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The structures of the unique sulfotransferase retinol dehydratase with product and inhibitors provide insight into enzyme mechanism and inhibition

¹ Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 70803, USA
² Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10021, USA

(RECEIVED August 19, 2004; FINAL REVISION September 13, 2004; ACCEPTED September 14, 2004)

The structure of retinol dehydratase (DHR) from Spodoptera frugiperda, a member of the sulfotransferase superfamily, in complexes with the inactive form of the cofactor PAP 3'-phosphoadenosine 5'-phosphate (PAP) and (1) the product of the reaction with retinol anhydroretinol (AR), (2) the retinoid inhibitor all-trans-4-oxoretinol (OR), and (3) the potent steroid inhibitor androsterone (AND) have been determined and compared to the enzyme complex with PAP and retinol. The structures show that the geometry of the active-site amino acids is largely preserved in the various complexes. However, the -ionone rings of the retinoids are oriented differently with respect to side chains that have been shown to be important for the enzymatic reaction. In addition, the DHR:PAP:AND complex reveals a novel mode for steroid binding that contrasts significantly with that for steroid binding in other sulfotransferases. The molecule is displaced and rotated ~180° along its length so that there is no acceptor hydroxyl in close proximity to the site of sulfate transfer. This observation explains why steroids are potent inhibitors of retinol dehydratase activity, rather than substrates for sulfonation. Most of the steroid-protein contacts are provided by the -helical cap that distinguishes this member of the superfamily. This observation suggests that in addition to providing a chemical environment that promotes the dehydration of a sulfonated intermediate, the cap may also serve to minimize a promiscuous sulfotransferases activity.

Keywords: X-ray crystallography; retinol dehydratase; sulfotransferase; anhydroretinol

Abbreviations: DHR, retinol dehydratase • ST, sulfotransferase • EST, mouse estrogen sulfotransferase • PAPS, 3'-phosphoadenosine 5'-phosphosulfate • PAP, 3'-phosphoadenosine 5'-phosphate • AND, androsterone • AR, anhydroretinol • OR, all-trans-4-oxoretinol • RTL, all-trans-retinol

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.041061105.

Reprint requests to: Marcia E. Newcomer, Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70810, USA; e-mail: newcomer{at}lsu.edu; fax: (225) 578-7258.

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