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Trevor M. Penning - One of the best experts on this subject based on the ideXlab platform.
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akr1c3 type 5 17β hydroxysteroid dehydrogenase Prostaglandin F synthase roles in malignancy and endocrine disorders
Molecular and Cellular Endocrinology, 2019Co-Authors: Trevor M. PenningAbstract:Abstract Aldo-Keto-Reductase 1C3 (type 5 17β-hydroxysteroid dehydrogenase (HSD)/Prostaglandin (PG) F2α synthase) is the only 17β-HSD that is not a short-chain dehydrogenase/reductase. By acting as a 17-ketosteroid reductase, AKR1C3 produces potent androgens in peripheral tissues which activate the androgen receptor (AR) or act as substrates For aromatase. AKR1C3 is implicated in the production oF androgens in castration-resistant prostate cancer (CRPC) and polycystic ovarian syndrome; and is implicated in the production oF aromatase substrates in breast cancer. By acting as an 11-ketoProstaglandin reductase, AKR1C3 generates 11β-PGF2α to activate the FP receptor and deprives peroxisome proliFerator activator receptorγ oF its putative PGJ2 ligands. These growth stimulatory signals implicate AKR1C3 in non-hormonal dependent malignancies e.g. acute myeloid leukemia (AML). AKR1C3 moonlights by acting as a co-activator oF the AR and stabilizes ubiquitin ligases. AKR1C3 inhibitors have been used clinically For CRPC and AML and can be used to probe its pluripotency.
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an indomethacin analogue n 4 chlorobenzoyl melatonin is a selective inhibitor oF aldo keto reductase 1c3 type 2 3α hsd type 5 17β hsd and Prostaglandin F synthase a potential target For the treatment oF hormone dependent and hormone independent malig
Biochemical Pharmacology, 2008Co-Authors: Michael C Byrns, Stephan Steckelbroeck, Trevor M. PenningAbstract:Abstract Aldo-keto reductase (AKR) 1C3 (type 2 3α-HSD, type 5 17β-HSD, and Prostaglandin F synthase) regulates ligand access to steroid hormone and Prostaglandin receptors and may stimulate proliFeration oF prostate and breast cancer cells. NSAIDs are known inhibitors oF AKR1C enzymes. An NSAID analogue that inhibits AKR1C3 but is inactive against the cyclooxygenases and the other AKR1C Family members would provide an important tool to examine the role oF AKR1C3 in proliFerative signaling. We tested NSAIDs and NSAID analogues For inhibition oF the reduction oF 9,10-phenanthrenequinone (PQ) catalyzed by AKR1C3 and the closely related isoForms AKR1C1 and AKR1C2. Two oF the compounds initially screened, indomethacin and its methyl ester, were speciFic For AKR1C3 versus the other AKR1C isoForms. Based on these results and the crystal structure oF AKR1C3, we predicted that N -(4-chlorobenzoyl)-melatonin (CBM), an indomethacin analogue that does not inhibit the cyclooxygenases, would selectively inhibit AKR1C3. CBM inhibited the reduction oF PQ by AKR1C3, but did not signiFicantly inhibit AKR1C1 or AKR1C2. Indomethacin and CBM also inhibited the AKR1C3-catalyzed reduction oF Δ 4 -androstene-3,17-dione but did not signiFicantly inhibit the reduction oF steroid hormones catalyzed by AKR1C1 or AKR1C2. The pattern oF inhibition oF AKR1C3 by indomethacin and CBM was uncompetitive versus PQ, but competitive versus Δ 4 -androstene-3,17-dione, indicating that two diFFerent inhibitory complexes Form during the ordered bi bi reactions. The identiFication oF CBM as a speciFic inhibitor oF AKR1C3 will aid the investigation oF its roles in steroid hormone and Prostaglandin signaling and the resultant eFFects on cancer development.
Michael C Byrns - One of the best experts on this subject based on the ideXlab platform.
