Carbonyl Reductases and Pluripotent Hydroxysteroid Dehydrogenases of the Short-chain Dehydrogenase/reductase Superfamily

Abstract

Carbonyl reduction of aldehydes, ketones, and quinones to their corresponding hydroxy derivatives plays an important role in the phase I metabolism of many endogenous (biogenic aldehydes, steroids, prostaglandins, reactive lipid peroxidation products) and xenobiotic (pharmacologic drugs, carcinogens, toxicants) compounds. Carbonyl-reducing enzymes are grouped into two large protein superfamilies: the aldo-keto reductases (AKR) and the short-chain dehydrogenases/reductases (SDR). Whereas aldehyde reductase and aldose reductase are AKRs, several forms of carbonyl reductase belong to the SDRs. In addition, there exist a variety of pluripotent hydroxysteroid dehydrogenases (HSDs) of both superfamilies that specifically catalyze the oxidoreduction at different positions of the steroid nucleus and also catalyze, rather nonspecifically, the reductive metabolism of a great number of nonsteroidal carbonyl compounds. The present review summarizes recent findings on carbonyl reductases and pluripotent HSDs of the SDR protein superfamily.

11β-Hydroxysteroid dehydrogenase-type 2 evolved from an ancestral 17β-Hydroxysteroid dehydrogenase-type 2

“…Thus, 11 -HSD3A evolved before the evolution of glucocorticoid signaling. The ancestral 11 -HSD3A may have metabolized novel oxysterols [7,9,11,17,25] or xenobiotics [21][22][23]25,41], as has been found for 11 -HSD1 [ Figure 1]. That is, one or more of the newly described "alternative" functions of 11 -HSD1 [13] may be related to an ancestral function of 11 -HSD3A.…”

“…11 -HSD1 appears to have a physiological role that involves reduction of 7-keto-cholesterol and 7-keto-DHEA. 11 -HSD1 also metabolizes tobacco-specific N-nitrosamines [21][22][23] [ Figure 1]. Thus, the physiological actions and substrates of 11 -HSD1 are complex [13].…”

“…Over-expression of 11 -HSD1 in fat cells leads to metabolic syndrome [18][19][20]. 11 -HSD1 also detoxifies xenobiotics by reducing their keto-groups [13,[21][22][23] [ Figure 1]. Thus, the physiological actions of 11 -HSD1 are diverse and complex.…”

Structure of a short-chain dehydrogenase/reductase (SDR) within a genomic island from a clinical strain ofAcinetobacter baumannii

“…in a markedly flexible region of the apoenzyme structure. As the SDR family utilizes diverse chemistry appropriate to a wide range of substrates (Hoffmann & Maser, 2007), it is not possible to define the specific substrate for SDR-WM99c by homology relationships alone.…”

Comparative inhibition of tetrameric carbonyl reductase activity in pig heart cytosol by alkyl 4-pyridyl ketones

“…Carbonyl reductase (EC 1.1.1.184) is an enzyme that catalyzes NADPH-dependent reduction of endogenous and xenobiotic carbonyl compounds [1][2][3][4] . The cDNA for carbonyl reductase was first cloned by Wermuth et al 5 , and the enzyme belongs to the short-chain dehydrogenase/reductase (SDR) superfamily.…”