Human hydroxysteroid dehydrogenases and pre-receptor regulation: Insights into inhibitor design and evaluation

Hydroxysteroid dehydrogenases (HSDs) represent a major class of NAD(P)(H) dependent steroid hormone oxidoreductases involved in the pre-receptor regulation of hormone action. This is achieved by HSDs working in pairs so that they can interconvert ketosteroids with hydroxysteroids resulting in a change in ligand potency for nuclear receptors. HSDs belong to two protein superfamilies the aldo–keto reductases and the short-chain dehydrogenase/reductases. In humans, many of the important enzymes have been thoroughly characterized including the elucidation of their three-dimensional structures. Because these enzymes play fundamental roles in steroid hormone action they can be considered to be drug targets for a variety of steroid driven diseases, e.g. metabolic syndrome and obesity, inflammation, and hormone dependent malignancies of the endometrium, prostate and breast. This article will review how fundamental knowledge of these enzymes can be exploited in the development of isoform specific HSD inhibitors from both protein superfamilies.Article from the Special issue on Targeted Inhibitors.

Research highlights
► Hydroxysteroid dehydrogenases (HSDs) belong to two protein superfamilies (AKRs and SDRs).
► Pairs of HSDs regulate ligand access to nuclear receptors.
► Knowledge of HSD structure, function, kinetic and catalytic mechanism can aid inhibitor design.
► Type 1 11β-HSD inhibitors can target metabolic syndrome and diabetes.
► 17β-HSD inhibitors can target hormonal dependent malignancies.