MPGES-2

{{Short description|Protein-coding gene in the species Homo sapiens}}

Microsomal prostaglandin E synthase-2 (mPGES-2){{cite journal |vauthors=Jakobsson PJ, Thorén S, Morgenstern R, etal | title = Identification of human prostaglandin E synthase: a microsomal glutathione-dependent, inducible enzyme, constituting a potential novel drug target. | journal = Proc Natl Acad Sci USA | volume = 96 | issue = 13| pages = 7220–7225 |date= 1989 | pmid = 10377395 | pmc = 22058| doi = 10.1073/pnas.96.13.7220 | doi-access = free | bibcode = 1999PNAS...96.7220J }}{{cite journal |author1=Hui-Hua Chang |author2=Emmanuelle J Meuillet | title = Identification and development of mPGES-1 inhibitors: where we are at? | journal = Future Med Chem | volume = 3 | issue = 15 | pages = 1909–1934 |date= 2011 | pmid = 22023034| pmc = 3232027 | doi = 10.4155/fmc.11.136 }} or Prostaglandin E synthase 2 is an enzyme that in humans encoded by the PTGES2 gene located on chromosome 9.{{cite journal | vauthors = Tanikawa N, Ohmiya Y, Ohkubo H, Hashimoto K, Kangawa K, Kojima M, Ito S, Watanabe K | title = Identification and characterization of a novel type of membrane-associated prostaglandin E synthase | journal = Biochemical and Biophysical Research Communications | volume = 291 | issue = 4 | pages = 884–9 | date = Mar 2002 | pmid = 11866447 | doi = 10.1006/bbrc.2002.6531 }}{{cite web | title = Entrez Gene: prostaglandin E synthase 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=80142}} 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.{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene/80142|title=PTGES2 prostaglandin E synthase 2 [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2016-10-18}}

Structure

Microsomal prostaglandin E synthase type-2 (mPTGES2) has been crystallized with an anti-inflammatory drug indomethacin (IMN).{{cite journal | vauthors = Yamada T, Komoto J, Watanabe K, Ohmiya Y, Takusagawa F | title = Crystal structure and possible catalytic mechanism of microsomal prostaglandin E synthase type 2 (mPGES-2) | journal = Journal of Molecular Biology | volume = 348 | issue = 5 | pages = 1163–76 | date = May 2005 | doi = 10.1016/j.jmb.2005.03.035 | pmid = 15854652 }} 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 {{cite journal |vauthors=Tanikawa N, Ohmiya Y, Ohkubo H, Hashimoto K, Kangawa K, Kojima M, Ito S, Watanabe K |title=Identification and characterization of a novel type of membrane-associated prostaglandin E synthase |journal=Biochem. Biophys. Res. Commun. |volume=291 |issue=4 |pages=884–9 |year=2002 |pmid=11866447 |doi=10.1006/bbrc.2002.6531 }} 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.{{cite journal |vauthors=Watanabe K, Ohkubo H, Niwa H, Tanikawa N, Koda N, Ito S, Ohmiya Y |title=Essential 110Cys in active site of membrane-associated prostaglandin E synthase-2 |journal=Biochem. Biophys. Res. Commun. |volume=306 |issue=2 |pages=577–81 |year=2003 |pmid=12804604 |doi= 10.1016/s0006-291x(03)01025-8}}

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.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:

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

Clinical significance

The excess production of prostaglandin E 2 is known to contribute to inflammatory diseases which includes rheumatoid arthritis, atherosclerosis, and cancer.{{cite journal | vauthors = Rullah K, Mohd Aluwi MF, Yamin BM, Abdul Bahari MN, Wei LS, Ahmad S, Abas F, Ismail NH, Jantan I, Wai LK | title = Inhibition of prostaglandin E(2) production by synthetic minor prenylated chalcones and flavonoids: synthesis, biological activity, crystal structure, and in silico evaluation | journal = Bioorganic & Medicinal Chemistry Letters | volume = 24 | issue = 16 | pages = 3826–34 | date = Aug 2014 | pmid = 25027933 | doi = 10.1016/j.bmcl.2014.06.061 | url = http://psasir.upm.edu.my/id/eprint/34213/1/Inhibition%20of%20prostaglandin%20E2%20production%20by%20synthetic%20minor%20prenylated%20chalcones%20and%20flavonoids.pdf }}{{cite journal | vauthors = Jongthawin J, Chusorn P, Techasen A, Loilome W, Boonmars T, Thanan R, Puapairoj A, Khuntikeo N, Tassaneeyakul W, Yongvanit P, Namwat N | title = PGE2 signaling and its biosynthesis-related enzymes in cholangiocarcinoma progression | journal = Tumour Biology | volume = 35 | issue = 8 | pages = 8051–64 | date = Aug 2014 | pmid = 24839005 | doi = 10.1007/s13277-014-2021-y | s2cid = 10579551 }} Furthermore, naturally occurring polymorphisms of PTGES2 have been shown to be associated with increased risks for diabetes mellitus and metabolic syndromes.{{cite journal |vauthors=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 |title=Association of prostaglandin E synthase 2 (PTGES2) Arg298His polymorphism with type 2 diabetes in two German study populations |journal=J. Clin. Endocrinol. Metab. |volume=92 |issue=8 |pages=3183–8 |year=2007 |pmid=17566096 |doi=10.1210/jc.2006-2550 |doi-access=free }}{{cite journal |vauthors=Lindner I, Helwig U, Rubin D, Fischer A, Marten B, Schreiber S, Döring F, Schrezenmeir J |title=Prostaglandin E synthase 2 (PTGES2) Arg298His polymorphism and parameters of the metabolic syndrome |journal=Mol Nutr Food Res |volume=51 |issue=12 |pages=1447–51 |year=2007 |pmid=17979097 |doi=10.1002/mnfr.200700144 }}

As such, pharmacological inhibition of prostaglandin E 2 production by synthetic minor prenylated chalcones and flavonoids has potential therapeutic viability. It has been shown that the synthesis of prostaglandin E 2 in the endothelial cells of the brain is important for inflammation-induced fever.{{cite journal | vauthors = Wilhelms DB, Kirilov M, Mirrasekhian E, Eskilsson A, Kugelberg UÖ, Klar C, Ridder DA, Herschman HR, Schwaninger M, Blomqvist A, Engblom D | title = Deletion of prostaglandin E2 synthesizing enzymes in brain endothelial cells attenuates inflammatory fever | journal = The Journal of Neuroscience | volume = 34 | issue = 35 | pages = 11684–90 | date = Aug 2014 | pmid = 25164664 | pmc = 6608410 | doi = 10.1523/JNEUROSCI.1838-14.2014 }} Additionally, investigators have observed elevations in cell doubling rates for several cancer cell types in the presence of prostaglandin E 2 –producing cell lines.{{cite journal | vauthors = Ruan D, So SP | title = Prostaglandin E2 produced by inducible COX-2 and mPGES-1 promoting cancer cell proliferation in vitro and in vivo | journal = Life Sciences | volume = 116 | issue = 1 | pages = 43–50 | date = Oct 2014 | pmid = 25139833 | doi = 10.1016/j.lfs.2014.07.042 }}

References

External links

{{PDBe-KB2|Q9N0A4|Macaca fascicularis (Crab-eating macaque)Prostaglandin E synthase 2}}