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PDBsum entry 3f8e
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* Residue conservation analysis
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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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+
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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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J Am Chem Soc
131:3057-3062
(2009)
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PubMed id:
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Non-zinc mediated inhibition of carbonic anhydrases: coumarins are a new class of suicide inhibitors.
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A.Maresca,
C.Temperini,
H.Vu,
N.B.Pham,
S.A.Poulsen,
A.Scozzafava,
R.J.Quinn,
C.T.Supuran.
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ABSTRACT
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The X-ray crystal structure of the adduct between the zinc metalloenzyme
carbonic anhydrase II (CA, EC 4.2.1.1) with the recently discovered natural
product coumarin derivative
6-(1S-hydroxy-3-methylbutyl)-7-methoxy-2H-chromen-2-one showed the coumarin
hydrolysis product, a cis-2-hydroxy-cinnamic acid derivative, and not the parent
coumarin, bound within the enzyme active site. The bound inhibitor exhibits an
extended, two-arm conformation that effectively plugs the entrance to the enzyme
active site with no interactions with the catalytically crucial zinc ion. The
inhibitor is sandwiched between Phe131, with which it makes an edge-to-face
stacking, and Asn67/Glu238sym, with which it makes several polar and hydrogen
bonding interactions. This unusual binding mode, with no interactions between
the inhibitor molecule and the active site metal ion is previously unobserved
for this enzyme class and presents a new opportunity for future drug design
campaigns to target a mode of inhibition that differs substantially from
classical inhibitors such as the clinically used sulfonamides and sulfamates.
Several structurally simple coumarin scaffolds were also shown to inhibit all 13
catalytically active mammalian CA isoforms, with inhibition constants ranging
from nanomolar to millimolar. The inhibition is time dependent, with maximum
inhibition being observed after 6 h.
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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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C.T.Supuran
(2011).
Carbonic anhydrase inhibition with natural products: novel chemotypes and inhibition mechanisms.
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Mol Divers,
15,
305-316.
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F.Carta,
A.Innocenti,
R.A.Hall,
F.A.Mühlschlegel,
A.Scozzafava,
and
C.T.Supuran
(2011).
Carbonic anhydrase inhibitors. Inhibition of the β-class enzymes from the fungal pathogens Candida albicans and Cryptococcus neoformans with branched aliphatic/aromatic carboxylates and their derivatives.
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Bioorg Med Chem Lett,
21,
2521-2526.
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F.Mincione,
F.Benedini,
S.Biondi,
A.Cecchi,
C.Temperini,
G.Formicola,
I.Pacileo,
A.Scozzafava,
E.Masini,
and
C.T.Supuran
(2011).
Synthesis and crystallographic analysis of new sulfonamides incorporating NO-donating moieties with potent antiglaucoma action.
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Bioorg Med Chem Lett,
21,
3216-3221.
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PDB code:
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H.Sahin,
R.Aliyazicioglu,
O.Yildiz,
S.Kolayli,
A.Innocenti,
and
C.T.Supuran
(2011).
Honey, polen, and propolis extracts show potent inhibitory activity against the zinc metalloenzyme carbonic anhydrase.
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J Enzyme Inhib Med Chem,
26,
440-444.
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Y.Liu,
M.She,
Z.Wu,
and
R.Dai
(2011).
The inhibition study of human UDP-glucuronosyltransferases with cytochrome P450 selective substrates and inhibitors.
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J Enzyme Inhib Med Chem,
26,
386-393.
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Z.Qiao,
L.Liu,
and
D.Wang
(2011).
10-Phenyl-6b,7,8,9,9a,10-hexa-hydro-6H-cyclo-penta-[4,5]pyrano[3,2-c]chromen-6,9-dione.
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Acta Crystallogr Sect E Struct Rep Online,
67,
o855.
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F.Pacchiano,
M.Aggarwal,
B.S.Avvaru,
A.H.Robbins,
A.Scozzafava,
R.McKenna,
and
C.T.Supuran
(2010).
Selective hydrophobic pocket binding observed within the carbonic anhydrase II active site accommodate different 4-substituted-ureido-benzenesulfonamides and correlate to inhibitor potency.
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Chem Commun (Camb),
46,
8371-8373.
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PDB codes:
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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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S.B.Sarikaya,
I.Gülçin,
and
C.T.Supuran
(2010).
Carbonic anhydrase inhibitors: Inhibition of human erythrocyte isozymes I and II with a series of phenolic acids.
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Chem Biol Drug Des,
75,
515-520.
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V.Alterio,
S.M.Monti,
E.Truppo,
C.Pedone,
C.T.Supuran,
and
G.De Simone
(2010).
The first example of a significant active site conformational rearrangement in a carbonic anhydrase-inhibitor adduct: the carbonic anhydrase I-topiramate complex.
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Org Biomol Chem,
8,
3528-3533.
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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
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.
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Links
