Molecular Endocrinology of Hydroxysteroid Dehydrogenases*

Abstract

HYDROXYSTEROID dehydrogenases (HSDs) play pivotal roles in the biosynthesis and inactivation of all steroid hormones. In steroidogenic tissues they catalyze the final steps in androgen, estrogen, and progesterone biosynthesis. In peripheral tissues, including steroid hormone target tissues, they convert potent steroid hormones into inactive metabolites and regulate the amount of hormone that can bind to members of the nuclear receptor superfamily, ultimately regulating gene expression. Target cells may depend on these reactions to control specificity of response to steroid hormones. Because HSDs catalyze bidirectional reactions, it has been difficult to understand how they can be involved in both the synthesis and inactivation of steroid hormones. cDNA cloning indicates that each HSD exists in multiple isoforms, which show tissue specificity in expression; this, coupled with the properties of each isoform (reductase or dehydrogenase), can determine the role of the enzyme in steroid hormone action. Advances in cDNA isolation have led to the concept that HSDs belong to at least two distinct protein phylogenies: the short-chain dehydrogenase/reductase family (SDR; formerly short-chain alcohol dehydrogenase) whose members include the 3β-HSD/ketosteroid isomerase (3β-HSD/KSI), 11β-HSD, and 17β-HSD (1, 2), and the aldo-keto reductase (AKR) superfamily (3–6) whose members include 3α-HSD and 20α-HSD. Three-dimensional structures now exist for mammalian HSDs that belong to each of the two families and serve as templates for structure-function studies on HSDs within each protein family. These represent the first available structures for mammalian enzymes involved in steroidogenesis and steroid metabolism.