プロスタグランジン合成酵素、プロスタグランジンシンターゼ

関: cyclo-oxygenase、cyclooxygenase、PGH synthase、prostaglandin H synthase、prostaglandin synthetase、prostaglandin-endoperoxide synthase

WordNet

either of two related enzymes that control the production of prostaglandins and are blocked by aspirin (同)Cox
a potent substance that acts like a hormone and is found in many bodily tissues (and especially in semen); produced in response to trauma and may affect blood pressure and metabolism and smooth muscle activity

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/12/07 09:13:41」(JST)

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cyclooxygenase 2
Cyclooxygenase-2 (Prostaglandin Synthase-2) in complex with a COX-2 selective inhibitor.^[2]
Identifiers
Symbol	PTGS2
Alt. symbols	COX-2
Entrez	5743
HUGO	9605
OMIM	600262
PDB	6COX
RefSeq	NM_000963
UniProt	P35354
Other data
EC number	1.14.99.1
Locus	Chr. 1 q25.2-25.3

Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (EC 1.14.99.1) that is responsible for formation of prostanoids, including prostaglandins such as prostacyclin and thromboxane.

The abbreviation "COX" is more often encountered in medicine. In genetics, the "PTGS" symbol is officially used for the prostaglandin-endoperoxide synthase (cyclooxygenase) family of genes and proteins, because the stem "COX" was already used for the cytochrome c oxidase family of genes and proteins.

Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain. Non-steroidal anti-inflammatory drugs (NSAID), such as aspirin and ibuprofen, exert their effects through inhibition of COX. The names "prostaglandin synthase (PHS)" and "prostaglandin endoperoxide synthetase (PES)" are still used to refer to COX.

Pharmacology

In terms of their molecular biology, COX-1 and COX-2 are of similar molecular weight, approximately 70 and 72 kDa, respectively, and having 65% amino acid sequence homology and near-identical catalytic sites. The most significant difference between the isoenzymes, which allows for selective inhibition, is the substitution of isoleucine at position 523 in COX-1 with valine in COX-2. The smaller Val₅₂₃ residue in COX-2 allows access to a hydrophobic side-pocket in the enzyme (which Ile₅₂₃ sterically hinders). Drug molecules, such as DuP-697 and the coxibs derived from it, bind to this alternative site and are considered to be selective inhibitors of COX-2.

Classical NSAIDs

The main COX inhibitors are the non-steroidal anti-inflammatory drugs (NSAIDs).

The classical COX inhibitors are not selective and inhibit all types of COX. The resulting inhibition of prostaglandin and thromboxane synthesis has the effect of reduced inflammation, as well as antipyretic, antithrombotic and analgesic effects. The most frequent adverse effect of NSAIDs is irritation of the gastric mucosa as prostaglandins normally have a protective role in the gastrointestinal tract. Some NSAIDs are also acidic which may cause additional damage to the gastrointestinal tract.

Newer NSAIDs

Selectivity for COX-2 is the main feature of celecoxib, etoricoxib, and other members of this drug class. Because COX-2 is usually specific to inflamed tissue, there is much less gastric irritation associated with COX-2 inhibitors, with a decreased risk of peptic ulceration. The selectivity of COX-2 does not seem to negate other side-effects of NSAIDs, most notably an increased risk of renal failure, and there is evidence that indicates an increase in the risk of heart attack, thrombosis, and stroke through an increase of thromboxane unbalanced by prostacyclin (which is reduced by COX-2 inhibition).^{[citation needed]} Rofecoxib (brand name Vioxx) was withdrawn in 2004 because of such concerns. Some other COX-2 selective NSAIDs, such as celecoxib, and etoricoxib, are still on the market.

Natural COX inhibition

Culinary mushrooms, like maitake, may be able to partially inhibit COX-1 and COX-2.^[3]^[4]

A variety of flavonoids have been found to inhibit COX-2.^[5]

Fish oils provide alternative fatty acids to arachidonic acid. These acids can be turned into some anti-inflammatory prostacyclins by COX instead of pro-inflammatory prostaglandins.^[6]

Hyperforin has been shown to inhibit COX-1 around 3-18 times as much as aspirin.^[7]

Calcitriol (vitamin D) significantly inhibits the expression of the COX-2 gene.^[8]

Caution should be exercised in combining low dose aspirin with COX-2 inhibitors due to potential increased damage to the gastric mucosa. COX-2 is upregulated when COX-1 is suppressed with aspirin, which is thought to be important in enhancing mucosal defense mechanisms and lessening the erosion by aspirin.^[9]

Cardiovascular side-effects of COX inhibitors

COX-2 inhibitors have been found to increase the risk of atherothrombosis even with short-term use. A 2006 analysis of 138 randomised trials and almost 150 000 participants^[10] showed that selective COX-2 inhibitors are associated with a moderately increased risk of vascular events, mainly due to a twofold increased risk of myocardial infarction, and also that high-dose regimens of some traditional NSAIDs such as diclofenac and ibuprofen are associated with a similar increase in risk of vascular events.

