20 alpha-Hydroxysteroid dehydrogenase (20 alpha-HSD) catalyses the conversion of progesterone into 20 alpha-dihydroprogesterone (20 alpha-OHP). It is an abundant 37-kDa protein, which comprises up to 30% of the soluble proteins of the rabbit ovary.
Inhibitors of human 20a-hydroxysteroid dehydrogenase (AKR1C1). El-Kabbani O et al. Human 20a-hydroxysteroid dehydrogenase (AKR1C1), a member of the aldo-keto reductase (AKR) superfamily, is one of four isoforms (with >84% amino acid sequence identity) existing in human tissues. AKR1C1 most efficiently reduces biologically active progesterone and 5a-pregnan-3a-ol-20-one into their corresponding 20a-hydroxysteroids among the isoforms. The enzyme also accepts endogenous and xenobiotic non-steroidal carbonyl compounds as the substrates. In addition to the up-regulation of the AKR1C1 gene in cancer cells, the enzyme's over-expression in the cells of lung, ovary, uterine cervix, skin and colon carcinomas was reported to be associated with resistance against several anticancer agents. Thus, AKR1C1 may be a marker of the above cancers and a target of poor prognosis in cancer therapy. The recently determined X-ray crystal structures of AKR1C1/NADP(+)/20a-hydroxyprogesterone and AKR1C1/NADP(+)/3,5-dichlorosalicylic acid ternary complexes have provided a strong foundation for structure-based design methods to improve inhibitor selectivity and potency. In this review we provide an overview of the different types of AKR1C1 inhibitors and an update on the design of potent and selective inhibitors based on the crystal structure of the enzyme-inhibitor complex.
NCBI Summary:
This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols by utilizing NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity. This enzyme catalyzes the reaction of progesterone to the inactive form 20-alpha-hydroxy-progesterone. This gene shares high sequence identity with three other gene members and is clustered with those three genes at chromosome 10p15-p14.
General function
Enzyme, Oxidoreductase
Comment
The steroidogenic enzyme 20 alpha HSD regulates the conversion of progesterone to 20 alpha-hydroxyprogesterone in many mammalian species. Complimentary DNA clones encoding a unique and abundant 20 alpha HSD were isolated from a mature rabbit ovary library using guinea pig antisera generated to the purified 37-kDa protein (Lacy et al., 1993). The sequence showed high similarity with those of rat liver 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD), bovine lung prostaglandin F synthase (PGFS), human liver chlordecone reductase (CDR), frog lens rho-crystallin and aldose reductases, indicating that 20 alpha-HSD belongs to the aldo-keto reductase family. Mao et al. (1994) reported the isolation and characterization of a full length cDNA encoding rat 20 alpha hydroxysteroid dehydrogenase derived from rat corpus luteum RNA. Miura et al. (1994) purified the enzyme (37 kDa) from rat ovary and determined its N-terminal amino acid sequence and cloned a full-length 20 alpha-HSD cDNA.
Cellular localization
Cytoplasmic
Comment
Ovarian function
Steroid metabolism, Luteolysis
Comment
Northern analysis revealed a 1.2 Kb 20 alpha HSD mRNA in corpora lutea undergoing luteolysis (Mao et al., 1994). Prolactin reduced markedly 20 alpha HSD mRNA expression. No signal was detected in other tissues examined, demonstrating the specific expression of this enzyme in the corpus luteum. Albarracin et al. (1994) demonstrated that 20 alpha HSD protein and mRNA levels are coordinately regulated, and that the profound inhibitory effect of PRL on 20 alpha HSD activity is apparently due to inhibition of 20 alpha HSD gene expression, leading to the disappearance of the protein from the corpus luteum.
Expression regulated by
FSH, LH, prolactin
Comment
Lahav et al. (1977) reported the suppression of 20 alpha-HSD by prolactin in cultured rat luteal cell. Jones et al. (1983) reported that PRL and the beta 2-adrenergic agonist stimulate progesterone production in cultured granulosa cells by increasing pregnenolone production and 3 beta-HSD activity as well as by decreasing 20 alpha-HSD activity, while hCG stimulates progesterone production by increasing pregnenolone production and 3 beta-HSD activity.
Ovarian localization
Granulosa, Luteal cells, Large luteal cells, Stromal cells, interstitial cells
Comment
Gene expression and localization of 20a-hydroxysteroid dehydrogenase (HSD) in reproductive tissues during early pregnancy of cattle. Kim SH 2014 et al.
The enzyme 20a-hydroxysteroid dehydrogenase (20a-HSD) catalyzes the conversion of progesterone to its inactive form, 20a-hydroxyprogesterone, and this enzyme has an important role in the regulation of luteal function in mammals. It has previously been determined that the 20a-HSD gene is primarily expressed by large luteal cells during the late stage of the estrous cycle. In the present study, the amounts of mRNA were determined in cultured cells of the corpus luteum (CL) cells. The localization of 20a-HSD was also determined in ovaries, placenta, and endometrium during early pregnancy. The amount of 20a-HSD mRNA in cultured luteal cells increased with time and by treatment with the luteolysis agent prostaglandin F2a (PGF2a). Immunofluorescence assays detected increased protein in cultured luteal cells. The 20a-HSD mRNA and protein were present in the ovaries, placenta, and endometrium on Days 30, 60, and 90 of pregnancy. In particular, gene expression was much greater in the ovary than in the placenta and endometrium. Immuno-histochemical analysis indicated that bovine 20a-HSD was primarily localized in ovarian large luteal cells, placental cytotrophoblast villus, and glandular epithelial cells of the endometrium during early pregnancy. Furthermore, in situ analyses demonstrated colocalization of 20a-HSD mRNA and protein. Taken together, results of the present study indicate that 20a-HSD mRNA and protein are co-localized in large luteal cells, the placenta, and the endometrium during early pregnancy, suggesting that 20a-HSD regulates mechanisms involved in the maintenance of early pregnancy.
