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PDBsum entry 2fmz
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References listed in PDB file
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Key reference
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Title
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Carbonic anhydrase activators. Activation of isoforms i, Ii, Iv, Va, Vii, And xiv with l- And d-Phenylalanine and crystallographic analysis of their adducts with isozyme ii: stereospecific recognition within the active site of an enzyme and its consequences for the drug design.
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Authors
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C.Temperini,
A.Scozzafava,
D.Vullo,
C.T.Supuran.
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Ref.
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J Med Chem, 2006,
49,
3019-3027.
[DOI no: ]
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PubMed id
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Abstract
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Activation of six human brain carbonic anhydrases (hCAs, EC 4.2.1.1), hCA I, II,
IV, VA, VII, and XIV, with l-/d-phenylalanine was investigated kinetically and
by X-ray crystallography. l-Phe was a potent activator of isozymes I, II, and
XIV (K(A)s of 13-240 nM), a weaker activator of hCA VA and VII (K(A)s of
9.8-10.9 microM), and a quite inefficient hCA IV activator (K(A) of 52 microM).
d-Phe showed good hCA II activatory properties (K(A) of 35 nM), being a moderate
hCA VA, VII, and XIV (K(A)s of 4.6-9.7 microM) and a weak hCA I and IV activator
(K(A)s of 63-86 microM). X-ray crystallography of the hCA II-l-Phe/d-Phe adducts
showed the activators to be anchored at the entrance of the active site,
participating in numerous bonds and hydrophobic interactions with amino acid
residues His64, Thr200, Trp5, and Pro201. This is the first study showing
different binding modes of stereoisomeric activators within the hCA II active
site, with consequences for overall proton transfer processes (rate-determining
for the catalytic cycle). It also points out differences of activation
efficiency between various isozymes with structurally related activators,
exploitable for designing alternative proton transfer pathways. CA activators
may lead to the design of pharmacologically useful derivatives for the
enhancement of synaptic efficacy, which may represent a conceptually new
approach for the treatment of Alzheimer's disease, aging, and other conditions
in which spatial learning and memory therapy must be enhanced. As the blood and
brain concentrations of l-Phe are quite variable (30-73 microM), activity of
some brain CAs may strongly be influenced by the level of activator(s) present
in such tissues.
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