Fish oils (e.g., cod liver oil) have been proposed as a reasonable alternative for the treatment of rheumatoid arthritis and other conditions as a consequence of the fact that they provide less cardiovascular risk than other treatments including NSAIDs.^[6]

References

^ PDB: 1CQE; Picot D, Loll PJ, Garavito RM (January 1994). "The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1". Nature 367 (6460): 243–9. doi:10.1038/367243a0. PMID 8121489.
^ PDB: 6COX; Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, Miyashiro JM, Penning TD, Seibert K, Isakson PC, Stallings WC (1996). "Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents". Nature 384 (6610): 644–8. doi:10.1038/384644a0. PMID 8967954.
^ Zhang Y, Mills GL, Nair MG (December 2002). "Cyclooxygenase inhibitory and antioxidant compounds from the mycelia of the edible mushroom Grifola frondosa". J. Agric. Food Chem. 50 (26): 7581–5. doi:10.1021/jf0257648. PMID 12475274.
^ Zhang Y, Mills GL, Nair MG (2003). "Cyclooxygenase inhibitory and antioxidant compounds from the fruiting body of an edible mushroom, Agrocybe aegerita". Phytomedicine 10 (5): 386–90. doi:10.1078/0944-7113-00272. PMID 12834003.
^ O'Leary KA, de Pascual-Tereasa S, Needs PW, Bao YP, O'Brien NM, Williamson G (July 2004). "Effect of flavonoids and vitamin E on cyclooxygenase-2 (COX-2) transcription". Mutat. Res. 551 (1–2): 245–54. doi:10.1016/j.mrfmmm.2004.01.015. PMID 15225597.
^ ^a ^b Fish oil: what the prescriber needs to know by Leslie G Cleland, Michael J James, and Susanna M Proudman http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1526555/
^ Albert D, Zündorf I, Dingermann T, Müller WE, Steinhilber D, Werz O. (December 2002). "Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase". Biochemical Pharmacology. 15;64(12):1767-75. PMID 12445866
^ Moreno J, Krishnan AV, Peehl DM, Feldman D. (July–August 2006). "Mechanisms of vitamin D-mediated growth inhibition in prostate cancer cells: inhibition of the prostaglandin pathway.". Anticancer Res. 26 (4A): 2525–2530. PMID 16886660.
^ Wallace JL (October 2008). "Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself?". Physiol. Rev. 88 (4): 1547–65. doi:10.1152/physrev.00004.2008. PMID 18923189.
^ Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C (June 2006). "Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials". BMJ 332 (7553): 1302–8. doi:10.1136/bmj.332.7553.1302. PMC 1473048. PMID 16740558.

External links

The Cyclooxygenase Protein
Cyclooxygenase at the US National Library of Medicine Medical Subject Headings (MeSH)
GONUTS Page: Cyclooxygenase
Cyclooxygenase: Proteopedia, life in 3D
A discussion of the enzymatic mechanism, including interactive 3D models

UpToDate Contents

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1. 非ステロイド性抗炎症剤（NSAIDs）：作用機序 nsaids mechanism of action
2. 陣痛誘発前に未成熟な頸管を熟化させる手技 techniques for ripening the unfavorable cervix prior to induction
3. 低アルドステロン症（4型RTA）の病因、診断、および治療 etiology diagnosis and treatment of hypoaldosteronism type 4 rta
4. COX-2阻害剤および胃十二指腸障害：大規模臨床試験 cox 2 inhibitors and gastroduodenal toxicity major clinical trials
5. COX-2選択的阻害剤の概要 overview of selective cox 2 inhibitors

English Journal

Validation of potential candidate biomarkers of drug-induced nephrotoxicity and allodynia in medication-overuse headache.

Bellei E1, Monari E, Bergamini S, Cuoghi A, Tomasi A, Guerzoni S, Ciccarese M, Pini LA.
The journal of headache and pain.J Headache Pain.2015 Dec;16(1):559. doi: 10.1186/s10194-015-0559-8. Epub 2015 Aug 15.
BACKGROUND: Medication-overuse headache (MOH) is a chronic disorder that results from the overuse of analgesics drugs, triptans or other acute headache compounds. Although the exact mechanisms underlying MOH remain still unknown, several studies suggest that it may be associated with development of
PMID 26272683

Trimeric microsomal glutathione transferase 2 displays one third of the sites reactivity.

