JBC Origene Your Gene Company

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

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
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
278/9/7655    most recent
M207246200v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gamage, N. U.
Right arrow Articles by Martin, J. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gamage, N. U.
Right arrow Articles by Martin, J. L.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

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.
Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 Mol. Pharmacol.Home page
L.-Y. Lu, Y.-C. Hsieh, M.-Y. Liu, Y.-H. Lin, C.-J. Chen, and Y.-S. Yang
Identification and Characterization of Two Amino Acids Critical for the Substrate Inhibition of Human Dehydroepiandrosterone Sulfotransferase (SULT2A1)
Mol. Pharmacol., March 1, 2008; 73(3): 660 - 668.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
M. Roupret, G. Cancel-Tassin, E. Comperat, G. Fromont, M. Sibony, V. Molinie, Y. Allory, S. Triau, J. Champigneulle, C. Gaffory, et al.
Phenol Sulfotransferase SULT1A1*2 Allele and Enhanced Risk of Upper Urinary Tract Urothelial Cell Carcinoma
Cancer Epidemiol. Biomarkers Prev., November 1, 2007; 16(11): 2500 - 2503.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
R. Shi, S. S. Lamb, S. Bhat, T. Sulea, G. D. Wright, A. Matte, and M. Cygler
Crystal Structure of StaL, a Glycopeptide Antibiotic Sulfotransferase from Streptomyces toyocaensis
J. Biol. Chem., April 27, 2007; 282(17): 13073 - 13086.
[Abstract] [Full Text] [PDF]

Home page
 BioinformaticsHome page
R. J. Najmanovich, A. Allali-Hassani, R. J. Morris, L. Dombrovsky, P. W. Pan, M. Vedadi, A. N. Plotnikov, A. Edwards, C. Arrowsmith, and J. M. Thornton
Analysis of binding site similarity, small-molecule similarity and experimental binding profiles in the human cytosolic sulfotransferase family
Bioinformatics, January 15, 2007; 23(2): e104 - e109.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
S. Nagar, S. Walther, and R. L. Blanchard
Sulfotransferase (SULT) 1A1 Polymorphic Variants *1, *2, and *3 Are Associated with Altered Enzymatic Activity, Cellular Phenotype, and Protein Degradation
Mol. Pharmacol., June 1, 2006; 69(6): 2084 - 2092.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
N. Gamage, A. Barnett, N. Hempel, R. G. Duggleby, K. F. Windmill, J. L. Martin, and M. E. McManus
Human Sulfotransferases and Their Role in Chemical Metabolism
Toxicol. Sci., March 1, 2006; 90(1): 5 - 22.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
N. U. Gamage, S. Tsvetanov, R. G. Duggleby, M. E. McManus, and J. L. Martin
The Structure of Human SULT1A1 Crystallized with Estradiol: AN INSIGHT INTO ACTIVE SITE PLASTICITY AND SUBSTRATE INHIBITION WITH MULTI-RING SUBSTRATES
J. Biol. Chem., December 16, 2005; 280(50): 41482 - 41486.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
J. C. Sacco and M. O. James
SULFONATION OF ENVIRONMENTAL CHEMICALS AND THEIR METABOLITES IN THE POLAR BEAR (Ursus maritimus)
Drug Metab. Dispos., September 1, 2005; 33(9): 1341 - 1348.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
S. G. J. van Breda, E. van Agen, S. van Sanden, T. Burzykowski, A. S. Kienhuis, J. C. S. Kleinjans, and J. H. M. van Delft
Vegetables Affect the Expression of Genes Involved in Anticarcinogenic Processes in the Colonic Mucosa of C57Bl/6 Female Mice
J. Nutr., August 1, 2005; 135(8): 1879 - 1888.
[Abstract] [Full Text] [PDF]

Home page
 Protein Sci.Home page
S. Pakhomova, J. Buck, and M. E. Newcomer
The structures of the unique sulfotransferase retinol dehydratase with product and inhibitors provide insight into enzyme mechanism and inhibition
Protein Sci., January 1, 2005; 14(1): 176 - 182.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
D. Cui, C. L. Booth-Genthe, E. Carlini, B. Carr, and M. L. Schrag
HETEROTROPIC MODULATION OF SULFOTRANSFERASE 2A1 ACTIVITY BY CELECOXIB: PRODUCT RATIO SWITCHING OF ETHYNYLESTRADIOL SULFATION
Drug Metab. Dispos., November 1, 2004; 32(11): 1260 - 1264.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
L.-Q. Wang, C. N. Falany, and M. O. James
TRICLOSAN AS A SUBSTRATE AND INHIBITOR OF 3'-PHOSPHOADENOSINE 5'-PHOSPHOSULFATE-SULFOTRANSFERASE AND UDP-GLUCURONOSYL TRANSFERASE IN HUMAN LIVER FRACTIONS
Drug Metab. Dispos., October 1, 2004; 32(10): 1162 - 1169.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
J. J. Sheng, A. Saxena, and M. W. Duffel
INFLUENCE OF PHENYLALANINES 77 AND 138 ON THE STEREOSPECIFICITY OF ARYL SULFOTRANSFERASE IV
Drug Metab. Dispos., May 1, 2004; 32(5): 559 - 565.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. C. Barnett, S. Tsvetanov, N. Gamage, J. L. Martin, R. G. Duggleby, and M. E. McManus
Active Site Mutations and Substrate Inhibition in Human Sulfotransferase 1A1 and 1A3
J. Biol. Chem., April 30, 2004; 279(18): 18799 - 18805.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
B. Ma, M. Shou, and M. L. Schrag
SOLVENT EFFECT ON cDNA-EXPRESSED HUMAN SULFOTRANSFERASE (SULT) ACTIVITIES IN VITRO
Drug Metab. Dispos., November 1, 2003; 31(11): 1300 - 1305.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 All ASBMB Journals   Molecular and Cellular Proteomics 
 Journal of Lipid Research   ASBMB Today 
Copyright © 2003 by the American Society for Biochemistry and Molecular Biology.