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.

Key Words :

• Reductive drug metabolism
• Carbonyl reductase
• Hydroxysteroid dehydrogenase
• Pluripotency
• Aldo-keto reductase (AKR) superfamily
• Short-chain dehydrogenasereductase (SDR) superfamily

Notes

Abbreviations: CBR1, CBR3 (human carbonyl reductase 1 and 3); CHCR1, CHCR2, CHCR3 (Chinese hamster carbonyl reductases 1–3); iCR, nCR, rtCR (inducible, non-inducible, and rat testis carbonyl reductase); Sniffer (carbonyl reductase Sniffer from Drosophila); 11β-HSD1-h, 11β-HSD1-m, 11β-HSD1-r, 11β-HSD1-g (11β-HSDs from human, mouse, rat, and guinea pig); PHCR (pig heart carbonyl reductase); MLCR (mouse lung carbonyl reductase); PLCR (pig lung carbonyl reductase); 3α/20β-HSD (S. hydrogenans); 3α-HSD/CR (C. testosteroni).The alignment indicates the existence of an extraloop-domain upstream of the conserved Tyr-x-x-x-Lys motif within the monomeric enzymes from human, Chinese hamster, and rat. This extraloop-domain can also be found in the dimeric 3α-HSD/CR from C. testosteroni. Monomeric enzymes are marked in blue, dimeric enzymes in red, and tetrameric enzymes in yellow. Colored residues represent conservation of 50% identity. Alignment was performed using the clustalW- and bioedit-program.

The conserved structural elements involved in oligomerization are named only for the upper one of the two subunits. Note that the four-helix bundle (Q-interface; blue) is blocked by the extraloop-domain (yellow). Therefore, oligomerization (dimerization) takes place only via helix αG and strand βG (P-interface; purple).

3α-HSD/CR contains an unordered substrate binding loop (SBL) and an extraloop-domain between strand βE and helix αF, which normally are part of the four-helix bundle as the main structural feature of the oligomerization Q-interface.

Abbreviations: DHN = 1,4-dihydroxynon-2-ene; HNA = 4-hydroxynonan-acid; HNE = 4-hydroxynon-2-enal; HNO = 1-hydroxynon-2-en-4-one; ONA = 4-oxononanal; ONE = 4-oxonon-2-enal; GSH = reduced glutathione, AR = aldose reductase (AKR1B1); ALDH = aldehyde dehydrogenase; CBR1 = human carbonyl reductase.

Abbreviations: TSNA, tobacco-specific nitrosamines; P450, cytochrome P450; NNAL, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol; UGT, UDP-glucuronosyltransferase; 11β-HSD 1, 11β-hydroxysteroid dehydrogenase type 1; CBR1, human carbonyl reductase; AKR, aldo-keto reductase.