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PDBsum entry 2osf
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Contents |
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* Residue conservation analysis
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PDB id:
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Lyase
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Title:
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Inhibition of carbonic anhydrase ii by thioxolone: a mechanistic and structural study
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Structure:
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Carbonic anhydrase 2. Chain: a. Fragment: carbonic anhydrase ii. Synonym: carbonic anhydrase ii, carbonate dehydratase ii, ca-ii, carbonic anhydrasE C. Ec: 4.2.1.1
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Source:
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Homo sapiens. Human
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Resolution:
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1.60Å
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R-factor:
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not given
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R-free:
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0.211
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Authors:
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A.B.Albert,G.Caroli,L.Govindasamy,M.Agbandje-Mckenna,R.Mckenna, B.C.Tripp
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Key ref:
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A.A.Barrese
et al.
(2008).
Inhibition of carbonic anhydrase II by thioxolone: a mechanistic and structural study.
Biochemistry,
47,
3174-3184.
PubMed id:
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Date:
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05-Feb-07
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Release date:
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27-May-08
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PROCHECK
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Headers
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References
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P00918
(CAH2_HUMAN) -
Carbonic anhydrase 2 from Homo sapiens
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Seq:
Struc:
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260 a.a.
257 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.4.2.1.1
- carbonic anhydrase.
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Reaction:
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hydrogencarbonate + H+ = CO2 + H2O
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hydrogencarbonate
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H(+)
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=
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CO2
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+
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H2O
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Cofactor:
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Zn(2+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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Biochemistry
47:3174-3184
(2008)
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PubMed id:
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Inhibition of carbonic anhydrase II by thioxolone: a mechanistic and structural study.
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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.
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ABSTRACT
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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.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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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.
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ChemMedChem,
5,
1609-1615.
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PDB code:
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
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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.
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Links