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Expression of aldo-keto reductase family 1 member C1 (AKR1C1) gene in porcine ovary and uterine endometrium during the estrous cycle and pregnancy. Seo KS et al. ABSTRACT: BACKGROUND: The aldo-keto reductase family 1 member C1 (AKR1C1) belongs to a superfamily of NADPH-dependent reductases that convert a wide range of substrates, including carbohydrates, steroid hormones, and endogenous prostaglandins. The 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD) is a member of AKR family. The aims of this study were to determine its expression in the ovary and uterus endometrium during the estrous cycle and pregnancy. METHODS: Rapid amplification of cDNA ends (RACE) experiments were performed to obtain the 5' and 3' ends of the porcine 20alpha-HSD cDNA. Reverse-transcriptase-PCR (RT-PCR), real-time PCR, northern blot analysis, and western blot analysis were performed to examine the expression of porcine 20alpha-HSD. Immunohistochemical analysis was also performed to determine the localization in the ovary. RESULTS: The porcine 20alpha-HSD cDNA is 957 bp in length and encodes a protein of 319 amino acids. The cloned cDNA was virtually the same as the porcine AKR1C1 gene (337 amino acids) reported recently, and only differed in the C-terminal region (the AKR1C1 gene has a longer C-terminal region than our sequence). The 20alpha-HSD gene (from now on referred to as AKR1C1) cloned in this paper encodes a deletion of 4 amino acids, compared with the C-terminal region of AKR1C1 genes from other animals. Porcine AKR1C1 mRNA was expressed on day 5, 10, 12, 15 of the cycle and 0-60 of pregnancy in the ovary. The mRNA was also specifically detected in the uterine endometrium on day 30 of pregnancy. Western blot analysis indicated that the pattern of AKR1C1 protein in the ovary during the estrous cycle and uterus during early pregnancy was similar to that of AKR1C1 mRNA expression. The recombinant protein produced in CHO cells was detected at approximately 37 kDa. Immunohistochemical analysis also revealed that pig AKR1C1 protein was localized in the large luteal cells in the early stages of the estrous cycle and before parturition. CONCLUSIONS: Our study demonstrated that AKR1C1 mRNA and protein are coordinately expressed in the luteal cell of ovary throughout the estrous cycle and in the uterus on day 30 of pregnancy. Thus, the porcine AKR1C1 gene might control important mechanisms during the estrous cycle.
Lacy et al. (1993) reported that Northern blot analysis demonstrated a 1.2-kilobase 20 alpha HSD mRNA in the interstitial tissue of mature rabbit ovaries and, to a lesser extent, in corpora luteal tissue.
Sex-related Expression of 20alpha-hydroxysteroid Dehydrogenase mRNA in the Adult Mouse
J Histochem Cytochem 51:1425-1436, 2003 .
The enzyme 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD) catalyzes the conversion of progesterone into its inactive form, 20alpha-hydroxyprogesterone. To gain information about the exact sites of 20alpha-HSD mRNA expression, we performed in situ hybridization using a (35)S-labeled cRNA probe in tissues of adult mice of both sexes. 20alpha-HSD mRNA was expressed in both male and female gonads. In the ovary, high expression was found in luteal cells of corpora lutea, while much lower expression could be detected in granulosa cells of growing follicles.
Follicle stages
Corpus luteum
Comment
Seong et al. (1992) reported that the rat ovary contains two isozymes of 20 alpha-hydroxysteroid dehydrogenase (HSD-1 and HSD-2). In normal pseudopregnancy, HSD-1 activity was low on days 5 and 9 and increased markedly on day 15, whereas HSD-2 was lower than HSD-1 and did not vary throughout pseudopregnancy. However, on days 5 and 9 of continuous-light pseudopregnancy, low activity of HSD-1 only was detected; by day 15, HSD-1 activity had increased sixfold and HSD-2 activity could be detected.
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: Reproductive Phenotypes in Mice with Targeted Disruption of the 20alpha-Hydroxysteroid Dehydrogenase Gene. Ishida M et al. In the corpus luteum of rats and mice, 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD) catalyzes the conversion of progesterone to a biologically inactive metabolite, 20alpha-dihydroprogesterone (20alpha-OHP). The reduction of progesterone by 20 alpha-HSD is believed to be important for functional luteolysis in these rodent species. In addition to the corpus luteum, expression of 20alpha-HSD has been demonstrated in tissues such as the placenta, endometrial epithelia, and fetal skin, although the roles it plays in the latter tissues remain to be determined. To determine the contribution of 20alpha-HSD to functional luteolysis and to the rodent reproductive system more generally, we generated a strain of mice with targeted disruption of the 20 alpha-HSD gene. In the 20alpha-HSD-/-mice we obtained, which lacked the genomic region essential for catalytic reaction, neither 20alpha-HSD activity in the corpus luteum nor an increase in the serum concentrations of 20alpha-OHP during pseudopregnancy or pregnancy was detected. The durations of the estrous cycle, pseudopregnancy, and pregnancy were significantly prolonged in the 20alpha-HSD-/-mice, although the serum progesterone levels decreased to levels low enough for delivery of pups at term of pregnancy. In addition, the number of pups, especially live pups, was markedly decreased in the 20alpha-HSD-/- mice. These findings suggest that the role of 20alpha-HSD in functional luteolysis is relatively minor but that it is involved in the survival of newborn mice.