5fdi
Crystal structure of Human Carbonic Anhydrase II with the anticonvulsant sulfamide JNJ-26990990 and its S,S-dioxide analog.
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] Publication Abstract from PubMedJNJ-26990990 ((benzo[b]thien-3-yl)methyl)sulfamide, a sulfamide derivative structurally related to the antiepileptic drug zonisamide, was reported to be devoid of carbonic anhydrase (CA, EC 4.2.1.1) inhibitory properties. Here we report that JNJ-26990990 and its S,S-dioxide analog significantly inhibit six human (h) isoforms, hCA I, II, VII, IX, XII and XIV, involved in crucial physiological processes. Inhibition and X-ray crystallographic data for the binding of the two compounds to these enzymes show significant similarity with the zonisamide inhibitory pattern. These findings prompted us to reconsider the structural/pharmacological requirements for designing effective antiepileptics possessing zinc-binding groups of the sulfamide, sulfamate or sulfonamide type in their molecules. The anticonvulsant sulfamide JNJ-26990990 and its S,S-dioxide analog strongly inhibit carbonic anhydrases: solution and X-ray crystallographic studies.,Di Fiore A, De Simone G, Alterio V, Riccio V, Winum JY, Carta F, Supuran CT Org Biomol Chem. 2016 Jun 7;14(21):4853-8. doi: 10.1039/c6ob00803h. Epub 2016 May, 6. PMID:27151329[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