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an indomethacin analogue n 4 chlorobenzoyl melatonin is a selective inhibitor oF aldo keto reductase 1c3 type 2 3α hsd type 5 17β hsd and Prostaglandin F synthase a potential target For the treatment oF hormone dependent and hormone independent malig
Biochemical Pharmacology, 2008Co-Authors: Michael C Byrns, Stephan Steckelbroeck, Trevor M. PenningAbstract:Abstract Aldo-keto reductase (AKR) 1C3 (type 2 3α-HSD, type 5 17β-HSD, and Prostaglandin F synthase) regulates ligand access to steroid hormone and Prostaglandin receptors and may stimulate proliFeration oF prostate and breast cancer cells. NSAIDs are known inhibitors oF AKR1C enzymes. An NSAID analogue that inhibits AKR1C3 but is inactive against the cyclooxygenases and the other AKR1C Family members would provide an important tool to examine the role oF AKR1C3 in proliFerative signaling. We tested NSAIDs and NSAID analogues For inhibition oF the reduction oF 9,10-phenanthrenequinone (PQ) catalyzed by AKR1C3 and the closely related isoForms AKR1C1 and AKR1C2. Two oF the compounds initially screened, indomethacin and its methyl ester, were speciFic For AKR1C3 versus the other AKR1C isoForms. Based on these results and the crystal structure oF AKR1C3, we predicted that N -(4-chlorobenzoyl)-melatonin (CBM), an indomethacin analogue that does not inhibit the cyclooxygenases, would selectively inhibit AKR1C3. CBM inhibited the reduction oF PQ by AKR1C3, but did not signiFicantly inhibit AKR1C1 or AKR1C2. Indomethacin and CBM also inhibited the AKR1C3-catalyzed reduction oF Δ 4 -androstene-3,17-dione but did not signiFicantly inhibit the reduction oF steroid hormones catalyzed by AKR1C1 or AKR1C2. The pattern oF inhibition oF AKR1C3 by indomethacin and CBM was uncompetitive versus PQ, but competitive versus Δ 4 -androstene-3,17-dione, indicating that two diFFerent inhibitory complexes Form during the ordered bi bi reactions. The identiFication oF CBM as a speciFic inhibitor oF AKR1C3 will aid the investigation oF its roles in steroid hormone and Prostaglandin signaling and the resultant eFFects on cancer development.
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an indomethacin analogue n 4 chlorobenzoyl melatonin is a selective inhibitor oF aldo keto reductase 1c3 type 2 3α hsd type 5 17β hsd and Prostaglandin F synthase a potential target For the treatment oF hormone dependent and hormone independent malignancies
Biochemical Pharmacology, 2008Co-Authors: Michael C Byrns, Stephan Steckelbroeck, T M PenningAbstract:Aldo-keto reductase (AKR) 1C3 (type 2 3alpha-HSD, type 5 17beta-HSD, and Prostaglandin F synthase) regulates ligand access to steroid hormone and Prostaglandin receptors and may stimulate proliFeration oF prostate and breast cancer cells. NSAIDs are known inhibitors oF AKR1C enzymes. An NSAID analogue that inhibits AKR1C3 but is inactive against the cyclooxygenases and the other AKR1C Family members would provide an important tool to examine the role oF AKR1C3 in proliFerative signaling. We tested NSAIDs and NSAID analogues For inhibition oF the reduction oF 9,10-phenanthrenequinone (PQ) catalyzed by AKR1C3 and the closely related isoForms AKR1C1 and AKR1C2. Two oF the compounds initially screened, indomethacin and its methyl ester, were speciFic For AKR1C3 versus the other AKR1C isoForms. Based on these results and the crystal structure oF AKR1C3, we predicted that N-(4-chlorobenzoyl)-melatonin (CBM), an indomethacin analogue that does not inhibit the cyclooxygenases, would selectively inhibit AKR1C3. CBM inhibited the reduction oF PQ by AKR1C3, but did not signiFicantly inhibit AKR1C1 or AKR1C2. Indomethacin and CBM also inhibited the AKR1C3-catalyzed reduction oF Delta(4)-androstene-3,17-dione but did not signiFicantly inhibit the reduction oF steroid hormones catalyzed by AKR1C1 or AKR1C2. The pattern oF inhibition oF AKR1C3 by indomethacin and CBM was uncompetitive versus PQ, but competitive versus Delta(4)-androstene-3,17-dione, indicating that two diFFerent inhibitory complexes Form during the ordered bi bi reactions. The identiFication oF CBM as a speciFic inhibitor oF AKR1C3 will aid the investigation oF its roles in steroid hormone and Prostaglandin signaling and the resultant eFFects on cancer development.
