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J. Biol. Chem., Vol. 282, Issue 41, 30189-30197, October 12, 2007

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Structural Basis of Substrate-binding Specificity of Human Arylamine N-Acetyltransferases^*

Hong Wu, Ludmila Dombrovsky, Wolfram Tempel, Fernando Martin, Peter Loppnau, Geoffrey H. Goodfellow, Denis M. Grant, and Alexander N. Plotnikov^¶1

From the Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L5, the Department of Pharmacology, University of Toronto, Toronto, Ontario M5S 1A8, and the ^¶Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada

The human arylamine N-acetyltransferases NAT1 and NAT2 play an important role in the biotransformation of a plethora of aromatic amine and hydrazine drugs. They are also able to participate in the bioactivation of several known carcinogens. Each of these enzymes is genetically variable in human populations, and polymorphisms in NAT genes have been associated with various cancers. Here we have solved the high resolution crystal structures of human NAT1 and NAT2, including NAT1 in complex with the irreversible inhibitor 2-bromoacetanilide, a NAT1 active site mutant, and NAT2 in complex with CoA, and have refined them to 1.7-, 1.8-, and 1.9-Å resolution, respectively. The crystal structures reveal novel structural features unique to human NATs and provide insights into the structural basis of the substrate specificity and genetic polymorphism of these enzymes.

Received for publication, May 18, 2007 , and in revised form, July 18, 2007.

^* This work was supported by the Structural Genomics Consortium with funds from Genome Canada through the Ontario Genomics Institute, the Canadian Institutes for Health Research, the Canada Foundation for Innovation, the Ontario Challenge Fund, the Ontario Innovation Trust, the Wellcome Trust, GlaxoSmithKline, the Knut and Alice Wallenberg Foundation, and the Vinnova and Swedish Foundation for Strategic Research. 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 on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: Structural Genomics Consortium, University of Toronto, 100 College St., Toronto, Ontario M5G 1L5, Canada. Tel.: 416-946-3868; Fax: 416-946-0588; E-mail: alexander.plotnikov{at}utoronto.ca.

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