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Originally published In Press as doi:10.1074/jbc.M204406200 on May 31, 2002

J. Biol. Chem., Vol. 277, Issue 32, 29242-29252, August 9, 2002
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Contribution of Molecular Modeling and Site-directed Mutagenesis to the Identification of Two Structural Residues, Arg-220 and Asp-227, in Aminopeptidase A*

Raphaël RozenfeldDagger , Xavier IturriozDagger , Bernard Maigret§, and Catherine Llorens-CortesDagger

From Dagger  INSERM, Unité 36, Collège de France, 11, place Marcelin Berthelot, 75005 Paris and § CNRS, Unité Mixte de Recherche 7565, Laboratoire de Chimie Théorique, Université de Nancy, 54506 Vandoeuvre-les-Nancy, France

Aminopeptidase A is a zinc metalloenzyme involved in the formation of brain angiotensin III, which exerts a tonic stimulatory action on the central control of blood pressure. Thus, central inhibitors of aminopeptidase A constitute putative central antihypertensive agents. Mutagenic studies have been performed to investigate organization of the aminopeptidase A active site, with a view to designing such inhibitors. The structure of one monozinc aminopeptidase (leukotriene A4 hydrolase) was recently resolved and used to construct a three-dimensional model of the aminopeptidase A ectodomain. This new model, highly consistent with the results of mutagenic studies, showed a critical structural interaction between two conserved residues, Arg-220 and Asp-227. Mutagenic replacement of either of these two residues disrupted maturation and subcellular localization and abolished the enzymatic activity of aminopeptidase A, confirming the critical structural role of these residues. In this study, we generated the first three-dimensional model of a strict aminopeptidase, aminopeptidase A. This model constitutes a new tool to probe further the active site of aminopeptidase A and to design new inhibitors of this enzyme.

* The costs of publication of this article were defrayed in part by the payment of page charges. The 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. Tel.: 33-1-44-27-1663; Fax: 33-1-44-27-1691; E-mail: c.llorens-cortes@college-de-france.fr.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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