2ez7
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Carbonic anhydrase activators. Activation of isozymes I, II, IV, VA, VII and XIV with L- and D-histidine and crystallographic analysis of their adducts with isoform II: engineering proton transfer processes within the active site of an enzyme
OverviewOverview
Activation of six human carbonic anhydrases (CA, EC 4.2.1.1), that is, hCA, I, II, IV, VA, VII, and XIV, with l- and d-histidine was investigated, through kinetics and by X-ray crystallography. l-His was a potent, activator of isozymes I, VA, VII, and XIV, and a weaker activator of hCA, II and IV. d-His showed good hCA I, VA, and VII activation properties, being a moderate activator of hCA XIV and a weak activator of hCA II and, IV. The structures as determined by X-ray crystallography of the hCA, II-l-His/d-His adducts showed the activators to be anchored at the, entrance of the active site, contributing to extended networks of hydrogen, bonds with amino acid residues/water molecules present in the cavity, explaining their different potency and interaction patterns with various, isozymes. The residues involved in l-His recognition were His64, Asn67, Gln92, whereas three water molecules connected the activator to the, zinc-bound hydroxide. Only the imidazole moiety of l-His interacted with, these amino acids. For the d-His adduct, the residues involved in, recognition of the activator were Trp5, His64, and Pro201, whereas two, water molecules connected the zinc-bound water to the activator. Only the, COOH and NH(2) moieties of d-His participated in hydrogen bonds with these, residues. 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). The study also points out differences of activation efficiency, between various isozymes with structurally related activators, convenient, for designing alternative proton-transfer pathways, useful both for a, better understanding of the catalytic mechanism and for obtaining, pharmacologically useful derivatives, for example, for the management of, Alzheimer's disease.
DiseaseDisease
Known disease associated with this structure: Osteopetrosis, autosomal recessive 3, with renal tubular acidosis OMIM:[611492]
About this StructureAbout this Structure
2EZ7 is a Single protein structure of sequence from Homo sapiens with HG, ZN and DHI as ligands. Active as Carbonate dehydratase, with EC number 4.2.1.1 Full crystallographic information is available from OCA.
ReferenceReference
Carbonic anhydrase activators. Activation of isozymes I, II, IV, VA, VII, and XIV with l- and d-histidine and crystallographic analysis of their adducts with isoform II: engineering proton-transfer processes within the active site of an enzyme., Temperini C, Scozzafava A, Vullo D, Supuran CT, Chemistry. 2006 Sep 18;12(27):7057-66. PMID:16807956
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