T M Penning - One of the best experts on this subject based on the ideXlab platform.
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an indomethacin analogue n 4 chlorobenzoyl melatonin is a selective inhibitor oF aldo keto reductase 1c3 type 2 3α hsd type 5 17β hsd and Prostaglandin F synthase a potential target For the treatment oF hormone dependent and hormone independent malignancies
Biochemical Pharmacology, 2008Co-Authors: Michael C Byrns, Stephan Steckelbroeck, T M PenningAbstract:Aldo-keto reductase (AKR) 1C3 (type 2 3alpha-HSD, type 5 17beta-HSD, and Prostaglandin F synthase) regulates ligand access to steroid hormone and Prostaglandin receptors and may stimulate proliFeration oF prostate and breast cancer cells. NSAIDs are known inhibitors oF AKR1C enzymes. An NSAID analogue that inhibits AKR1C3 but is inactive against the cyclooxygenases and the other AKR1C Family members would provide an important tool to examine the role oF AKR1C3 in proliFerative signaling. We tested NSAIDs and NSAID analogues For inhibition oF the reduction oF 9,10-phenanthrenequinone (PQ) catalyzed by AKR1C3 and the closely related isoForms AKR1C1 and AKR1C2. Two oF the compounds initially screened, indomethacin and its methyl ester, were speciFic For AKR1C3 versus the other AKR1C isoForms. Based on these results and the crystal structure oF AKR1C3, we predicted that N-(4-chlorobenzoyl)-melatonin (CBM), an indomethacin analogue that does not inhibit the cyclooxygenases, would selectively inhibit AKR1C3. CBM inhibited the reduction oF PQ by AKR1C3, but did not signiFicantly inhibit AKR1C1 or AKR1C2. Indomethacin and CBM also inhibited the AKR1C3-catalyzed reduction oF Delta(4)-androstene-3,17-dione but did not signiFicantly inhibit the reduction oF steroid hormones catalyzed by AKR1C1 or AKR1C2. The pattern oF inhibition oF AKR1C3 by indomethacin and CBM was uncompetitive versus PQ, but competitive versus Delta(4)-androstene-3,17-dione, indicating that two diFFerent inhibitory complexes Form during the ordered bi bi reactions. The identiFication oF CBM as a speciFic inhibitor oF AKR1C3 will aid the investigation oF its roles in steroid hormone and Prostaglandin signaling and the resultant eFFects on cancer development.
Stephan Steckelbroeck - One of the best experts on this subject based on the ideXlab platform.
