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J. Biol. Chem., Vol. 279, Issue 4, 2719-2727, January 23, 2004

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Characterization of CA XIII, a Novel Member of the Carbonic Anhydrase Isozyme Family^*

Jonna Lehtonen, Bairong Shen, Mauno Vihinen, Angela Casini, Andrea Scozzafava, Claudiu T. Supuran, Anna-Kaisa Parkkila¶, Juha Saarnio||, Antti J. Kivelä**, Abdul Waheed, William S. Sly, and Seppo Parkkila¶¶

From the Institute of Medical Technology and the ^¶Department of Neurology, University of Tampere and Tampere University Hospital, Lenkkeilijänkatu 8, 33520 Tampere, Finland, the Università degli Studi di Firenze, Dipartimento di Chimica, Laboratorio di Chimica Bioinorganica, Room 188, Via della Lastruccia 3, I-50019, Sesto Fiorentino (Firenze), Italy, the Departments of ^||Surgery, ^**Anatomy and Cell Biology, and Clinical Chemistry, University of Oulu, Kajaanintie 50, 90220 Oulu, Finland, and the Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri 63104

The carbonic anhydrase (CA) gene family has been reported to consist of at least 11 enzymatically active members and a few inactive homologous proteins. Recent analyses of human and mouse databases provided evidence that human and mouse genomes contain genes for still another novel CA isozyme hereby named CA XIII. In the present study, we modeled the structure of human CA XIII. This model revealed a globular molecule with high structural similarity to cytosolic isozymes, CA I, II, and III. Recombinant mouse CA XIII showed catalytic activity similar to those of mitochondrial CA V and cytosolic CA I, with k_cat/K_m of 4.3 x 10⁷ M^–1 s^–1, and k_cat of 8.3 x 10⁴ s^–1. It is very susceptible to inhibition by sulfonamide and anionic inhibitors, with inhibition constants of 17 nM for acetazolamide, a clinically used sulfonamide, and of 0.25 µM, for cyanate, respectively. Using panels of cDNAs we evaluated human and mouse CA13 gene expression in a number of different tissues. In human tissues, positive signals were identified in the thymus, small intestine, spleen, prostate, ovary, colon, and testis. In mouse, positive tissues included the spleen, lung, kidney, heart, brain, skeletal muscle, and testis. We also investigated the cellular and subcellular localization of CA XIII in human and mouse tissues using an antibody raised against a polypeptide of 14 amino acids common for both human and mouse orthologues. Immunohistochemical staining showed a unique and widespread distribution pattern for CA XIII compared with the other cytosolic CA isozymes. In conclusion, the predicted amino acid sequence, structural model, distribution, and activity data suggest that CA XIII represents a novel enzyme, which may play important physiological roles in several organs.

Received for publication, August 13, 2003 , and in revised form, November 3, 2003.

^* The work was supported by grants from the Sigrid Juselius Foundation, the Medical Research Funds of Tampere and Oulu University Hospitals and Academy of Finland (to S. P.), from the Academy of Finland and the Medical Research Fund of Tampere University Hospital (to M. V.), and from the National Institutes of Health (GM34182 and DK40163) (to W. S. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶¶ To whom correspondence should be addressed: Institute of Medical Technology, University of Tampere, Lenkkeilijänkatu 8, 33520 Tampere, Finland. Tel.: 358-3-2158595; Fax: 358-3-2158597; E-mail: Seppo.Parkkila{at}uta.fi.

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