Promiscuity and diversity in 3-ketosteroid reductases

• Steroid hormones with a Δ4-3-ketone group are reduced sequentially by 5α/β-reductases and ketosteroid reductases.
• All enzymes other than 5α-reductase belong to the aldo-keto reductase (AKR) superfamily.
• AKR1C1–AKR1C4 are the principal 3-ketosteroid reductases in human and are promiscuous.
• The structural basis for this promiscuity is discussed.
• AKR1C1–AKR1C4 play important roles in the metabolism of endogenous steroids and steroid therapeutics.

Many steroid hormones contain a Δ4-3-ketosteroid functionality that undergoes sequential reduction by 5α- or 5β- steroid reductases to produce 5α- or 5β-dihydrosteroids; and a subsequent 3-keto-reduction to produce a series of isomeric tetrahydrosteroids. Apart from steroid 5α-reductase all the remaining enzymes involved in the two step reduction process in humans belong to the aldo-keto reductase (AKR) superfamily. The enzymes involved in 3-ketosteroid reduction are AKR1C1–AKR1C4. These enzymes are promiscuous and also catalyze 20-keto- and 17-keto-steroid reduction. Interest in these reactions exist since they regulate steroid hormone metabolism in the liver, and in steroid target tissues, they may regulate steroid hormone receptor occupancy. In addition many of the dihydrosteroids are not biologically inert. The same enzymes are also involved in the metabolism of synthetic steroids e.g., hormone replacement therapeutics, contraceptive agents and inhaled glucocorticoids, and may regulate drug efficacy at their cognate receptors. This article reviews these reactions and the structural basis for substrate diversity in AKR1C1–AKR1C4, ketosteroid reductases.This article is part of a Special Issue entitled ‘Steroid/Sterol signaling’.

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