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an indomethacin analogue n 4 chlorobenzoyl melatonin is a selective inhibitor oF aldo keto reductase 1c3 type 2 3α hsd type 5 17β hsd and Prostaglandin F synthase a potential target For the treatment oF hormone dependent and hormone independent malig
Biochemical Pharmacology, 2008Co-Authors: Michael C Byrns, Stephan Steckelbroeck, Trevor M. PenningAbstract:Abstract Aldo-keto reductase (AKR) 1C3 (type 2 3α-HSD, type 5 17β-HSD, and Prostaglandin F synthase) regulates ligand access to steroid hormone and Prostaglandin receptors and may stimulate proliFeration oF prostate and breast cancer cells. NSAIDs are known inhibitors oF AKR1C enzymes. An NSAID analogue that inhibits AKR1C3 but is inactive against the cyclooxygenases and the other AKR1C Family members would provide an important tool to examine the role oF AKR1C3 in proliFerative signaling. We tested NSAIDs and NSAID analogues For inhibition oF the reduction oF 9,10-phenanthrenequinone (PQ) catalyzed by AKR1C3 and the closely related isoForms AKR1C1 and AKR1C2. Two oF the compounds initially screened, indomethacin and its methyl ester, were speciFic For AKR1C3 versus the other AKR1C isoForms. Based on these results and the crystal structure oF AKR1C3, we predicted that N -(4-chlorobenzoyl)-melatonin (CBM), an indomethacin analogue that does not inhibit the cyclooxygenases, would selectively inhibit AKR1C3. CBM inhibited the reduction oF PQ by AKR1C3, but did not signiFicantly inhibit AKR1C1 or AKR1C2. Indomethacin and CBM also inhibited the AKR1C3-catalyzed reduction oF Δ 4 -androstene-3,17-dione but did not signiFicantly inhibit the reduction oF steroid hormones catalyzed by AKR1C1 or AKR1C2. The pattern oF inhibition oF AKR1C3 by indomethacin and CBM was uncompetitive versus PQ, but competitive versus Δ 4 -androstene-3,17-dione, indicating that two diFFerent inhibitory complexes Form during the ordered bi bi reactions. The identiFication oF CBM as a speciFic inhibitor oF AKR1C3 will aid the investigation oF its roles in steroid hormone and Prostaglandin signaling and the resultant eFFects on cancer development.
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an indomethacin analogue n 4 chlorobenzoyl melatonin is a selective inhibitor oF aldo keto reductase 1c3 type 2 3α hsd type 5 17β hsd and Prostaglandin F synthase a potential target For the treatment oF hormone dependent and hormone independent malignancies
Biochemical Pharmacology, 2008Co-Authors: Michael C Byrns, Stephan Steckelbroeck, T M PenningAbstract:Aldo-keto reductase (AKR) 1C3 (type 2 3alpha-HSD, type 5 17beta-HSD, and Prostaglandin F synthase) regulates ligand access to steroid hormone and Prostaglandin receptors and may stimulate proliFeration oF prostate and breast cancer cells. NSAIDs are known inhibitors oF AKR1C enzymes. An NSAID analogue that inhibits AKR1C3 but is inactive against the cyclooxygenases and the other AKR1C Family members would provide an important tool to examine the role oF AKR1C3 in proliFerative signaling. We tested NSAIDs and NSAID analogues For inhibition oF the reduction oF 9,10-phenanthrenequinone (PQ) catalyzed by AKR1C3 and the closely related isoForms AKR1C1 and AKR1C2. Two oF the compounds initially screened, indomethacin and its methyl ester, were speciFic For AKR1C3 versus the other AKR1C isoForms. Based on these results and the crystal structure oF AKR1C3, we predicted that N-(4-chlorobenzoyl)-melatonin (CBM), an indomethacin analogue that does not inhibit the cyclooxygenases, would selectively inhibit AKR1C3. CBM inhibited the reduction oF PQ by AKR1C3, but did not signiFicantly inhibit AKR1C1 or AKR1C2. Indomethacin and CBM also inhibited the AKR1C3-catalyzed reduction oF Delta(4)-androstene-3,17-dione but did not signiFicantly inhibit the reduction oF steroid hormones catalyzed by AKR1C1 or AKR1C2. The pattern oF inhibition oF AKR1C3 by indomethacin and CBM was uncompetitive versus PQ, but competitive versus Delta(4)-androstene-3,17-dione, indicating that two diFFerent inhibitory complexes Form during the ordered bi bi reactions. The identiFication oF CBM as a speciFic inhibitor oF AKR1C3 will aid the investigation oF its roles in steroid hormone and Prostaglandin signaling and the resultant eFFects on cancer development.
Kikuko Watanabe - One of the best experts on this subject based on the ideXlab platform.
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Prostaglandin F2alpha Formation From Prostaglandin H2 by Prostaglandin F synthase (PGFS): crystal structure oF PGFS containing bimatoprost.
