Human Carbonyl Reductases

Petra      Malatkova; Edmund      Maser; Vladimir      Wsol

doi:10.2174/138920010794233530

Abstract

Enzymatic carbonyl reduction means the formation of a hydroxy function out of a ketone or aldehyde moiety and applies for the metabolism of physiological (endogenous) or xenobiotic (exogenous) molecules. As for endogenous substrates, carbonyl reduction is often part of a reversible oxidoreductase process and involves the activation or inactivation of important signal molecules like steroids, prostaglandins, retinoids and biogenic amines. These reactions are carried out by NAD(P)(H)-dependent dehydrogenases belonging to two protein superfamilies, the aldo-keto reductases (AKR) and the short-chain dehydrogenases/reductases (SDR). With regard to exogenous substrates, carbonyl reduction of xenobiotics is generally a “one-way” detoxification reaction, since the resulting alcohol is easier to conjugate and to eliminate. Interestingly, the participating enzymes do also belong to the AKR and SDR superfamilies. Moreover, some enzymes from the two protein superfamilies exhibit pluripotency in that they are able to catalyze the oxidoreduction of endobiotics but do also function in the reductive metabolism of carbonyl group bearing xenobiotics. A special case are carbonyl reductases per se which belong to the SDR superfamily and whose substrates or physiological roles are not quite clear. Usually, carbonyl reductases have a broad and diverse substrate spectrum for xenobiotics, however, for some of them a specific physiological function has been speculated. In the human genome, three SDR genes have been identified to code for the carbonyl reductases CBR1 (SDR21C1), CBR3 (SDR21C2) and CBR4 (SDR45C1). The present review summarizes the current knowledge on these enzymes with special emphasis on their role as a defence system against toxicants, as well as their possible physiological function and medical application. In detail, we have screened the recent literature on these three enzymes with regard to endogenous and exogenous substrates, their three-dimensional structure, tissues specific expression, polymorphisms, transcriptional regulation, occurrence in pathological states, and their possible association with cancer. Combined, this review contributes to understanding the complex nature and biological role(s) of the human carbonyl reductases CBR1, CBR3 and CBR4.

Keywords: CBR1, CBR3, CBR4, metabolism, detoxification, polymorphism, regulation, endogenous substrates, xenobiotics, Enzymatic carbonyl reduction, xenobiotic, reversible oxidoreductase, prostaglandins, retinoids, biogenic amines, aldo-keto reductases, short-chain dehydrogenases/reductases, 11-hydroxysteroid dehydrogenase type 1 (11-HSD1), dicar-bonyl/xylulose reductase (DCXR), quinone reductase, tetrameric -ketoacyl thioester reductase, tetrahydrobiopterin, 9-keto-reduction, PGE1, PGE2, PGF2 synthesis, 15-hydroxyprostaglandin, Tetrahydrobiopterin (BH4), Isatin, NNK, AKR1C1, AKR1C2, AKR1C4, haloperidol, bromoperidol, timiperone, metyrapone, loxoprofen, serotin-antagonists (dolasetron), 7-monohydroxyethylrutosid, 2,3,7,8-tetrachlorodibenzo-p-dioxin, nitrosoglutathione (GSNO), Rossmann-fold con-sensus sequence (Gly-x-x-x-Gly-x-Gly), Menadione, Oracin, 1-OXPH4, 4-ONA, 4-ONE, AhR, DAUNol, DCXR, DOX, DOXol, DS, GSH, GSNO, hydroxy-PP-Me