Keywords: Carbonic Anhydrase Ix, Co2 Hydration, Drug Design, Sulfonamide Inhibitor, X-Ray Crystallography, Antineoplastic Agent, Carbonate Dehydratase Ix, Coumarin Derivative, Dimer, Isoenzyme, Phenol Derivative, Proteoglycan, Sulfanilamide, Tumor Marker, Biochemistry, Cancer Inhibition, Carboxy Terminal Sequence, Carcinogenesis, Cell Adhesion, Cell Membrane, Chemical Structure, Disulfide Bond, Drug Targeting, Enzyme Inhibition, Human, Hypoxia, Nonhuman, Ph Measurement, Priority Journal, Prognosis, Protein Quaternary Structure, Review, Antigens, Carbonic Anhydrase Inhibitors, Animalia, Mammalia,
Affiliations: *** IBB - CNR ***
Istituto di Biostrutture e Bioimmagini-CNR, via Mezzocannone 16, 80134 Naples, Italy
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy
Universit degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy
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Carbonic anhydrase IX: Biochemical and crystallographic characterization of a novel antitumor target
Isoform IX of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), CA IX, is a transmembrane protein involved in solid tumor acidification through the HIF-1 alpha activation cascade. CA IX has a very high catalytic activity for the hydration of carbon dioxide to bicarbonate and protons, even at acidic pH values (of around 6.5), typical of solid, hypoxic tumors, which are largely unresponsive to classical chemo- and radiotherapy. Thus, CA IX is used as a marker of tumor hypoxia and as a prognostic factor for many human cancers. CA IX is involved in tumorigenesis through many pathways, such as pH regulation and cell adhesion control. The Xray structure of the catalytic domain of CA IX has been recently reported, being shown that CA IX has a typical alpha-CA fold. However, the CA IX structure differs significantly from the other CA isozymes when the protein quaternary structure is considered. Thus, two catalytic domains of CA IX associate to form a dimer, which is stabilized by the formation of an intermolecular disulfide bond. The active site clefts and the proteoglycan (PG) domains are located on one face of the dimer, while the C-termini are located on the opposite face to facilitate protein anchoring to the cell membrane. As all mammalian CAs, CA IX is inhibited by several main classes of inhibitors, such as the inorganic anions, the sulfonamides and their bioisosteres (sulfamates, sulfamides, etc.), the phenols, and the coumarins. The mechanism of inhibition with all these classes of compounds is understood at the molecular level, but the sulfonamides and their congeners have important applications. It has been recently shown that both in vitro, in cell cultures, as well as in animals with transplanted tumors, CA IX inhibition with sulfonamides lead to a return of the extracellular pH to more normal values, which leads to a delay in tumor growth. As a consequence, CA IX represents a promising antitumor target for the development of anticancer agents with an alternative mechanism of action. (C) 2009 Elsevier B.V. All rights reserved.
Carbonic anhydrase IX: Biochemical and crystallographic characterization of a novel antitumor target