MPGES-2 explained

Microsomal prostaglandin E synthase-2 (mPGES-2)^{[1] [2]} or Prostaglandin E synthase 2 is an enzyme that in humans encoded by the PTGES2 gene located on chromosome 9.^{[3] [4]} The protein encoded by this gene is a membrane-associated prostaglandin E synthase, which catalyzes the conversion of prostaglandin H2 to prostaglandin E2. This protein also has been shown to activate the transcription regulated by a gamma-interferon-activated transcription element (GATE). Multiple transcript variants have been found for this gene.^[5]

Structure

Microsomal prostaglandin E synthase type-2 (mPTGES2) has been crystallized with an anti-inflammatory drug indomethacin (IMN).^[6] The N-terminal of mPTGES2 is attached to the lipid membrane and the two hydrophobic pockets connected to form a V shape are located in the bottom of a large cavity for IMN binding. The mPTGES2 exists in a dimer.

Function

The gene encoding the PTGES2 protein contains 10 exons. The PTGE2 protein encoded by the gene is a 33-kDa membrane-associated ^[7] prostaglandin E synthase that is thought to be targeted to the Golgi apparatus as well as the mitochondrion within the cell. Prostaglandin E synthase catalyzes the conversion of prostaglandin H2 to prostaglandin E2. The particular reaction catalyzed by PTGE2 is thought to be:

(5Z,13E)-(15S)-9-alpha,11-alpha-epidioxy-15-hydroxyprosta-5,13-dienoate = (5Z,13E)-(15S)-11-alpha,15-dihydroxy-9-oxoprosta-5,13-dienoate.^[8]

The PTGE2 protein functions in part of the prostaglandin synthesis pathway, which forms a component of the overall lipid synthesis mechanism in the human body. The activity of PTGES2 is thought to be increased in the presence of sulfhydryl compounds, in particular dithiothreitol.^[9]

The PTGE2 protein also has been shown to activate the transcription regulated by an interferon-gamma gamma-interferon-activated transcription element (GATE).^[4]

Clinical significance

The excess production of prostaglandin E 2 is known to contribute to inflammatory diseases which includes rheumatoid arthritis, atherosclerosis, and cancer.^{[10] [11]} Furthermore, naturally occurring polymorphisms of PTGES2 have been shown to be associated with increased risks for diabetes mellitus and metabolic syndromes.^{[12] [13]}

As such, pharmacological inhibition of prostaglandin E 2 production by synthetic minor prenylated chalcones and flavonoids has potential therapeutic viability.^[14] Additionally, investigators have observed elevations in cell doubling rates for several cancer cell types in the presence of prostaglandin E 2 –producing cell lines.^[16]

