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International Journal of Cell Biology
Volume 2013 (2013), Article ID 769536, 8 pages
Research Article

Cysteine-10 on 17β-Hydroxysteroid Dehydrogenase 1 Has Stabilizing Interactions in the Cofactor Binding Region and Renders Sensitivity to Sulfhydryl Modifying Chemicals

1Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstraße 50, 4056 Basel, Switzerland
2Department of Pharmacognosy, University of Vienna, Althanstraße 14, 1090 Vienna, Austria
3Department of Medicine, 0693, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA 92093, USA

Received 5 August 2013; Accepted 15 September 2013

Academic Editor: Christian Appenzeller-Herzog

Copyright © 2013 Lyubomir G. Nashev et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the conversion of estrone to the potent estrogen estradiol. 17β-HSD1 is highly expressed in breast and ovary tissues and represents a prognostic marker for the tumor progression and survival of patients with breast cancer and other estrogen-dependent tumors. Therefore, the enzyme is considered a promising drug target against estrogen-dependent cancers. For the development of novel inhibitors, an improved understanding of the structure-function relationships is essential. In the present study, we examined the role of a cysteine residue, Cys10, in the Rossmann-fold NADPH binding region, for 17β-HSD1 function and tested the sensitivity towards sulfhydryl modifying chemicals. 3D structure modeling revealed important interactions of Cys10 with residues involved in the stabilization of amino acids of the NADPH binding pocket. Analysis of enzyme activity revealed that 17β-HSD1 was irreversibly inhibited by the sulfhydryl modifying agents N-ethylmaleimide (NEM) and dithiocarbamates. Preincubation with increasing concentrations of NADPH protected 17β-HSD1 from inhibition by these chemicals. Cys10Ser mutant 17β-HSD1 was partially protected from inhibition by NEM and dithiocarbamates, emphasizing the importance of Cys10 in the cofactor binding region. Substitution of Cys10 with serine resulted in a decreased protein half-life, without significantly altering kinetic properties. Despite the fact that Cys10 on 17β-HSD1 seems to have limited potential as a target for new enzyme inhibitors, the present study provides new insight into the structure-function relationships of this enzyme.