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J. Biol. Chem., Vol. 279, Issue 48, 50214-50220, November 26, 2004

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Crystal Structure of Human Kynurenine Aminotransferase I^*

Franca Rossi, Qian Han, Junsuo Li, Jianyong Li, and Menico Rizzi¶

From the Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche, Farmacologiche–Istituto Nazionale di Fisica della Materia, University of Piemonte Orientale "Amedeo Avogadro," Via Bovio 6, 28100 Novara, Italy and Department of Pathobiology, University of Illinois, Urbana, Illinois 61802

The kynurenine pathway has long been regarded as a valuable target for the treatment of several neurological disorders accompanied by unbalanced levels of metabolites along the catabolic cascade, kynurenic acid among them. The irreversible transamination of kynurenine is the sole source of kynurenic acid, and it is catalyzed by different isoforms of the 5'-pyridoxal phosphate-dependent kynurenine aminotransferase (KAT). The KAT-I isozyme has also been reported to possess -lyase activity toward several sulfur- and selenium-conjugated molecules, leading to the proposal of a role of the enzyme in carcinogenesis associated with environmental pollutants. We solved the structure of human KAT-I in its 5'-pyridoxal phosphate and pyridoxamine phosphate forms and in complex with the competing substrate L-Phe. The enzyme active site revealed a striking crown of aromatic residues decorating the ligand binding pocket, which we propose as a major molecular determinant for substrate recognition. Ligand-induced conformational changes affecting Tyr¹⁰¹ and the Trp¹⁸-bearing -helix H1 appear to play a central role in catalysis. Our data reveal a key structural role of Glu²⁷, providing a molecular basis for the reported loss of enzymatic activity displayed by the equivalent Glu Gly mutation in KAT-I of spontaneously hypertensive rats.

Received for publication, August 13, 2004 , and in revised form, September 7, 2004.

The atomic coordinates and structure factors (codes 1W7L, 1W7N, and 1W7M) 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 Grant AI 44399 from the National Institutes of Health and Ministero dell'Istruzione, dell'Università e della Ricera project FIRB2001. 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: DiSCAFF, University of Piemonte Orientale, Via Bovio 6, 28100 Novara, Italy. Tel.: 39-0321-375812; Fax: 39-0321-375821; E-mail: rizzi{at}ipvgen.unipv.it.

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