Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 2002 May 15;364(Pt 1):165–171. doi: 10.1042/bj3640165

Crystal structure of human dehydroepiandrosterone sulphotransferase in complex with substrate.

Peter H Rehse 1, Ming Zhou 1, Sheng-Xiang Lin 1
PMCID: PMC1222558  PMID: 11988089

Abstract

Dehydroepiandrosterone sulphotransferase (DHEA-ST) is an enzyme that converts dehydroepiandrosterone (DHEA), and some other steroids, into their sulphonated forms. The enzyme catalyses the sulphonation of DHEA on the 3alpha-oxygen, with 3'-phosphoadenosine-5'-phosphosulphate contributing the sulphate. The structure of human DHEA-ST in complex with its preferred substrate DHEA has been solved here to 1.99 A using molecular replacement with oestradiol sulphotransferase (37% sequence identity) as a model. Two alternative substrate-binding orientations have been identified. The primary, catalytic, orientation has the DHEA 3alpha-oxygen and the highly conserved catalytic histidine in nearly identical positions as are seen for the related oestradiol sulphotransferase. The substrate, however, shows rotations of up to 30 degrees, and there is a corresponding rearrangement of the protein loops contributing to the active site. This may also reflect the low identity between the two enzymes. The second orientation penetrates further into the active site and can form a potential hydrogen bond with the desulphonated cofactor 3',5'-phosphoadenosine (PAP). This second site contains more van der Waal interactions with hydrophobic residues than the catalytic site and may also reflect the substrate-inhibition site. The PAP position was obtained from the previously solved structure of DHEA-ST co-crystallized with PAP. This latter structure, due to the arrangement of loops within the active site and monomer interactions, cannot bind substrate. The results presented here describe details of substrate binding to DHEA-ST and the potential relationship to substrate inhibition.

