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J. Biol. Chem., Vol. 283, Issue 6, 3559-3566, February 8, 2008

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Crystal Structure of Human Kynurenine Aminotransferase II, a Drug Target for the Treatment of Schizophrenia^*

Franca Rossi¹, Silvia Garavaglia¹, Valeria Montalbano, Martin A. Walsh, and Menico Rizzi²

From the DiSCAFF-INFM, University of Piemonte Orientale "A. Avogadro", 28100 Novara, Italy and Medical Research Council France, c/o European Synchrotron Radiation Facility, 38043 Grenoble Cedex, France

Kynurenic acid is an endogenous neuroactive compound whose unbalancing is involved in the pathogenesis and progression of several neurological diseases. Kynurenic acid synthesis in the human brain is sustained by the catalytic activity of two kynurenine aminotransferases, hKAT I and hKAT II. A wealth of pharmacological data highlight hKAT II as a sensible target for the treatment of neuropathological conditions characterized by a kynurenic acid excess, such as schizophrenia and cognitive impairment. We have solved the structure of human KAT II by means of the single-wavelength anomalous dispersion method at 2.3-Å resolution. Although closely resembling the classical aminotransferase fold, the hKAT II architecture displays unique features. Structural comparison with a prototypical aspartate aminotransferase reveals a novel antiparallel strand-loop-strand motif that forms an unprecedented intersubunit β-sheet in the functional hKAT II dimer. Moreover, the N-terminal regions of hKAT II and aspartate aminotransferase appear to have converged to highly similar although 2-fold symmetry-related conformations, which fulfill the same functional role. A detailed structural comparison of hKAT I and hKAT II reveals a larger and more aliphatic character to the active site of hKAT II due to the absence of the aromatic cage involved in ligand binding in hKAT I. The observed structural differences could be exploited for the rational design of highly selective hKAT II inhibitors.

Received for publication, September 21, 2007

The atomic coordinates and structure factors (code 2vgz) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by a grant from the Regione Piemonte (CIPE 2004) and by MUR (Interlink, 2004). 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.

¹ These authors contributed equally to the work.

² To whom correspondence should be addressed: DiSCAFF, University of Piemonte Orientale, Via Bovio 6, 28100 Novara, Italy. Tel.: 39-0321-375712; Fax: 39-0321-375821; E-mail: rizzi{at}pharm.unipmn.it.

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