Biochemistry, 2006Co-Authors: Junichi Komoto, Taro Yamada, Kikuko Watanabe, David F. Woodward, Fusao TakusagawaAbstract:Prostaglandin H2 (PGH2) Formed From arachidonic acid is an unstable intermediate and is eFFiciently converted into more stable arachidonate metabolites by the action oF enzymes. Prostaglandin F synthase (PGFS) has dual catalytic activities: Formation oF PGF2α From PGH2 by the PGH2 9,11-endoperoxide reductase activity and 9α,11β-PGF2 (PGF2αβ) From PGD2 by the PGD2 11-ketoreductase activity in the presence oF NADPH. Bimatoprost (BMP), which is a highly eFFective ocular hypotensive agent, is a PGF2α analogue that inhibits both the PGD2 11-ketoreductase and PGH2 9,11-endoperoxide reductase activities oF PGFS. To examine the catalytic mechanism oF PGH2 9,11-endoperoxide reductase, a crystal structure oF PGFS[NADPH + BMP] has been determined at 2.0 A resolution. BMP binds near the PGD2 binding site, but the α- and ω-chains oF BMP are locate on the ω- and α-chains oF PGD2, respectively. Consequently, the bound BMP and PGD2 direct their opposite Faces oF the cyclopentane moieties toward the nicotinamide ring oF ...
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synthesis oF Prostaglandin F ethanolamide by Prostaglandin F synthase and identiFication oF bimatoprost as a potent inhibitor oF the enzyme new enzyme assay method using lc esi ms
Archives of Biochemistry and Biophysics, 2004Co-Authors: Noriko Koda, David F. Woodward, Yasutaka Tsutsui, Haruki Niwa, Seiji Ito, Kikuko WatanabeAbstract:Abstract Prostaglandin (PG) D 2 ethanolamide (prostamide D 2 ) was reduced to 9α,11β-PGF 2 ethanolamide (9α,11β-prostamide F 2 ) by PGF synthase, which also catalyzes the reduction oF PGH 2 and PGD 2 to PGF 2α and 9α,11β-PGF 2 , respectively. These enzyme activities were measured by a new method, the liquid chromatographic–electrospray ionization–mass spectrometry (LC/ESI/MS) technique, which could simultaneously detect the substrate and all products. PGF 2α , 9α,11β-PGF 2 , PGD 2 , PGH 2 , 9α,11β-prostamide F 2 , and prostamide D 2 were separated on a TSKgel ODS 80Ts column, ionized by electrospray, and detected in the negative mode. Selected ion monitoring (SIM) oF m / z 353 ([M–H] − ), 353 ([M–H] − ), 351 ([M–H] − ), 333 ([M–H–H 2 O] − ), 456 ([M+59] − ), and m / z 358 ([M−37] − ) was used For quantiFying PGF 2α , 9α,11β-PGF 2 , PGD 2 , PGH 2 , 9α,11β-prostamide F 2 , and prostamide D 2 , respectively. The detection limit For PGF 2α and 9α,11β-PGF 2 was 0.01 pmol; that For PGH 2 and PGD 2 , 0.1 pmol; and that For prostamide D 2 and 9α,11β-prostamide F 2 , 0.5 and 0.03 pmol, respectively. The LC/ESI/MS technique For measuring PGF synthase activity showed higher sensitivity than other methods. Using this method, we Found that Bimatoprost, the ethyl amide analog oF 17-phenyl-trinor PGF 2α and an anti-glaucoma agent, inhibited all three reductase activities oF PGF synthase when used at a low concentration. These results suggest that Bimatoprost also behaves as a potent PGF synthase inhibitor in addition to having prostamide-like activity.
