3-Ketosteroid Receptor Assays

Background of 3-Ketosteroid Receptor

Present in the nucleus, cytosol and plasma membrane of target cells, steroid hormone receptors are always intracellular receptors to initiate signal transduction for steroid hormones. Nuclear receptor subfamily 3 (NR3) is the well-studied steroid hormone receptor that includes estrogen receptors and 3-ketosteroid receptors.

Members and Functions of 3-Ketosteroid Receptor

There are four members of 3-Ketosteroid receptors that include glucocorticoid receptor (GR), mineralocorticoid receptor (MR), progesterone receptor (PR), and androgen receptor (AR). The expression of GR can be observed in almost all cells for the regulation of genes that control the development, metabolism, and immune response. Expressed in many tissues, MR can be activated by mineralocorticoids and leads to signal transduction affecting specific gene expression in the nucleus. PRs exist in the female reproductive tract, mammary glands, brain, and pituitary gland. The AR can be activated by binding any of the androgenic hormones. It can act as a DNA-binding transcription factor for the regulation of gene expression.

Receptor	Gene	Mechanism	Agonists	Antagonists
Glucocorticoid receptor	NR3C1	Glucocorticoid receptor regulates genes controlling the development, metabolism, and immune response.	Dexamethasone Corticosteroids	Mifepristone ketoconazole
Mineralocorticoid receptor	NR3C2	Activation of mineralocorticoid receptor leads to the expression of proteins regulating ionic and water transports resulting in the reabsorption of sodium. The major signaling pathway used by MRs is via direct DNA binding and transcriptional regulation of target genes.	Corticosterone	Eplerenone Spironolactone
Progesterone receptor	NR3C3	Progesterone receptor can signal by binding to transcription factors such as NF-κB, AP-1, or STAT.	Levonorgestrel Megestrol Acetate Mometasone furoate Progesterone	Mifepristone
Androgen receptor	NR3C4	Androgen receptor can be a DNA-binding transcription factor to regulate gene expression.	BMS 564929 Cl-4AS-1	Bicalutamide Flutamide Galeterone

Published Data

Paper Title	Promiscuity and diversity in 3-ketosteroid reductases
Journal	The Journal of steroid biochemistry and molecular biology
Published	2015
Abstract	Many steroid hormones contain a Δ4-3-ketosteroid function and undergo successive reductions to produce 5α- or 5β-dihydrosteroids as well as a series of isomeric tetrahydrosteroids. AKR1C1–AKR1C4 belongs to the aldoketone reductase (AKR) superfamily, enzymes involved in the reduction of 3-ketosteroids. In addition, these enzymes catalyze the reduction of 20-ketosteroids and 17-ketosteroids. In addition, many dihydrosteroids are not biologically inert and participate in the metabolism of anabolic steroids, such as hormone replacement therapy, contraceptives, and inhaled corticosteroids. This paper describes in detail these reactions and the structural basis for substrate diversity in the AKR1C1–AKR1C4 ketosteroid reductases.
Result	The human AKR1C enzyme is important for steroid hormone metabolism in the liver and for steroid hormones at the prereceptor level in target tissues. A body of evidence is still needed to characterize the role of AKR1C1–AKR1C4 in the metabolism of 5α-dihydroprogesterone, 5α/5β-dihydroglucocorticoid, and 5α/5β-dihydromineralocorticoid. Recent technological developments, such as real-time PCR and microarrays, have revealed more details about changes in the expression of these enzymes and the way they regulate autocrine and paracrine. The AKR1C gene contains many steroid response elements and is controlled by steroid hormones. These enzymes involved in the inactivation of steroid hormones are upregulated by hormone excess and downregulated by hormone deficiency. For enzymes that produce active steroid hormones, such as AKR1C3, the expression levels of these enzymes may change during the course of the experiment. The function of the AKR1C enzyme can also be further revealed by the si-RNA/sh-RNA approach and by using isoform-specific inhibitors as chemical probes. Fig.1. Inversion of stereochemistry in the 3α- to 3β-reduction of ketosteroids. (Penning, et al., 2015)

Reference

Penning, T.M.; et al. Promiscuity and diversity in 3-ketosteroid reductases. The Journal of steroid biochemistry and molecular biology. 2015, 151: 93-101.

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