series of structural analogues of thioxolone yielded similar estimates of inhibition constants for most compounds, although two compounds with bromine groups at the C1 carbon of thioxolone were not inhibitory, suggesting a possible steric effect.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20629007 J.Schulze Wischeler, A.Innocenti, D.Vullo, A.Agrawal, S.M.Cohen, A.Heine, C.T.Supuran, and G.Klebe (2010).
Bidentate Zinc chelators for alpha-carbonic anhydrases that produce a trigonal bipyramidal coordination geometry.
  ChemMedChem, 5, 1609-1615.
PDB code: 3m1k
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