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J. Biol. Chem., Vol. 279, Issue 4, 2689-2696, January 23, 2004

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Identifying Androsterone (ADT) as a Cognate Substrate for Human Dehydroepiandrosterone Sulfotransferase (DHEA-ST) Important for Steroid Homeostasis

STRUCTURE OF THE ENZYME-ADT COMPLEX^*

Ho-Jin Chang, Rong Shi, Peter Rehse, and Sheng-Xiang Lin¶

From the Canadian Institutes of Health Research Group in Oncology and Molecular Endocrinology Laboratory, CHUL Research Center and Laval University, Sainte-Foy, Quebec G1V 4G2, Canada

In steroid biosynthesis, human dehydroepiandrosterone sulfotransferase (DHEA-ST) in the adrenals has been reported to catalyze the transfer of the sulfonate group from 3'-phosphoadenosine-5'-phosphosulfate to dehydroepiandrosterone (DHEA). DHEA and its sulfate play roles as steroid precursors; however, the role of the enzyme in the catabolism of androgens is poorly understood. Androsterone sulfate is clinically recognized as one of the major androgen metabolites found in urine. Here it is demonstrated that this enzyme recognizes androsterone (ADT) as a cognate substrate with similar kinetics but a 2-fold specificity and stronger substrate inhibition than DHEA. The structure of human DHEA-ST in complex with ADT has been solved at 2.7 Å resolution, confirming ADT recognition. Structural analysis has revealed the binding mode of ADT differs from that of DHEA, despite the similarity of the overall structure between the ADT and the DHEA binary complexes. Our results identify that this human enzyme is an ADT sulfotransferase as well as a DHEA sulfotransferase, implying an important role in steroid homeostasis for the adrenals and liver.

Received for publication, September 22, 2003 , and in revised form, October 18, 2003.

^* This work has been supported by the Canadian Space Agency and the Canadian Institutes of Health 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 atomic coordinates and structure factors (code 1OV4) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

Present address: RIKEN Harima Institute at Spring-8, 1-1-1 Kouto, Mikazuki-cho, Sayo-gun, Hyogo 679-5148, Japan.

^¶ To whom correspondence should be addressed: CIHR Group in Oncology and Molecular Endocrinology Laboratory, CHUL Research Center and Laval University, 2705 Laurier Blvd, Sainte-Foy, Quebec G1V 4G2, Canada. Tel.: 418-654-2296; Fax: 418-654-2729; E-mail: sxlin{at}crchul.ulaval.ca.

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