The structural differences between prostaglandins account for their different biological activities. A given prostaglandin may have different and even opposite effects in different tissues in some cases. The ability of the same prostaglandin to stimulate a reaction in one tissue and inhibit the same reaction in another tissue is determined by the type ofreceptor to which the prostaglandin binds. They act asautocrine orparacrine factors with their target cells present in the immediate vicinity of the site of theirsecretion. Prostaglandins differ fromendocrinehormones in that they are not produced at a specific site but in many places throughout the human body.
Prostaglandins are powerful, locally-actingvasodilators and inhibit the aggregation of bloodplatelets. Through their role in vasodilation, prostaglandins are also involved ininflammation. They are synthesized in the walls of blood vessels and serve the physiological function of preventing needless clot formation, as well as regulating the contraction ofsmooth muscle tissue.[3] Conversely,thromboxanes (produced by platelet cells) arevasoconstrictors and facilitate platelet aggregation. Their name comes from their role in clot formation (thrombosis).
Specific prostaglandins are named with a letter indicating the type of ring structure, followed by a number indicating the number ofdouble bonds in thehydrocarbon structure. For example,prostaglandin E1 has the abbreviation PGE1 andprostaglandin I2 has the abbreviation PGI2.
Systematic studies of prostaglandins began in 1930, when Kurzrock and Lieb found that human seminal fluid caused either stimulation or relaxation of strips of isolated human uterus. They noted that uteri from patients who had gone through successful pregnancies responded to the fluid with relaxation, while uteri from sterile women responded with contraction.[4] The nameprostaglandin derives from theprostategland, chosen when prostaglandin was first isolated fromseminal fluid in 1935 by the SwedishphysiologistUlf von Euler,[5] and independently by the Irish-English physiologist Maurice Walter Goldblatt (1895–1967).[6][7][8] Prostaglandins were believed to be part of the prostatic secretions, and eventually were discovered to be produced by theseminal vesicles. Later, it was shown that many other tissues secrete prostaglandins and that they perform a variety of functions. The firsttotal syntheses ofprostaglandin F2α andprostaglandin E2 were reported byElias James Corey in 1969,[9] an achievement for which he was awarded theJapan Prize in 1989.
Prostaglandins were originally believed to leave the cells via passive diffusion because of their high lipophilicity. The discovery of theprostaglandin transporter (PGT, SLCO2A1), which mediates the cellular uptake of prostaglandin, demonstrated that diffusion alone cannot explain the penetration of prostaglandin through the cellular membrane. The release of prostaglandin has now also been shown to be mediated by a specific transporter, namely themultidrug resistance protein 4 (MRP4, ABCC4), a member of theATP-binding cassette transporter superfamily. Whether MRP4 is the only transporter releasing prostaglandins from the cells is still unclear.[citation needed]
Prostaglandins are produced following the sequential oxygenation of arachidonic acid, DGLA or EPA bycyclooxygenases (COX-1 and COX-2) and terminal prostaglandin synthases. The classic dogma is as follows:
COX-1 is responsible for the baseline levels of prostaglandins.
COX-2 produces prostaglandins through stimulation.
Prostaglandin E2 (PGE2) — the most abundant prostaglandin[10] — is generated from the action ofprostaglandin E synthases on prostaglandin H2 (prostaglandin H2, PGH2). Several prostaglandin E synthases have been identified. To date, microsomal (named asmisoprostol) prostaglandin E synthase-1 emerges as a key enzyme in the formation of PGE2.[citation needed]
Terminal prostaglandin synthases have been identified that are responsible for the formation of other prostaglandins. For example, hematopoietic andlipocalinprostaglandin D synthases (hPGDS and lPGDS) are responsible for the formation ofPGD2 from PGH2. Similarly, prostacyclin (PGI2) synthase (PGIS) converts PGH2 into PGI2. A thromboxane synthase (TxAS) has also been identified.Prostaglandin-F synthase (PGFS) catalyzes the formation of 9α,11β-PGF2α,β from PGD2 and PGF2α from PGH2 in the presence of NADPH. This enzyme has recently been crystallized in complex with PGD2[11] and bimatoprost[12] (a synthetic analogue of PGF2α).
There are currently ten knownprostaglandin receptors on various cell types. Prostaglandins ligate a sub-family of cell surface seven-transmembrane receptors,G-protein-coupled receptors. These receptors are termed DP1-2, EP1-4, FP, IP1-2, and TP, corresponding to the receptor that ligates the corresponding prostaglandin (e.g., DP1-2 receptors bind toPGD2).