Further reading

• Lehner B, Sanderson CM . A protein interaction framework for human mRNA degradation . Genome Research . 14 . 7 . 1315–23 . Jul 2004 . 15231747 . 442147 . 10.1101/gr.2122004 .
• Palmieri RT, Wilson MA, Iversen ES, Clyde MA, Calingaert B, Moorman PG, Poole C, Anderson AR, Anderson S, Anton-Culver H, Beesley J, Hogdall E, Brewster W, Carney ME, Chen X, Chenevix-Trench G, Chang-Claude J, Cunningham JM, Dicioccio RA, Doherty JA, Easton DF, Edlund CK, Gayther SA, Gentry-Maharaj A, Goode EL, Goodman MT, Kjaer SK, Hogdall CK, Hopkins MP, Jenison EL, Blaakaer J, Lurie G, McGuire V, Menon U, Moysich KB, Ness RB, Pearce CL, Pharoah PD, Pike MC, Ramus SJ, Rossing MA, Song H, Terada KY, Vandenberg D, Vierkant RA, Wang-Gohrke S, Webb PM, Whittemore AS, Wu AH, Ziogas A, Berchuck A, Schildkraut JM . Polymorphism in the IL18 gene and epithelial ovarian cancer in non-Hispanic white women . Cancer Epidemiology, Biomarkers & Prevention . 17 . 12 . 3567–72 . Dec 2008 . 19064572 . 2664299 . 10.1158/1055-9965.EPI-08-0548 .
• Chaudhry UA, Dore S . Cytosolic prostaglandin E synthase: expression patterns in control and Alzheimer's disease brains . American Journal of Alzheimer's Disease & Other Dementias . 24 . 1 . 46–51 . 2009 . 19001348 . 2859688 . 10.1177/1533317508323655 .
• Wu T, Wu H, Wang J, Wang J . Expression and cellular localization of cyclooxygenases and prostaglandin E synthases in the hemorrhagic brain . Journal of Neuroinflammation . 8 . 22 . 2011 . 21385433 . 3062590 . 10.1186/1742-2094-8-22 . free .
• Dagle JM, Lepp NT, Cooper ME, Schaa KL, Kelsey KJ, Orr KL, Caprau D, Zimmerman CR, Steffen KM, Johnson KJ, Marazita ML, Murray JC . Determination of genetic predisposition to patent ductus arteriosus in preterm infants . Pediatrics . 123 . 4 . 1116–23 . Apr 2009 . 19336370 . 2734952 . 10.1542/peds.2008-0313 .
• Fischer A, Grallert H, Böhme M, Gieger C, Boomgaarden I, Heid I, Wichmann HE, Döring F, Illig T . Association analysis between the prostaglandin E synthase 2 R298H polymorphism and body mass index in 8079 participants of the KORA study cohort . Genetic Testing and Molecular Biomarkers . 13 . 2 . 223–6 . Apr 2009 . 19371221 . 10.1089/gtmb.2008.0111 .
• Mattila S, Tuominen H, Koivukangas J, Stenbäck F . The terminal prostaglandin synthases mPGES-1, mPGES-2, and cPGES are all overexpressed in human gliomas . Neuropathology . 29 . 2 . 156–65 . Apr 2009 . 19347995 . 10.1111/j.1440-1789.2008.00963.x . 22681905 .
• Lindner I, Helwig U, Rubin D, Fischer A, Marten B, Schreiber S, Döring F, Schrezenmeir J . Prostaglandin E synthase 2 (PTGES2) Arg298His polymorphism and parameters of the metabolic syndrome . Molecular Nutrition & Food Research . 51 . 12 . 1447–51 . Dec 2007 . 17979097 . 10.1002/mnfr.200700144 .
