MPGES-2

Microsomal prostaglandin E synthase-2 (mPGES-2)[5][6] or Prostaglandin E synthase 2 is an enzyme that in humans encoded by the PTGES2 gene located on chromosome 9.[7][8] 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.[9]

PTGES2
Identifiers
AliasesPTGES2, C9orf15, GBF-1, GBF1, PGES2, mPGES-2, prostaglandin E synthase 2
External IDsOMIM: 608152 MGI: 1917592 HomoloGene: 11819 GeneCards: PTGES2
EC number5.3.99.3
Orthologs
SpeciesHumanMouse
Entrez

80142

96979

Ensembl

ENSG00000148334

ENSMUSG00000026820

UniProt

Q9H7Z7

Q8BWM0

RefSeq (mRNA)

NM_001256335
NM_025072
NM_198938
NM_198939
NM_198940

NM_133783

RefSeq (protein)

NP_001243264
NP_079348
NP_945176

NP_598544

Location (UCSC)Chr 9: 128.12 – 128.13 MbChr 2: 32.29 – 32.3 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

Microsomal prostaglandin E synthase type-2 (mPTGES2) has been crystallized with an anti-inflammatory drug indomethacin (IMN).[10] 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.[10]

Function

The gene encoding the PTGES2 protein contains 10 exons. The PTGE2 protein encoded by the gene is a 33-kDa membrane-associated [11] 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.[12]

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.[13]

The PTGE2 protein also has been shown to activate the transcription regulated by an interferon-gamma gamma-interferon-activated transcription element (GATE).[8]

Model organisms have been used in the study of PTGES2 function. A conditional knockout mouse line, called Ptges2tm1a(EUCOMM)Wtsi[18][19] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[20][21][22]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[16][23] Twenty two tests were carried out on mutant mice, but no significant abnormalities were observed.[16]

Clinical significance

The excess production of prostaglandin E 2 is known to contribute to inflammatory diseases which includes rheumatoid arthritis, atherosclerosis, and cancer.[24][25] Furthermore, naturally occurring polymorphisms of PTGES2 have been shown to be associated with increased risks for diabetes mellitus and metabolic syndromes.[26][27]

As such, pharmacological inhibition of prostaglandin E 2 production by synthetic minor prenylated chalcones and flavonoids has potential therapeutic viability.[24] It has been shown that the synthesis of prostaglandin E 2 in the endothelial cells of the brain is important for inflammation-induced fever.[28] Additionally, investigators have observed elevations in cell doubling rates for several cancer cell types in the presence of prostaglandin E 2 –producing cell lines.[29]

References
  1. GRCh38: Ensembl release 89: ENSG00000148334 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000026820 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Jakobsson PJ, Thorén S, Morgenstern R, et al. (1989). "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. doi:10.1073/pnas.96.13.7220. PMC 22058. PMID 10377395.
  6. Hui-Hua Chang; Emmanuelle J Meuillet (2011). "Identification and development of mPGES-1 inhibitors: where we are at?". Future Med Chem. 3 (15): 1909–1934. doi:10.4155/fmc.11.136. PMC 3232027. PMID 22023034.
  7. Tanikawa N, Ohmiya Y, Ohkubo H, Hashimoto K, Kangawa K, Kojima M, Ito S, Watanabe K (Mar 2002). "Identification and characterization of a novel type of membrane-associated prostaglandin E synthase". Biochemical and Biophysical Research Communications. 291 (4): 884–9. doi:10.1006/bbrc.2002.6531. PMID 11866447.
  8. "Entrez Gene: prostaglandin E synthase 2".
  9. "PTGES2 prostaglandin E synthase 2 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2016-10-18.
  10. Yamada T, Komoto J, Watanabe K, Ohmiya Y, Takusagawa F (May 2005). "Crystal structure and possible catalytic mechanism of microsomal prostaglandin E synthase type 2 (mPGES-2)". Journal of Molecular Biology. 348 (5): 1163–76. doi:10.1016/j.jmb.2005.03.035. PMID 15854652.
  11. Tanikawa N, Ohmiya Y, Ohkubo H, Hashimoto K, Kangawa K, Kojima M, Ito S, Watanabe K (2002). "Identification and characterization of a novel type of membrane-associated prostaglandin E synthase". Biochem. Biophys. Res. Commun. 291 (4): 884–9. doi:10.1006/bbrc.2002.6531. PMID 11866447.
  12. Watanabe K, Ohkubo H, Niwa H, Tanikawa N, Koda N, Ito S, Ohmiya Y (2003). "Essential 110Cys in active site of membrane-associated prostaglandin E synthase-2". Biochem. Biophys. Res. Commun. 306 (2): 577–81. doi:10.1016/s0006-291x(03)01025-8. PMID 12804604.
  13. 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:
  14. "Salmonella infection data for Ptges2". Wellcome Trust Sanger Institute.
  15. "Citrobacter infection data for Ptges2". Wellcome Trust Sanger Institute.
  16. Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88 (S248). doi:10.1111/j.1755-3768.2010.4142.x. S2CID 85911512.
  17. Mouse Resources Portal, Wellcome Trust Sanger Institute.
  18. "International Knockout Mouse Consortium".
  19. "Mouse Genome Informatics".
  20. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
  21. Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  22. Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247. S2CID 18872015.
  23. van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biology. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
  24. Rullah K, Mohd Aluwi MF, Yamin BM, Abdul Bahari MN, Wei LS, Ahmad S, Abas F, Ismail NH, Jantan I, Wai LK (Aug 2014). "Inhibition of prostaglandin E(2) production by synthetic minor prenylated chalcones and flavonoids: synthesis, biological activity, crystal structure, and in silico evaluation" (PDF). Bioorganic & Medicinal Chemistry Letters. 24 (16): 3826–34. doi:10.1016/j.bmcl.2014.06.061. PMID 25027933.
  25. Jongthawin J, Chusorn P, Techasen A, Loilome W, Boonmars T, Thanan R, Puapairoj A, Khuntikeo N, Tassaneeyakul W, Yongvanit P, Namwat N (Aug 2014). "PGE2 signaling and its biosynthesis-related enzymes in cholangiocarcinoma progression". Tumour Biology. 35 (8): 8051–64. doi:10.1007/s13277-014-2021-y. PMID 24839005. S2CID 10579551.
  26. 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 (2007). "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. doi:10.1210/jc.2006-2550. PMID 17566096.
  27. Lindner I, Helwig U, Rubin D, Fischer A, Marten B, Schreiber S, Döring F, Schrezenmeir J (2007). "Prostaglandin E synthase 2 (PTGES2) Arg298His polymorphism and parameters of the metabolic syndrome". Mol Nutr Food Res. 51 (12): 1447–51. doi:10.1002/mnfr.200700144. PMID 17979097.
  28. Wilhelms DB, Kirilov M, Mirrasekhian E, Eskilsson A, Kugelberg UÖ, Klar C, Ridder DA, Herschman HR, Schwaninger M, Blomqvist A, Engblom D (Aug 2014). "Deletion of prostaglandin E2 synthesizing enzymes in brain endothelial cells attenuates inflammatory fever". The Journal of Neuroscience. 34 (35): 11684–90. doi:10.1523/JNEUROSCI.1838-14.2014. PMC 6608410. PMID 25164664.
  29. Ruan D, So SP (Oct 2014). "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. doi:10.1016/j.lfs.2014.07.042. PMID 25139833.
  • Overview of all the structural information available in the PDB for UniProt: Q9N0A4 (Macaca fascicularis (Crab-eating macaque)Prostaglandin E synthase 2) at the PDBe-KB.

Further reading

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