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crystal structure oF human Prostaglandin F synthase akr1c3
Biochemistry, 2004Co-Authors: Junichi Komoto, Taro Yamada, Kikuko Watanabe, Fusao TakusagawaAbstract:Prostaglandin H2 (PGH2) Formed From arachidonic acid is an unstable intermediate and is eFFiciently converted into more stable arachidonate metabolites (PGD2, PGE2, and PGF2) by the action oF three groups oF enzymes. Prostaglandin F synthase (PGFS) was First puriFied From bovine lung and catalyzes the Formation oF 9α,11β-PGF2 From PGD2 and PGF2α From PGH2 in the presence oF NADPH. Human PGFS is 3α-hydroxysteroid dehydrogenase (3α-HSD) type II and has PGFS activity and 3α-HSD activity. Human lung PGFS has been crystallized with the coFactor NADP+ and the substrate PGD2, and with the coFactor NADPH and the inhibitor rutin. These complex structures have been determined at 1.69 A resolution. PGFS has an (α/β)8 barrel structure. The coFactor and substrate or inhibitor bind in a cavity at the C-terminal end oF the barrel. The coFactor binds deeply in the cavity and has extensive interactions with PGFS through hydrogen bonds, whereas the substrate (PGD2) is located above the bound coFactor and has little interac...
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cdna cloning expression and mutagenesis study oF liver type Prostaglandin F synthase
Journal of Biological Chemistry, 1999Co-Authors: Toshiko Suzuki, Yutaka Fujii, Masashi Miyano, Lanying Chen, Tomohiro Takahashi, Kikuko WatanabeAbstract:Abstract Prostaglandin (PG) F synthase catalyzes the reduction oF PGD2 to 9α,11β-PGF2 and that oF PGH2 to PGF2α on the same molecule. PGF synthase has at least two isoForms, the lung-type enzyme (K m value oF 120 μm For PGD2 (Watanabe, K., Yoshida, R., Shimizu, T., and Hayaishi, O. (1985) J. Biol. Chem. 260, 7035–7041) and the liver-type one (K m value oF 10 μm For PGD2 (Chen, L. -Y., Watanabe, K., and Hayaishi, O. (1992)Arch. Biochem. Biophys. 296, 17–26)). The liver-type enzyme was presently Found to consist oF a 969-base pair open reading Frame coding For a 323-amino acid polypeptide with aM r oF 36,742. Sequence analysis indicated that the bovine liver PGF synthase had 87, 79, 77, and 76% identity with the bovine lung PGF synthase and human liver dihydrodiol dehydrogenase (DD) isozymes DD1, DD2, and DD4, respectively. Moreover, the amino acid sequence oF the liver-type PGF synthase was identical with that oF bovine liver DD3. The liver-type PGF synthase was expressed in COS-7 cells, and its recombinant enzyme had almost the same properties as the native enzyme. Furthermore, to investigate the nature oF catalysis and/or substrate binding oF PGF synthase, we constructed and characterized various mutant enzymes as Follows: R27E, R91Q, H170C, R223L, K225S, S301R, and N306Y. Although the reductase activities toward PGH2 and phenanthrenequinone (PQ) oF almost all mutants were not inactivated, the K m values oF R27E, R91Q, H170C, R223L, and N306Y For PGD2 were increased From 15 to 110, 145, 75, 180, and 100 μm, respectively, indicating that Arg27, Arg91, His170, Arg223, and Asn306 are essential to give a low K m value For PGD2 oF the liver-type PGF synthase and that these amino acid residues serve in the binding oF PGD2. Moreover, the R223L mutant among these seven mutants especially has a proFound eFFect on k cat For PGD2 reduction. TheK m values oF R223L, K225S, and S301R For PQ were about 2–10-Fold lower than the wild-type value, indicating that the amino acid residues at 223, 225 and 301 serve in the binding oF PQ to the enzyme. On the other hand, the K m value oF H170C For PGH2 was 8-Fold lower than that oF the wild type, indicating that the amino acid residue at 170 is related to the binding oF PGH2 to the enzyme and that Cys170 conFer high aFFinity For PGH2. Additionally, the 5-Fold increase in k cat/K m value oF the N306Y mutant For PGH2 compared with the wild-type value suggests that the amino acid at 306 plays an important role in catalytic eFFiciency For PGH2.
