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Originally published In Press as doi:10.1074/jbc.M207246200 on December 5, 2002

J. Biol. Chem., Vol. 278, Issue 9, 7655-7662, February 28, 2003
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Structure of a Human Carcinogen-converting Enzyme, SULT1A1
STRUCTURAL AND KINETIC IMPLICATIONS OF SUBSTRATE INHIBITION*

Niranjali U. GamageDagger , Ronald G. Duggleby§, Amanda C. BarnettDagger , Michael TresillianDagger , Catherine F. LathamDagger , Nancy E. LiyouDagger , Michael E. McManusDagger , and Jennifer L. Martin||

From the Dagger  Department of Physiology and Pharmacology, School of Biomedical Sciences, § Department of Biochemistry and Molecular Biology, School of Molecular and Microbial Sciences, and  Centre for Drug Design and Development and Special Research Centre for Functional and Applied Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia

Sulfonation catalyzed by sulfotransferase enzymes plays an important role in chemical defense mechanisms against various xenobiotics but also bioactivates carcinogens. A major human sulfotransferase, SULT1A1, metabolizes and/or bioactivates many endogenous compounds and is implicated in a range of cancers because of its ability to modify diverse promutagen and procarcinogen xenobiotics. The crystal structure of human SULT1A1 reported here is the first sulfotransferase structure complexed with a xenobiotic substrate. An unexpected finding is that the enzyme accommodates not one but two molecules of the xenobiotic model substrate p-nitrophenol in the active site. This result is supported by kinetic data for SULT1A1 that show substrate inhibition for this small xenobiotic. The extended active site of SULT1A1 is consistent with binding of diiodothyronine but cannot easily accommodate beta -estradiol, although both are known substrates. This observation, together with evidence for a disorder-order transition in SULT1A1, suggests that the active site is flexible and can adapt its architecture to accept diverse hydrophobic substrates with varying sizes, shapes and flexibility. Thus the crystal structure of SULT1A1 provides the molecular basis for substrate inhibition and reveals the first clues as to how the enzyme sulfonates a wide variety of lipophilic compounds.

* This project was supported by a grant from the Australian National Health and Medical Research Council.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.

The atomic coordinates and the structure factors (code 1LS6) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

|| Recipient of an Australian Research Council senior research fellowship. To whom correspondence should be addressed. Tel.: 61-7-3365-4942; Fax: 61-7-3365-1990; E-mail: J.Martin@imb.uq.edu.au.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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