Journal
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Volume 507, Issue 2, Pages 232-240Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2010.12.027
Keywords
Sulfotransferase; Hydroxysteroid; hSULT2A1; Substrate inhibition; Negative cooperativity; Non-productive enzyme complexes
Categories
Funding
- National Institutes of Health, National Cancer Institute [R01 CA038683]
- National Institute of Environmental Health Sciences, NIEHS [P42 ES013661, P30 ES05605]
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The cytosolic sulfotransferase hSULT2A1 is the major hydroxysteroid (alcohol) sulfotransferase in human liver, and it catalyzes the 3'-phosphoadenosine-5'-phosphosulfate (PAPS)-dependent sulfation of various endogenous hydroxysteroids as well as many xenobiotics that contain alcohol and phenol functional groups. The hSULT2A1 often displays substrate inhibition, and we have hypothesized that a key element in this response to increasing substrate concentration is the formation of non-productive ternary dead-end enzyme complexes involving the nucleotide product, adenosine 3',5'-diphosphate (PAP). One of these substrates for hSULT2A1 is dehydroepiandrosterone (DHEA), a major circulating steroid hormone in humans that serves as precursor to both androgens and estrogens. We have utilized DHEA in both initial velocity studies and equilibrium binding experiments in order to evaluate the potential role of ternary complexes in substrate inhibition of the enzyme. Our results indicate that hSULT2A1 forms non-productive ternary complexes that involve either DHEA or dehydroepiandrosterone sulfate, and the formation of these ternary complexes displays negative cooperativity in the binding of DHEA. (C) 2010 Elsevier Inc. All rights reserved.
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