• Seo T, Tatsuguchi A, Shinji S, Yonezawa M, Mitsui K, Tanaka S, Fujimori S, Gudis K, Fukuda Y, Sakamoto C . Microsomal prostaglandin E synthase protein levels correlate with prognosis in colorectal cancer patients . Virchows Archiv . 454 . 6 . 667–76 . Jun 2009 . 19412621 . 10.1007/s00428-009-0777-z . 6233883 .
• Lee E, Choi MK, Lee YJ, Ku JL, Kim KH, Choi JS, Lim SJ . Alpha-tocopheryl succinate, in contrast to alpha-tocopherol and alpha-tocopheryl acetate, inhibits prostaglandin E2 production in human lung epithelial cells . Carcinogenesis . 27 . 11 . 2308–15 . Nov 2006 . 16714329 . 10.1093/carcin/bgl073 . free .
• Meng Q, Raha A, Roy S, Hu J, Kalvakolanu DV . IFN-gamma-stimulated transcriptional activation by IFN-gamma-activated transcriptional element-binding factor 1 occurs via an inducible interaction with CAAAT/enhancer-binding protein-beta . Journal of Immunology . 174 . 10 . 6203–11 . May 2005 . 15879117 . 10.4049/jimmunol.174.10.6203 . free .
• Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S . The LIFEdb database in 2006 . Nucleic Acids Research . 34 . Database issue . D415–8 . Jan 2006 . 16381901 . 1347501 . 10.1093/nar/gkj139 .
• Oh JH, Yang JO, Hahn Y, Kim MR, Byun SS, Jeon YJ, Kim JM, Song KS, Noh SM, Kim S, Yoo HS, Kim YS, Kim NS . Transcriptome analysis of human gastric cancer . Mammalian Genome . 16 . 12 . 942–54 . Dec 2005 . 16341674 . 10.1007/s00335-005-0075-2 . 69278 .
• Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A . From ORFeome to biology: a functional genomics pipeline . Genome Research . 14 . 10B . 2136–44 . Oct 2004 . 15489336 . 528930 . 10.1101/gr.2576704 .
• Chaudhry UA, Zhuang H, Crain BJ, Doré S . Elevated microsomal prostaglandin-E synthase-1 in Alzheimer's disease . Alzheimer's & Dementia . 4 . 1 . 6–13 . Jan 2008 . 18631945 . 2500207 . 10.1016/j.jalz.2007.10.015 .
• Nitz I, Fisher E, Grallert H, Li Y, Gieger C, Rubin D, Boeing H, Spranger J, Lindner I, Schreiber S, Rathmann W, Gohlke H, Döring A, Wichmann HE, Schrezenmeir J, Döring F, Illig T . Association of prostaglandin E synthase 2 (PTGES2) Arg298His polymorphism with type 2 diabetes in two German study populations . The Journal of Clinical Endocrinology and Metabolism . 92 . 8 . 3183–8 . Aug 2007 . 17566096 . 10.1210/jc.2006-2550 . free .
• Colombe L, Vindrios A, Michelet JF, Bernard BA . Prostaglandin metabolism in human hair follicle . Experimental Dermatology . 16 . 9 . 762–9 . Sep 2007 . 17697149 . 10.1111/j.1600-0625.2007.00586.x . 43663330 . free .
• Fisher E, Nitz I, Lindner I, Rubin D, Boeing H, Möhlig M, Hampe J, Schreiber S, Schrezenmeir J, Döring F . Candidate gene association study of type 2 diabetes in a nested case-control study of the EPIC-Potsdam cohort - role of fat assimilation . Molecular Nutrition & Food Research . 51 . 2 . 185–91 . Feb 2007 . 17266179 . 10.1002/mnfr.200600162 . free .

