NDLI: Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX

Content Provider	PubMed Central
Author	Alterio, Vincenzo Mika, Hilvo Fiore, Anna Di Supuran, Claudiu T. Pan, Peiwen Parkkila, Seppo Scaloni, Andrea Pastorek, Jaromir Silvia, Pastorekova Pedone, Carlo Scozzafava, Andrea Monti, Simona Maria Simone, Giuseppina De
Abstract	Carbonic anhydrase (CA) IX is a plasma membrane-associated member of the α-CA enzyme family, which is involved in solid tumor acidification. It is a marker of tumor hypoxia and a prognostic factor in several human cancers. An aberrant increase in CA IX expression in chronic hypoxia and during development of various carcinomas contributes to tumorigenesis through at least two mechanisms: pH regulation and cell adhesion control. Here we report the X-ray structure of the catalytic domain of CA IX in complex with a classical, clinically used sulfonamide inhibitor, acetazolamide. The structure reveals a typical α-CA fold, which significantly differs 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 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. A correlation between the three-dimensional structure and the physiological role of the enzyme is here suggested, based on the measurement of the pH profile of the catalytic activity for the physiological reaction, CO2 hydration to bicarbonate and protons. On the basis of the structural differences observed between CA IX and the other membrane-associated α-CAs, further prospects for the rational drug design of isozyme-specific CA inhibitors are proposed, given that inhibition of this enzyme shows antitumor activity both in vitro and in vivo.
Related Links	http://dx.doi.org/10.1073/pnas.0908301106
Ending Page	16238
Page Count	6
Starting Page	16233
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	38
Volume Number	106
Language	English
Publisher	National Academy of Sciences
Publisher Date	2009-09-22
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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