Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: HUMANGGP:014866 (AKR1C1)
 209 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We sought to determine relative mRNA expression of AKR1C1 and SRD5A1, which respectively encode for the key progesterone metabolizing enzymes, 20alpha-hydroxysteroid dehydrogenase and 5alpha-reductase type 1, in the myometrium and chorioamniotic membranes during human spontaneous or induced labor and nonlabor. Quantitative real-time reverse-transcriptase polymerase chain reaction was used to compare relative mRNA expression of AKR1C1 and SRD5A1 in the myometrium and chorioamniotic membranes from 20 subjects during three different states of labor: not in labor ( N = 10), spontaneous labor ( N = 5), or induced labor ( N = 5). Labor was defined as regular uterine contractions that resulted in cervical dilation. Myometrial AKR1C1 mRNA expression was significantly greater in spontaneously laboring subjects compared with those not in labor (2.4-fold [1.97 to 2.98], P = 0.02). There was no difference in myometrial AKR1C1 mRNA expression between those with induced labor compared with those not in labor. Regardless of labor status, no differences were observed in the chorioamniotic membrane AKR1C1 mRNA expression between the groups. SRD5A1 mRNA expression was significantly lower in the membranes of both laboring groups when compared with those not in labor (spontaneous: 0.10-fold [0.06 to 0.18], P = 0.007; induced: 0.09-fold [0.03 to 0.25], P = 0.013). Regardless of labor status, there was no difference in SRD5A1 mRNA expression in the myometrium. Our study demonstrated tissue-specific changes in progesterone metabolizing enzyme mRNA expression in human intrauterine tissue at term associated with labor status. These observed changes in mRNA expression may have important implications for progesterone metabolism at those specific sites and thereby may differentially regulate the tissue-specific progesterone concentration and/or the level of specific progesterone metabolites.
 ...
PMID:AKR1C1 and SRD5A1 messenger RNA expression at term in the human myometrium and chorioamniotic membranes. 1877 Apr 91

The structure of aldehyde reductase (ALR1) in ternary complex with the coenzyme NADPH and 3,5-dichlorosalicylic acid (DCL), a potent inhibitor of human 20alpha-hydroxysteroid dehydrogenase (AKR1C1), was determined at a resolution of 2.41A. The inhibitor formed a network of hydrogen bonds with the active site residues Trp22, Tyr50, His113, Trp114 and Arg312. Molecular modelling calculations together with inhibitory activity measurements indicated that DCL was a less potent inhibitor of ALR1 (256-fold) when compared to AKR1C1. In AKR1C1, the inhibitor formed a 10-fold stronger binding interaction with the catalytic residue (Tyr55), non-conserved hydrogen bonding interaction with His222, and additional van der Waals contacts with the non-conserved C-terminal residues Leu306, Leu308 and Phe311 that contribute to the inhibitor's selectivity advantage for AKR1C1 over ALR1.
 ...
PMID:Structure of aldehyde reductase in ternary complex with coenzyme and the potent 20alpha-hydroxysteroid dehydrogenase inhibitor 3,5-dichlorosalicylic acid: implications for inhibitor binding and selectivity. 1878 56

Endometrial cancer is related to estrogen stimulation not opposed by progesterone. We have examined expression of the pre-receptor regulatory enzymes aromatase, 17beta-hydroxysteroid dehydrogenases (17beta-HSDs), 20alpha-hydroxysteroid dehydrogenases (20alpha-HSDs), sulfatase and sulfotransferase, and estrogen (ERs) and progesterone (PRs) receptors in samples of endometrial cancer and adjacent normal endometrium. No significant gene up-regulation was seen, although aromatase, AKR1C3, a 17beta-HSD and 20alpha-HSD, and AKR1C1, the major 20alpha-HSD, were up-regulated in 50% of samples. Significant down-regulation was seen for 17beta-HSD types 1 and 7, sulfotransferase, ERalpha, ERbeta, PR-AB. Western blotting revealed higher levels of AKR1C3 and PR-B and lower levels of ERalpha in cancerous endometrium, and immunohistochemistry confirmed expression of AKR1C3, PR-B and ERalpha at the cellular level. Up-regulation of aromatase in concert with AKR1C3 can lead to increased levels of estradiol, which acts via ERalpha. Up-regulation of AKR1C1 and AKR1C3 can result in lower levels of the protective progesterone, which acts mainly via PR-B.
 ...
PMID:Aberrant pre-receptor regulation of estrogen and progesterone action in endometrial cancer. 1893 Jul 84