Full Text

The Full Text of this article is available as a PDF (257.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adams J. B. Control of secretion and the function of C19-delta 5-steroids of the human adrenal gland. Mol Cell Endocrinol. 1985 Jun;41(1):1–17. doi: 10.1016/0303-7207(85)90138-8. [DOI] [PubMed] [Google Scholar]
  2. Bamforth K. J., Dalgliesh K., Coughtrie M. W. Inhibition of human liver steroid sulfotransferase activities by drugs: a novel mechanism of drug toxicity? Eur J Pharmacol. 1992 May 1;228(1):15–21. doi: 10.1016/0926-6917(92)90006-x. [DOI] [PubMed] [Google Scholar]
  3. Brünger A. T., Adams P. D., Clore G. M., DeLano W. L., Gros P., Grosse-Kunstleve R. W., Jiang J. S., Kuszewski J., Nilges M., Pannu N. S. Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):905–921. doi: 10.1107/s0907444998003254. [DOI] [PubMed] [Google Scholar]
  4. Chang H. J., Zhou M., Lin S. X. Human dehydroepiandrosterone sulfotransferase: purification and characterization of a recombinant protein. J Steroid Biochem Mol Biol. 2001 May;77(2-3):159–165. doi: 10.1016/s0960-0760(01)00048-6. [DOI] [PubMed] [Google Scholar]
  5. Demyan W. F., Song C. S., Kim D. S., Her S., Gallwitz W., Rao T. R., Slomczynska M., Chatterjee B., Roy A. K. Estrogen sulfotransferase of the rat liver: complementary DNA cloning and age- and sex-specific regulation of messenger RNA. Mol Endocrinol. 1992 Apr;6(4):589–597. doi: 10.1210/mend.6.4.1374839. [DOI] [PubMed] [Google Scholar]
  6. Driscoll W. J., Martin B. M., Chen H. C., Strott C. A. Isolation of two distinct 3-hydroxysteroid sulfotransferases from the guinea pig adrenal. Evidence for 3 alpha-hydroxy versus 3 beta-hydroxy stereospecificity. J Biol Chem. 1993 Nov 5;268(31):23496–23503. [PubMed] [Google Scholar]
  7. Elekima O. T., Mills C. O., Ahmad A., Skinner G. R., Ramsden D. B., Bown J., Young T. W., Elias E. Reduced hepatic content of dehydroepiandrosterone sulphotransferase in chronic liver diseases. Liver. 2000 Feb;20(1):45–50. doi: 10.1034/j.1600-0676.2000.020001045.x. [DOI] [PubMed] [Google Scholar]
  8. Falany C. N., Comer K. A., Dooley T. P., Glatt H. Human dehydroepiandrosterone sulfotransferase. Purification, molecular cloning, and characterization. Ann N Y Acad Sci. 1995 Dec 29;774:59–72. doi: 10.1111/j.1749-6632.1995.tb17372.x. [DOI] [PubMed] [Google Scholar]
  9. Falany C. N. Enzymology of human cytosolic sulfotransferases. FASEB J. 1997 Mar;11(4):206–216. doi: 10.1096/fasebj.11.4.9068609. [DOI] [PubMed] [Google Scholar]
  10. Jones T. A., Zou J. Y., Cowan S. W., Kjeldgaard M. Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr A. 1991 Mar 1;47(Pt 2):110–119. doi: 10.1107/s0108767390010224. [DOI] [PubMed] [Google Scholar]
  11. Kakuta Y., Pedersen L. G., Carter C. W., Negishi M., Pedersen L. C. Crystal structure of estrogen sulphotransferase. Nat Struct Biol. 1997 Nov;4(11):904–908. doi: 10.1038/nsb1197-904. [DOI] [PubMed] [Google Scholar]
  12. Khaw K. T. Dehydroepiandrosterone, dehydroepiandrosterone sulphate and cardiovascular disease. J Endocrinol. 1996 Sep;150 (Suppl):S149–S153. [PubMed] [Google Scholar]
  13. Labrie F., Dupont A., Belanger A. Complete androgen blockade for the treatment of prostate cancer. Important Adv Oncol. 1985:193–217. [PubMed] [Google Scholar]
  14. Labrie F. Intracrinology. Mol Cell Endocrinol. 1991 Jul;78(3):C113–C118. doi: 10.1016/0303-7207(91)90116-a. [DOI] [PubMed] [Google Scholar]
  15. Longcope C. Dehydroepiandrosterone metabolism. J Endocrinol. 1996 Sep;150 (Suppl):S125–S127. [PubMed] [Google Scholar]
  16. Luu-The V., Bernier F., Dufort I. Steroid sulfotransferases. J Endocrinol. 1996 Sep;150 (Suppl):S87–S97. [PubMed] [Google Scholar]
  17. Luu-The V., Dufort I., Paquet N., Reimnitz G., Labrie F. Structural characterization and expression of the human dehydroepiandrosterone sulfotransferase gene. DNA Cell Biol. 1995 Jun;14(6):511–518. doi: 10.1089/dna.1995.14.511. [DOI] [PubMed] [Google Scholar]
  18. Negishi M., Pedersen L. G., Petrotchenko E., Shevtsov S., Gorokhov A., Kakuta Y., Pedersen L. C. Structure and function of sulfotransferases. Arch Biochem Biophys. 2001 Jun 15;390(2):149–157. doi: 10.1006/abbi.2001.2368. [DOI] [PubMed] [Google Scholar]
  19. Oeda T., Lee Y. C., Driscoll W. J., Chen H. C., Strott C. A. Molecular cloning and expression of a full-length complementary DNA encoding the guinea pig adrenocortical estrogen sulfotransferase. Mol Endocrinol. 1992 Aug;6(8):1216–1226. doi: 10.1210/mend.6.8.1406700. [DOI] [PubMed] [Google Scholar]
  20. Ogura K., Kajita J., Narihata H., Watabe T., Ozawa S., Nagata K., Yamazoe Y., Kato R. cDNA cloning of the hydroxysteroid sulfotransferase STa sharing a strong homology in amino acid sequence with the senescence marker protein SMP-2 in rat livers. Biochem Biophys Res Commun. 1990 Feb 14;166(3):1494–1500. doi: 10.1016/0006-291x(90)91036-r. [DOI] [PubMed] [Google Scholar]
  21. Otterness D. M., Wieben E. D., Wood T. C., Watson W. G., Madden B. J., McCormick D. J., Weinshilboum R. M. Human liver dehydroepiandrosterone sulfotransferase: molecular cloning and expression of cDNA. Mol Pharmacol. 1992 May;41(5):865–872. [PubMed] [Google Scholar]
  22. Parker C. R., Jr, Stankovic A. K., Falany C. N., Grizzle W. E. Effect of TGF-beta on dehydroepiandrosterone sulfotransferase in cultured human fetal adrenal cells. Ann N Y Acad Sci. 1995 Dec 29;774:326–328. doi: 10.1111/j.1749-6632.1995.tb17399.x-i1. [DOI] [PubMed] [Google Scholar]
  23. Parker C. R., Jr, Stankovic A. K., Faye-Petersen O., Falany C. N., Li H., Jian M. Effects of ACTH and cytokines on dehydroepiandrosterone sulfotransferase messenger RNA in human adrenal cells. Endocr Res. 1998 Aug-Nov;24(3-4):669–673. doi: 10.3109/07435809809032668. [DOI] [PubMed] [Google Scholar]
  24. Pedersen L. C., Petrotchenko E. V., Negishi M. Crystal structure of SULT2A3, human hydroxysteroid sulfotransferase. FEBS Lett. 2000 Jun 9;475(1):61–64. doi: 10.1016/s0014-5793(00)01479-4. [DOI] [PubMed] [Google Scholar]
  25. Petrotchenko E. V., Pedersen L. C., Borchers C. H., Tomer K. B., Negishi M. The dimerization motif of cytosolic sulfotransferases. FEBS Lett. 2001 Feb 9;490(1-2):39–43. doi: 10.1016/s0014-5793(01)02129-9. [DOI] [PubMed] [Google Scholar]
  26. Wilborn T. W., Comer K. A., Dooley T. P., Reardon I. M., Heinrikson R. L., Falany C. N. Sequence analysis and expression of the cDNA for the phenol-sulfating form of human liver phenol sulfotransferase. Mol Pharmacol. 1993 Jan;43(1):70–77. [PubMed] [Google Scholar]
  27. Zerah M., Rhéaume E., Mani P., Schram P., Simard J., Labrie F., New M. I. No evidence of mutations in the genes for type I and type II 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) in nonclassical 3 beta HSD deficiency. J Clin Endocrinol Metab. 1994 Dec;79(6):1811–1817. doi: 10.1210/jcem.79.6.7989489. [DOI] [PubMed] [Google Scholar]
  28. Zhou M., Rehse P., Chang H. J., Luu-The V., Lin S. X. Crystallization and preliminary crystallographic results of apo and complex forms of human dehydroepiandrosterone sulfotransferase. Acta Crystallogr D Biol Crystallogr. 2001 Oct 25;57(Pt 11):1630–1633. doi: 10.1107/s0907444901010964. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES