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

Koda, Noriko; Tsutsui, Yasutaka; Niwa, Haruki; Ito, Seiji; Woodward, David F.; Watanabe, Kikuko

doi:10.1016/j.abb.2004.02.009

Cited by 54 publications

(61 citation statements)

References 28 publications

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“…With the reduction of PQ, which displays high catalytic efficiency, indomethacin and its analogues exhibit an uncompetitive pattern of AKR1C3 inhibition, while with the less efficient substrate Δ 4 -androstene-3,17-dione, a competitive pattern of inhibition was observed. Koda et al [47] found that prostaglandin H 2 reduction catalyzed by AKR1C3 was competitively inhibited by a prostamide H 2 analogue, but was noncompetitively inhibited by the prostamide F 2α analogue bimatoprost. Crystal structures indicate that both indomethacin and bimatoprost bind the active site of AKR1C3, suggesting that a classical noncompetitive mechanism of inhibition is unlikely (Fig.…”

Section: Discussionmentioning

confidence: 99%

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

Byrns

Steckelbroeck

Penning

2008

Biochemical Pharmacology

126

141

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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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Section: Discussionmentioning

confidence: 99%

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

Byrns

Steckelbroeck

Penning

2008

Biochemical Pharmacology

126

141

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“…AKR1C3 is identical to prostaglandin F synthase [44][45][46]. The enzyme catalyzes two reactions on PGs which have important consequences for nuclear receptor signaling and pro-inflammatory and proliferative responses [46]. With PGH 2 the product of the AKR1C3 reaction is PGF 2α , however, the enzyme also has substantial 11-ketoprostaglandin reductase activity and will convert PGD 2 to 9α,11β-PGF 2 , Fig.…”

Section: Orphan Nuclear Receptorsmentioning

confidence: 99%

Human aldo–keto reductases: Function, gene regulation, and single nucleotide polymorphisms

Penning

Drury

2007

Archives of Biochemistry and Biophysics

242

211

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Aldo-Keto Reductases (AKRs) are a superfamily of NAD(P)H linked oxidoreductases that are generally monomeric 34-37 kDa proteins present in all phyla. The superfamily consists of 15 families, which contains 151 members (www.med.upenn.edu/akr). Thirteen human AKRs exist that use endogenous substrates (sugar and lipid aldehydes, prostaglandins, retinals and steroid hormones), and in many instances they regulate nuclear receptor signaling. Exogenous substrates include metabolites implicated in chemical carcinogenesis: NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone), polycyclic aromatic hydrocarbon trans-dihydrodiols, and aflatoxin dialdehyde. Promoter analysis of the human genes identifies common elements involved in their regulation which include osmotic response elements, antioxidant response elements, xenobiotic response elements, AP-1 sites and steroid response elements. The human AKRs are highly polymorphic, and in some instances single nucleotide polymorphisms (SNPs) of high penetrance exist. This suggests that there will be inter-individual variation in endogenous and xenobiotic metabolism which in turn affect susceptibility to nuclear receptor signaling and chemical carcinogenesis.

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“…To overcome the limitations of GC-MS and immunoassays for prostaglandin measurements, LC-MS [15][16][17] and LC-MS-MS [18][19][20][21][22][23][24][25][26][27] based methods have evolved as powerful tools for measuring prostaglandins in biological samples because of their high sensitivity, high selectivity and simplicity of sample preparation. Although five of these LC-MS or LC-MS-MS methods have measured PGD 2 [15][16][17][18][19], none have controlled for the inherent chemical instability of PGD 2 which is critical for determining accurate levels and for comparison with the values of other, more stable eicosanoids.…”

Section: Introductionmentioning

confidence: 99%

“…Although five of these LC-MS or LC-MS-MS methods have measured PGD 2 [15][16][17][18][19], none have controlled for the inherent chemical instability of PGD 2 which is critical for determining accurate levels and for comparison with the values of other, more stable eicosanoids. Our method addresses this important issue by incorporation of both a d 4 -PGD 2 and d 4 -PGE 2 internal standards in the reaction mixture in order to accurately quantify the relative amounts of PGE 2 and PGD 2 in the same sample.…”

Section: Introductionmentioning

confidence: 99%

An improved LC–MS/MS method for the quantification of prostaglandins E2 and D2 production in biological fluids

Cao

Xiao

Park

et al. 2008

Analytical Biochemistry

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We report an improved LC-MS-MS assay that accurately measures prostaglandins D 2 (PGD 2 ) and E 2 (PGE 2 ) in cell culture supernatants and other biological fluids. The limit of detection for each prostaglandin was 20 pg/mL (0.20 pg; 0.55 fmol on-column), and the inter-day and intra-day coefficients of variation were less than 5%. Both d 4 -PGE 2 and d 4 -PGD 2 were used as surrogate standards to control for differential loss and degradation of the analytes. Stability studies indicated that sample preparation time should be less than 8 h to measure PGD 2 accurately, whereas preparation time did not affect PGE 2 measurement due to its greater stability in biological samples. As an application of the method, PGD 2 and PGE 2 were measured in culture supernatants from A549 cells and RAW 264.7 cells. The human lung alveolar cell line A549 was found to produce PGE 2 but no PGD 2 while the murine macrophage cell line RAW 264.7 produced PGD 2 and only trace amounts of PGE 2 . This direct comparison showed that COX-2 gene expression can lead to differential production of PGD 2 and PGE 2 by epithelial cells and macrophages. Since PGE 2 is anti-asthmatic and PGD 2 is pro-asthmatic, we speculate that the balance of production of these eicosanoids by epithelial cells and macropahges in the lung contributes to the pathogenesis of COPD, bronchiectasis, asthma, and lung cancer.

show abstract

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

Cited by 54 publications

References 28 publications

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

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

Human aldo–keto reductases: Function, gene regulation, and single nucleotide polymorphisms

An improved LC–MS/MS method for the quantification of prostaglandins E2 and D2 production in biological fluids

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