The aim of the present study was to investigate pathways of progesterone metabolism in human adipose cells. Adipose tissue samples from the omental (OM) and subcutaneous (SC) fat compartments were surgically obtained in women. In isolated mature adipocytes, progesterone was converted to 20alpha-hydroxyprogesterone as the main metabolite, most likely through the activity of aldo-keto reductases 1C1, 2 and 3 (20alpha-HSD, 3alpha-HSD type 3 and 17beta-HSD type 5, respectively). In cultured preadipocytes, progesterone was converted to several metabolites identified using bidimensional thin layer chromatography, with or without the dual inhibitor of 5alpha-reductase type 1 and 2 (17beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5alpha-androstan-3-one (4-MA)). Major metabolites identified in OM and SC preadipocytes which were incubated for 24h with (14)C-labelled progesterone were 20alpha-hydroxyprogesterone, 5alpha-pregnane-3alpha/beta-ol-20-one, 5alpha- and 5beta-pregnanedione, 5alpha- and 5beta-pregnane-20alpha-ol-3-one, 5alpha-pregnane-3alpha/beta-ol-20-one and 5beta-pregnane-3alpha/beta-20alpha-diol. Induction of preadipocyte differentiation increased expression levels of AKR1C1 and modified the pattern of progesterone metabolism substantially, leaving 20alpha-hydroxyprogesterone as the main metabolite generated. On the other hand, progesterone itself showed no consistent effect on adipocyte differentiation. In conclusion, preadipocytes and lipid-storing, mature adipocytes efficiently generate progesterone metabolites in women, which is consistent with rather modest effects progesterone on abdominal fat cell differentiation.
 ...
PMID:Progesterone metabolism in adipose cells. 1898 31

Prostate and breast cancer are hormone-dependent malignancies of the aging male and female and require the local production of androgens and estrogens to stimulate cell proliferation. Aldo-keto reductases (AKR) play key roles in this process. In the prostate, AKR1C3 (type 5 17beta-HSD) reduces Delta(4)-androstene-3,17-dione to yield testosterone while AKR1C2 (type 3 3alpha-HSD) eliminates 5alpha-dihydrotestosterone (5alpha-DHT), and AKR1C1 forms 3beta-androstanediol (a ligand for ERbeta). In the breast, AKR1C3 forms testosterone, which is converted to 17beta-estradiol by aromatase or reduces estrone to 17beta-estradiol directly. AKR1C3 also acts as a prostaglandin (PG) F synthase and forms PGF(2alpha) and 11beta-PGF(2alpha), which stimulate the FP receptor and prevent the activation of PPARgamma by PGJ(2) ligands. This proproliferative signaling may stimulate the growth of hormone-dependent and -independent prostate and breast cancer.
 ...
PMID:Steroid hormone transforming aldo-keto reductases and cancer. 1925 Jan 90

The first design, synthesis, and evaluation of human 20alpha-hydroxysteroid dehydrogenase (AKR1C1) inhibitors based on the recently published crystal structure of its ternary complex with inhibitor are reported. While the enzyme-inhibitor interactions observed in the crystal structure remain conserved with the newly designed inhibitors, the additional phenyl group of the most potent compound, 3-bromo-5-phenylsalicylic acid, targets a nonconserved hydrophobic pocket in the active site of AKR1C1 resulting in 21-fold improved potency (K(i) = 4 nM) over the structurally similar 3alpha-hydroxysteroid dehydrogenase isoform (AKR1C2). The compound is hydrogen bonded to Tyr55, His117, and His222, and the phenyl ring forms additional van der Waals interactions with residues Leu308, Phe311, and the nonconserved Leu54 (Val in AKR1C2). Additionally, the metabolism of progesterone in AKR1C1-overexpressed cells was potently inhibited by 3-bromo-5-phenylsalicylic acid, which was effective from 10 nM with an IC(50) value equal to 460 nM.
 ...
PMID:Structure-guided design, synthesis, and evaluation of salicylic acid-based inhibitors targeting a selectivity pocket in the active site of human 20alpha-hydroxysteroid dehydrogenase (AKR1C1). 1939 69

A comparison of the structures and kinetic properties of human 20alpha-hydroxysteroid dehydrogenase (AKR1C1) and its mutant enzymes (Leu308Val and Leu308Ala) indicates that Leu308 is a selectivity determinant for substrate binding. While the Leu308Val mutation improved the catalytic efficiency (k(cat)/K(m)) of AKR1C1 towards the two substrates 5alpha-pregnane-3alpha,20alpha-diol (PregA) and 5beta-pregnan-3alpha-ol-20-one (PregB), the Leu308Ala mutation rendered the enzyme inactive. In the docked model of PregA the conformation of the steroid molecule was similar to that of 20alpha-hydroxyprogesterone in the crystal structure of the AKR1C1 complex where the steroid did not interact with the catalytic residues Tyr55 and His117. In the case of PregB the steroid interacted with the catalytic residue His117 and formed close contacts with Leu308, suggesting that the binding mechanism of 3alpha-hydroxysteroids in the active site of AKR1C1 is different from that of 20alpha-hydroxysteroids.
 ...
PMID:Factorizing the role of a critical leucine residue in the binding of substrate to human 20alpha-hydroxysteroid dehydrogenase (AKR1C1): molecular modeling and kinetic studies of the Leu308Val mutant enzyme. 2065 85


<< Previous 1 2