Notes and References

1. Jakobsson PJ, Thorén S, Morgenstern R, etal . Identification of human prostaglandin E synthase: a microsomal glutathione-dependent, inducible enzyme, constituting a potential novel drug target. . Proc Natl Acad Sci USA . 96 . 13. 7220–7225 . 1989 . 10377395 . 22058. 10.1073/pnas.96.13.7220 . free . 1999PNAS...96.7220J .
2. Hui-Hua Chang . Emmanuelle J Meuillet . Identification and development of mPGES-1 inhibitors: where we are at? . Future Med Chem . 3 . 15 . 1909–1934 . 2011 . 22023034. 3232027 . 10.4155/fmc.11.136 .
3. Tanikawa N, Ohmiya Y, Ohkubo H, Hashimoto K, Kangawa K, Kojima M, Ito S, Watanabe K . Identification and characterization of a novel type of membrane-associated prostaglandin E synthase . Biochemical and Biophysical Research Communications . 291 . 4 . 884–9 . Mar 2002 . 11866447 . 10.1006/bbrc.2002.6531 .
4. Web site: Entrez Gene: prostaglandin E synthase 2.
5. Web site: PTGES2 prostaglandin E synthase 2 [Homo sapiens (human)] - Gene - NCBI]. www.ncbi.nlm.nih.gov. 2016-10-18.
6. Yamada T, Komoto J, Watanabe K, Ohmiya Y, Takusagawa F . Crystal structure and possible catalytic mechanism of microsomal prostaglandin E synthase type 2 (mPGES-2) . Journal of Molecular Biology . 348 . 5 . 1163–76 . May 2005 . 10.1016/j.jmb.2005.03.035 . 15854652 .
7. Tanikawa N, Ohmiya Y, Ohkubo H, Hashimoto K, Kangawa K, Kojima M, Ito S, Watanabe K . Identification and characterization of a novel type of membrane-associated prostaglandin E synthase . Biochem. Biophys. Res. Commun. . 291 . 4 . 884–9 . 2002 . 11866447 . 10.1006/bbrc.2002.6531 .
8. Watanabe K, Ohkubo H, Niwa H, Tanikawa N, Koda N, Ito S, Ohmiya Y . Essential 110Cys in active site of membrane-associated prostaglandin E synthase-2 . Biochem. Biophys. Res. Commun. . 306 . 2 . 577–81 . 2003 . 12804604 . 10.1016/s0006-291x(03)01025-8.
9. The gene encoding the PTGES2 protein contains 10 exons. The PTGE2 protein is a membrane-associated prostaglandin E synthase. Prostaglandin E synthase catalyzes the conversion of prostaglandin H2 to prostaglandin E2. The particular reaction catalyzed by PTGE2 is thought to be:
10. Rullah K, Mohd Aluwi MF, Yamin BM, Abdul Bahari MN, Wei LS, Ahmad S, Abas F, Ismail NH, Jantan I, Wai LK . Inhibition of prostaglandin E(2) production by synthetic minor prenylated chalcones and flavonoids: synthesis, biological activity, crystal structure, and in silico evaluation . Bioorganic & Medicinal Chemistry Letters . 24 . 16 . 3826–34 . Aug 2014 . 25027933 . 10.1016/j.bmcl.2014.06.061 .
11. Jongthawin J, Chusorn P, Techasen A, Loilome W, Boonmars T, Thanan R, Puapairoj A, Khuntikeo N, Tassaneeyakul W, Yongvanit P, Namwat N . PGE2 signaling and its biosynthesis-related enzymes in cholangiocarcinoma progression . Tumour Biology . 35 . 8 . 8051–64 . Aug 2014 . 24839005 . 10.1007/s13277-014-2021-y . 10579551 .
12. Nitz I, Fisher E, Grallert H, Li Y, Gieger C, Rubin D, Boeing H, Spranger J, Lindner I, Schreiber S, Rathmann W, Gohlke H, Döring A, Wichmann HE, Schrezenmeir J, Döring F, Illig T . Association of prostaglandin E synthase 2 (PTGES2) Arg298His polymorphism with type 2 diabetes in two German study populations . J. Clin. Endocrinol. Metab. . 92 . 8 . 3183–8 . 2007 . 17566096 . 10.1210/jc.2006-2550 . free .
13. Lindner I, Helwig U, Rubin D, Fischer A, Marten B, Schreiber S, Döring F, Schrezenmeir J . Prostaglandin E synthase 2 (PTGES2) Arg298His polymorphism and parameters of the metabolic syndrome . Mol Nutr Food Res . 51 . 12 . 1447–51 . 2007 . 17979097 . 10.1002/mnfr.200700144 .
14. Wilhelms DB, Kirilov M, Mirrasekhian E, Eskilsson A, Kugelberg UÖ, Klar C, Ridder DA, Herschman HR, Schwaninger M, Blomqvist A, Engblom D . Deletion of prostaglandin E2 synthesizing enzymes in brain endothelial cells attenuates inflammatory fever . The Journal of Neuroscience . 34 . 35 . 11684–90 . Aug 2014 . 25164664 . 6608410 . 10.1523/JNEUROSCI.1838-14.2014 .
15. It has been shown that the synthesis of prostaglandin E 2 in the endothelial cells of the brain is important for inflammation-induced fever.^[14]
16. Ruan D, So SP . Prostaglandin E2 produced by inducible COX-2 and mPGES-1 promoting cancer cell proliferation in vitro and in vivo . Life Sciences . 116 . 1 . 43–50 . Oct 2014 . 25139833 . 10.1016/j.lfs.2014.07.042 .