ReviewRole of aldo–keto reductase family 1 (AKR1) enzymes in human steroid metabolism
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Enzymes of steroid metabolism
Imbalance in the biosynthesis and inactivation of steroids can lead to development of disease, including hormonally dependent cancer, of the breast, prostate, endometrium and ovary [1], and to diseases such as benign prostatic hyperplasia, endometriosis, cholestasis, neonatal liver failure, neurological disorders [2], [3], [4], [5], [6] and malformation or differentiation of the genitalia [7]. The metabolism of steroids involves phase I and phase II enzymes and has an important role in human
Human AKR1 enzymes implicated in steroid metabolism
Human AKR1 enzymes implicated in steroid metabolism are members of the AKR1C and AKR1D subfamilies. AKR1C enzymes (AKR1C1–AKR1C4) function in vivo as 3-keto-, 17-keto- and 20-ketosteroid reductases to form 3α/β, 17β- and 20α-hydroxy-metabolites to varying extents and thus metabolize a broad spectrum of natural and synthetic therapeutic steroids [14], Fig. 1. These enzymes are expressed in different tissues, while AKR1C4 is mainly liver specific [14]. AKR1C enzymes share a high percentage of
AKR1 enzymes control concentrations of receptor ligands
Human AKR1 enzymes catalyze the conversion of either weak ligands to form potent ligands for nuclear receptors or they are involved in the elimination of these ligands. In this manner AKR1 enzymes control the levels of potent ligands that can occupy and trans-activate nuclear receptors within endocrine target tissues. These receptors bind to DNA response elements as homo or heterodimers, recruit co-activators or co-repressors and thus regulate gene transcription [4], [14], [47]. Additionally,
Expression of human AKR1 genes in disease
As AKR1 enzymes play pivotal roles in regulating steroid levels changes in gene expression are anticipated to play roles in disease pathogenesis. The AKR1C1–AKR1C4 genes are located on chromosome 10p15-p14, and the AKR1D1 gene is located on chromosome 7q32-q33. AKR1C1–AKR1C4 genes comprise 12 exons and AKR1D1 has 9 exons. Three alternatively spliced protein encoding mRNA variants were predicted for AKR1C2, AKR1C3 and AKR1D1 genes in the NCBI database (Table 5). AKR1C2 transcript variants 1 and
Genetics of human AKR1 enzymes
Inherited or SNP allelic variants in AKR1 genes may affect the metabolism of exogenous and endogenous steroids and may also contribute to the development of pathophysiological processes.
Future directions
AKR1 enzymes play important roles in metabolism of androgens, estrogens, progesterone, glucococorticoids, neurosteroids, conjugated steroids, and in the biosynthesis of bile acids. Although AKR1 activities towards representative substrates from these steroid classes have been studied the list is far from comprehensive. A more complete understanding of substrate specificities of AKR1 enzymes and the products they generate may reveal additional physiological and/or pathophysiological roles for
Acknowledgements
This work was supported by grants 1R01-DK47015, 1R01-CA90744 and P30-ES013508 to T.M.P. from the National Institutes of Health, J3-4135 and SLO-USA grants from Slovenian Research Agency, and a Fulbright Grant from Council of International Exchange of Scholars to T.L.R.
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