The diversity of receptors means that prostaglandins act on an array of cells and have a wide variety of effects such as:
The original synthesis of prostaglandins F2α and E2 is shown below. It involves a Diels–Alder reaction which establishes the relative stereochemistry of three contiguous stereocenters on the prostaglandin cyclopentane core.[32]
Diels-Alder in the total synthesis of prostaglandin F2α by E. J. Corey
^Prostaglandins are released duringmenstruation, due to the destruction of theendometrial cells, and the resultant release of their contents.[14][needs update] Release of prostaglandins and other inflammatory mediators in theuterus cause the uterus to contract. These substances are thought to be a major factor in primarydysmenorrhea.[15][16][17]
^Nelson RF (2005).An introduction to behavioral endocrinology (3rd ed.). Sunderland, Mass: Sinauer Associates. p. 100.ISBN0-87893-617-3.
^Kurzrock, Raphael; Lieb, Charles C. (1930). "Biochemical Studies of Human Semen. II. The Action of Semen on the Human Uterus".Proceedings of the Society for Experimental Biology and Medicine.28 (3): 268.doi:10.3181/00379727-28-5265.S2CID85374636.
^Von Euler US (1935). "Über die spezifische blutdrucksenkende Substanz des menschlichen Prostata- und Samenblasensekrets" [On the specific blood-pressure-reducing substance of human prostate and seminal vesicle secretions].Wiener Klinische Wochenschrift.14 (33):1182–1183.doi:10.1007/BF01778029.S2CID38622866.
^Rubinstein, William D.; Jolles, Michael A.; Rubinstein, Hillary L., eds. (2011)."Goldblatt, Maurice Walter".The Palgrave Dictionary of Anglo-Jewish History. Basingstoke, England: Palgrave Macmillan. p. 333.ISBN978-0-230-30466-6.
^Komoto J, Yamada T, Watanabe K, Takusagawa F (March 2004). "Crystal structure of human prostaglandin F synthase (AKR1C3)".Biochemistry.43 (8):2188–98.doi:10.1021/bi036046x.PMID14979715.
^Komoto J, Yamada T, Watanabe K, Woodward DF, Takusagawa F (February 2006). "Prostaglandin F2alpha formation from prostaglandin H2 by prostaglandin F synthase (PGFS): crystal structure of PGFS containing bimatoprost".Biochemistry.45 (7):1987–96.doi:10.1021/bi051861t.PMID16475787.
^Lethaby A, Duckitt K, Farquhar C (January 2013). "Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding".The Cochrane Database of Systematic Reviews (1): CD000400.doi:10.1002/14651858.CD000400.pub3.PMID23440779.
^Wright, Jason and Solange Wyatt.The Washington Manual Obstetrics and Gynecology Survival Guide. Lippincott Williams & Wilkins, 2003.ISBN0-7817-4363-X[page needed]
^Harel Z (December 2006). "Dysmenorrhea in adolescents and young adults: etiology and management".Journal of Pediatric and Adolescent Gynecology.19 (6):363–71.doi:10.1016/j.jpag.2006.09.001.PMID17174824.
^Moreno JJ (February 2017). "Eicosanoid receptors: Targets for the treatment of disrupted intestinal epithelial homeostasis".European Journal of Pharmacology.796:7–19.doi:10.1016/j.ejphar.2016.12.004.PMID27940058.S2CID1513449.
^abRang HP (2003).Pharmacology (5th ed.). Edinburgh: Churchill Livingstone. p. 234.ISBN0-443-07145-4.
^Koshihara Y, Hoshi K, Shiraki M (1993). "Vitamin K2 (menatetrenone) inhibits prostaglandin synthesis in cultured human osteoblast-like periosteal cells by inhibiting prostaglandin H synthase activity".Biochem Pharmacol.46 (8):1355–62.doi:10.1016/0006-2952(93)90099-i.PMID8240383.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^"WHO Recommendations for Induction of Labour".NCBI Bookshelf. Retrieved2020-07-15.Induction of labour is defined as the process of artificially stimulating the uterus to start labour (1). It is usually performed by administering oxytocin or prostaglandins to the pregnant woman or by manually rupturing the amniotic membranes.
^Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. (1969). "Stereo-controlled synthesis of prostaglandins F-2a and E-2 (dl)".Journal of the American Chemical Society.91 (20):5675–7.doi:10.1021/ja01048a062.PMID5808505.
^Mary Anne Koda-Kimble (2007).Handbook of Applied Therapeutics (8th ed.). Lippincott Williams & Wilkins. p. 1104.ISBN978-0-7817-9026-0.