Ahmad S1, Thulasingam M2, Palombo I3, Daley DO4, Johnson KA5, Morgenstern R6, Haeggström JZ7, Rinaldo-Matthis A8.
Biochimica et biophysica acta.Biochim Biophys Acta.2015 Oct;1854(10 Pt A):1365-71. doi: 10.1016/j.bbapap.2015.06.003. Epub 2015 Jun 9.
Human microsomal glutathione transferase 2 (MGST2) is a trimeric integral membrane protein that belongs to the membrane-associated proteins in eicosanoid and glutathione metabolism (MAPEG) family. The mammalian MAPEG family consists of six members where four have been structurally determined. MGST2
PMID 26066610

Professional phagocytic granulocyte-derived PGD2 regulates the resolution of inflammation in fish.

Gómez-Abellán V1, Montero J1, López-Muñoz A1, Figueras A2, Arizcun M3, Mulero V1, Sepulcre MP4.
Developmental and comparative immunology.Dev Comp Immunol.2015 Oct;52(2):182-91. doi: 10.1016/j.dci.2015.04.017. Epub 2015 May 28.
Prostaglandins (PGs) play a key role in the development on the immune response through the regulation of both pro- and anti-inflammatory processes. PGD2 can be either pro- or anti-inflammatory depending on the inflammatory milieu. Prostaglandin D synthase (PGDS) is the enzyme responsible for the con
PMID 26027798

Japanese Journal

Biological Effects of the Herbal Plant-Derived Phytoestrogen Bavachin in Primary Rat Chondrocytes

Lee Gyeong-Je,Cho In-A,Kang Kyeong-Rok,Kim Do Kyung,Sohn Hong-Moon,You Jae-Won,Oh Ji-Su,Seo Yo-Seob,Yu Sang-Joun,You Jae-Seek,Kim Chun Sung,Kim Su-Gwan,Im Hee-Jeong,Kim Jae-Sung
Biological and Pharmaceutical Bulletin 38(8), 1199-1207, 2015
… Bavachin inhibits the expression of inducible nitric oxide synthase, a representative catabolic factor, and downregulated the expression of nitric oxide, cyclooxygenase-2, and prostaglandin E2 in a dose-dependent manner in chondrocytes. …
NAID 130005090647

Fulgidic Acid Isolated from the Rhizomes of Cyperus rotundus Suppresses LPS-Induced iNOS, COX-2, TNF-α, and IL-6 Expression by AP-1 Inactivation in RAW264.7 Macrophages

Shin Ji-Sun,Hong Yujin,Lee Hwi-Ho [他],Ryu Byeol,Cho Young-Wuk,Kim Nam-Jung,Jang Dae Sik,Lee Kyung-Tae
Biological and Pharmaceutical Bulletin 38(7), 1081-1086, 2015
… Fulgidic acid reduced the production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. … Consistent with these findings, fulgidic acid suppressed the LPS-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the protein level, as well as iNOS, COX-2, TNF-α, and IL-6 at mRNA levels. …
NAID 130005086300

Time-dependent changes in inhibitory action of lipopolysaccharide on intestinal motility in rat

MIKAWA Shoma,OHTA Yasuhiro,KAJI Noriyuki,ISLAM Md Shafiqul,MURATA Takahisa,OZAKI Hiroshi,HORI Masatoshi
Journal of Veterinary Medical Science advpub(0), 2015
… Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) genes were also upregulated, but iNOS expression was preceded by a rising of COX-2. … All subtypes of prostaglandin E2 (PGE2) receptors (EP1-EP4) were expressed in ileum, and PGE2 and selective EP2 or EP4 agonist inhibited CCh-mediated contraction. …
NAID 130005074228

Related Pictures

★リンクテーブル★

リンク元	「プロスタグランジンシンターゼ」「PGH synthase」「prostaglandin-endoperoxide synthase」「プロスタグランジン合成酵素」
関連記事	「synthase」「prostaglandin」「prostaglandins」

「プロスタグランジンシンターゼ」

cyclooxygenase 1
	Crystallographic structure of prostaglandin H2 synthase-1 complex with flurbiprofen.
Identifiers
Symbol	PTGS1
Alt. symbols	COX-1
Entrez	5742
HUGO	9604
OMIM	176805
PDB	1CQE
RefSeq	NM_080591
UniProt	P23219
Other data
EC number	1.14.99.1
Locus	Chr. 9 q32-q33.3

Search
PMC	articles
PubMed	articles
NCBI	proteins

prostaglandin-endoperoxide synthase
Identifiers
EC number	1.14.99.1
CAS number	9055-65-6
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
Search
PMC	articles
PubMed	articles
NCBI	proteins