2ez7
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 enzymeCarbonic 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
Structural highlights
Disease[CAH2_HUMAN] Defects in CA2 are the cause of osteopetrosis autosomal recessive type 3 (OPTB3) [MIM:259730]; also known as osteopetrosis with renal tubular acidosis, carbonic anhydrase II deficiency syndrome, Guibaud-Vainsel syndrome or marble brain disease. Osteopetrosis is a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. The disorder occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Autosomal recessive osteopetrosis is usually associated with normal or elevated amount of non-functional osteoclasts. OPTB3 is associated with renal tubular acidosis, cerebral calcification (marble brain disease) and in some cases with mental retardation.[1] [2] [3] [4] [5] Function[CAH2_HUMAN] Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye.[6] [7] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedActivation 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. 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[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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