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

ABSTRACT: 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.

SUBMITTER: Penning TM

PROVIDER: S-EPMC3104102 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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

Penning Trevor M TM

The Journal of steroid biochemistry and molecular biology 20110125 1-2

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 hav ...[more]

PMID: 21272640

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Project description:Bile acids are important cholesterol-derived nutrient signaling hormones, synthesized in the liver, that act as detergents to solubilize dietary lipids. Bile acid 7?-dehydroxylating gut bacteria generate the toxic bile acids deoxycholic acid and lithocholic acid from host bile acids. The ability of these bacteria to remove the 7-hydroxyl group is partially dependent on 7?-hydroxysteroid dehydrogenase (HSDH) activity, which reduces 7-oxo-bile acids generated by other gut bacteria. 3?-HSDH has an important enzymatic activity in the bile acid 7?-dehydroxylation pathway. 12?-HSDH activity has been reported for the low-activity bile acid 7?-dehydroxylating bacterium Clostridium leptum; however, this activity has not been reported for high-activity bile acid 7?-dehydroxylating bacteria, such as Clostridium scindens, Clostridium hylemonae, and Clostridium hiranonis Here, we demonstrate that these strains express bile acid 12?-HSDH. The recombinant enzymes were characterized from each species and shown to preferentially reduce 12-oxolithocholic acid to deoxycholic acid, with low activity against 12-oxochenodeoxycholic acid and reduced activity when bile acids were conjugated to taurine or glycine. Phylogenetic analysis suggests that 12?-HSDH is widespread among Firmicutes, Actinobacteria in the Coriobacteriaceae family, and human gut ArchaeaIMPORTANCE 12?-HSDH activity has been established in the medically important bile acid 7?-dehydroxylating bacteria C. scindens, C. hiranonis, and C. hylemonae Experiments with recombinant 12?-HSDHs from these strains are consistent with culture-based experiments that show a robust preference for 12-oxolithocholic acid over 12-oxochenodeoxycholic acid. Phylogenetic analysis identified novel members of the gut microbiome encoding 12?-HSDH. Future reengineering of 12?-HSDH enzymes to preferentially oxidize cholic acid may provide a means to industrially produce the therapeutic bile acid ursodeoxycholic acid. In addition, a cholic acid-specific 12?-HSDH expressed in the gut may be useful for the reduction in deoxycholic acid concentration, a bile acid implicated in cancers of the gastrointestinal (GI) tract.

Dataset Information

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

Publications

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

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