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J. Biol. Chem., Vol. 280, Issue 19, 18782-18789, May 13, 2005

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Structure and Function of Carbonic Anhydrases from Mycobacterium tuberculosis^*

Adrian Suarez Covarrubias, Anna M. Larsson, Martin Högbom, Jimmy Lindberg, Terese Bergfors, Christofer Björkelid, Sherry L. Mowbray, Torsten Unge, and T. Alwyn Jones¶

From the Department of Cell and Molecular Biology, Uppsala University, S-751 24 Uppsala, Sweden and Department of Molecular Biology, Swedish University of Agricultural Sciences, S-751 24 Uppsala, Sweden

Carbonic anhydrases catalyze the reversible hydration of carbon dioxide to form bicarbonate. This activity is universally required for fatty acid biosynthesis as well as for the production of a number of small molecules, pH homeostasis, and other functions. At least three different carbonic anhydrase families are known to exist, of which the -class found in humans has been studied in most detail. In the present work, we describe the structures of two of the three -class carbonic anhydrases that have been identified in Mycobacterium tuberculosis, i.e. Rv1284 and Rv3588c. Both structures were solved by molecular replacement and then refined to resolutions of 2.0 and 1.75 Å, respectively. The active site of Rv1284 is small and almost completely shielded from solvent, whereas that of Rv3588c is larger and quite open to solution. Differences in coordination of the active site metal are also observed. In Rv3588c, an aspartic acid side chain displaces a water molecule and coordinates directly to the zinc ion, thereby closing the zinc coordination sphere and breaking the salt link to a nearby arginine that is a feature of Rv1284. The two carbonic anhydrases thus exhibit both of the metal coordination geometries that have previously been observed for structures in this family. Activity studies demonstrate that Rv3588c is a completely functional carbonic anhydrase. The apparent lack of activity of Rv1284 in the present assay system is likely exacerbated by the observed depletion of zinc in the preparation.

Received for publication, December 21, 2004

^* This work was supported by the Swedish Foundation for Strategic Research, the Swedish Research Council, and the European Commission programs SPINE (QLG2-CT-2002-00988) and X-TB (QLRT-2000-02018). 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.

The atomic coordinates and structure factors (codes 1YLK and 1YM3) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^¶ To whom correspondence should be addressed: Dept. of Cell and Molecular Biology, Uppsala University, Biomedical Center, Box 596, S-751 24 Uppsala, Sweden. Tel.: 46-18-4714982; Fax: 46-18-536971; E-mail: alwyn{at}xray.bmc.uu.se.

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