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J. Biol. Chem., Vol. 281, Issue 40, 30175-30185, October 6, 2006

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Structure-based Functional Annotation

YEAST ymr099c CODES FOR A D-HEXOSE-6-PHOSPHATE MUTAROTASE^*

Marc Graille, Jean-Pierre Baltaze, Nicolas Leulliot, Dominique Liger, Sophie Quevillon-Cheruel, and Herman van Tilbeurgh¹

From the Institut de Biochimie et de Biophysique Moléculaire et Cellulaire, Université Paris-Sud, IFR115, CNRS UMR8619, F-91405 Orsay CEDEX, and the Institut de Chimie Moléculaire et des Matériaux, Orsay, Université Paris-Sud, CNRS UMR8182, F-91405 Orsay CEDEX, France

Despite the generation of a large amount of sequence information over the last decade, more than 40% of well characterized enzymatic functions still lack associated protein sequences. Assigning protein sequences to documented biochemical functions is an interesting challenge. We illustrate here that structural genomics may be a reasonable approach in addressing these questions. We present the crystal structure of the Saccharomyces cerevisiae YMR099cp, a protein of unknown function. YMR099cp adopts the same fold as galactose mutarotase and shares the same catalytic machinery necessary for the interconversion of the and anomers of galactose. The structure revealed the presence in the active site of a sulfate ion attached by an arginine clamp made by the side chain from two strictly conserved arginine residues. This sulfate is ideally positioned to mimic the phosphate group of hexose 6-phosphate. We have subsequently successfully demonstrated that YMR099cp is a hexose-6-phosphate mutarotase with broad substrate specificity. We solved high resolution structures of some substrate enzyme complexes, further confirming our functional hypothesis. The metabolic role of a hexose-6-phosphate mutarotase is discussed. This work illustrates that structural information has been crucial to assign YMR099cp to the orphan EC activity: hexose-phosphate mutarotase.

Received for publication, May 10, 2006 , and in revised form, July 12, 2006.

The atomic coordinates and structure factors (code 2CIQ, 2CIR, and 2CIS) 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 grants from the Ministère de la Recherche et de la Technologie (Programme Génopoles). 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 To whom correspondence should be addressed. Tel.: 33-1-69-15-31-55; Fax: 33-1-69-85-37-15; E-mail: Herman.Van-Tilbeurgh{at}ibbmc.u-psud.fr.

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