6b4d
From Proteopedia
Crystal structure of human carbonic anhydrase II in complex with a heteroaryl-pyrazole carboxylic acid derivative.
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 PubMedWe report the synthesis, biological evaluation, and structural study of a series of substituted heteroaryl-pyrazole carboxylic acid derivatives. These compounds have been developed as inhibitors of specific isoforms of carbonic anhydrase (CA), with potential as prototypes of a new class of chemotherapeutics. Both X-ray crystallography and computational modeling provide insights into the CA inhibition mechanism. Results indicate that this chemotype produces an indirect interference with the zinc ion, thus behaving differently from other related nonclassical inhibitors. Among the tested compounds, 2c with Ki = 0.21 muM toward hCA XII demonstrated significant antiproliferative activity against hypoxic tumor cell lines. Taken together, the results thus provide the basis of structural determinants for the development of novel anticancer agents. Exploring Heteroaryl-pyrazole Carboxylic Acids as Human Carbonic Anhydrase XII Inhibitors.,Cadoni R, Pala N, Lomelino C, Mahon BP, McKenna R, Dallocchio R, Dessi A, Carcelli M, Rogolino D, Sanna V, Rassu M, Iaccarino C, Vullo D, Supuran CT, Sechi M ACS Med Chem Lett. 2017 Jul 31;8(9):941-946. doi: 10.1021/acsmedchemlett.7b00229., eCollection 2017 Sep 14. PMID:28947941[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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