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The crystal structure of the human carbonic anhydrase II in complex with an aliphatic sulfamate inhibitor
Structural highlights
DiseaseCAH2_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] FunctionCAH2_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 PubMedTwo approaches were used to design inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1): the tail and the ring approaches. Aliphatic sulfamates constitute a class of CA inhibitors (CAIs) that cannot be classified in either one of these categories. We report here the detailed inhibition profile of four such compounds against isoforms CAs I-XIV, the first crystallographic structures of these compounds in adduct with isoform II, and molecular modeling studies for their interaction with hCA IX. Aliphatic monosulfamates/bis-sulfamates were nanomolar inhibitors of hCAs II, IX, and XII, unlike aromatic/heterocyclic sulfonamides that promiscuously inhibit most CA isozymes with low nanomolar affinity. The bis-sulfamates incorporating 8 or 10 carbon atoms showed higher affinity for the tumor-associated hCA IX compared to hCA II, whereas the opposite was true for the monosulfamates. The explanation for their interaction with CA active site furnishes insights for obtaining compounds with increased affinity/selectivity for various isozymes. Carbonic Anhydrase Inhibitors. Comparison of Aliphatic Sulfamate/Bis-sulfamate Adducts with Isozymes II and IX as a Platform for Designing Tight-Binding, More Isoform-Selective Inhibitors.,Vitale RM, Alterio V, Innocenti A, Winum JY, Monti SM, De Simone G, Supuran CT J Med Chem. 2009 Sep 4. PMID:19731956[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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