Prostaglandin

Chemical structure of prostaglandin E₁ (alprostadil)

Chemical structure of prostaglandin I₂ (prostacyclin)

Prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> that have diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derived enzymatically from the fatty acid arachidonic acid.<ref name=":0">Template:Cite journal</ref> Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring. They are a subclass of eicosanoids and of the prostanoid class of fatty acid derivatives.

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 of receptor to which the prostaglandin binds. They act as autocrine or paracrine factors with their target cells present in the immediate vicinity of the site of their secretion. Prostaglandins differ from endocrine hormones in that they are not produced at a specific site but in many places throughout the human body.

Prostaglandins are powerful, locally-acting vasodilators and inhibit the aggregation of blood platelets. Through their role in vasodilation, prostaglandins are also involved in inflammation. 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 of smooth muscle tissue.<ref name="isbn0-87893-617-3">Template:Cite book</ref> Conversely, thromboxanes (produced by platelet cells) are vasoconstrictors 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 of double bonds in the hydrocarbon structure. For example, prostaglandin E₁ has the abbreviation PGE₁ and prostaglandin I₂ has the abbreviation PGI₂.

History and nameEdit

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.<ref>Template:Cite journal</ref> The name prostaglandin derives from the prostate gland, chosen when prostaglandin was first isolated from seminal fluid in 1935 by the Swedish physiologist Ulf von Euler,<ref>Template:Cite journal</ref> and independently by the Irish-English physiologist Maurice Walter Goldblatt (1895–1967).<ref>Template:Cite journal</ref><ref>Template:Cite book</ref><ref>Template:Cite journal</ref> Prostaglandins were believed to be part of the prostatic secretions, and eventually were discovered to be produced by the seminal vesicles. Later, it was shown that many other tissues secrete prostaglandins and that they perform a variety of functions. The first total syntheses of prostaglandin F_2α and prostaglandin E₂ were reported by Elias James Corey in 1969,<ref name="Nicolaou">Template:Cite book</ref> an achievement for which he was awarded the Japan Prize in 1989.

In 1971, it was determined that aspirin-like drugs could inhibit the synthesis of prostaglandins. The biochemists Sune K. Bergström, Bengt I. Samuelsson and John R. Vane jointly received the 1982 Nobel Prize in Physiology or Medicine for their research on prostaglandins.Template:Citation needed

BiochemistryEdit

BiosynthesisEdit

File:Eicosanoid synthesis.svg

Biosynthesis of eicosanoids

Prostaglandins are found in most tissues and organs. They are produced by almost all nucleated cells. They are autocrine and paracrine lipid mediators that act upon platelets, endothelium, uterine and mast cells. They are synthesized in the cell from the fatty acid arachidonic acid.<ref name=":0" />

Arachidonic acid is created from diacylglycerol via phospholipase-A₂, then brought to either the cyclooxygenase pathway or the lipoxygenase pathway. The cyclooxygenase pathway produces thromboxane, prostacyclin and prostaglandin D, E and F. Alternatively, the lipoxygenase enzyme pathway is active in leukocytes and in macrophages and synthesizes leukotrienes.Template:Citation needed

Release of prostaglandins from the cellEdit

Prostaglandins were originally believed to leave the cells via passive diffusion because of their high lipophilicity. The discovery of the prostaglandin 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 the multidrug resistance protein 4 (MRP4, ABCC4), a member of the ATP-binding cassette transporter superfamily. Whether MRP4 is the only transporter releasing prostaglandins from the cells is still unclear.Template:Citation needed

CyclooxygenasesEdit

Prostaglandins are produced following the sequential oxygenation of arachidonic acid, DGLA or EPA by cyclooxygenases (COX-1 and COX-2) and terminal prostaglandin syntheses. The classic dogma is as follows:

COX-1 is responsible for the baseline levels of prostaglandins.
COX-2 produces prostaglandins through stimulation.

However, while COX-1 and COX-2 are both located in the blood vessels, stomach and the kidneys, prostaglandin levels are increased by COX-2 in scenarios of inflammation and growth.

Prostaglandin E synthaseEdit

Prostaglandin E₂ (PGE₂) — the most abundant prostaglandin<ref>Template:Cite journal</ref> — is generated from the action of prostaglandin E synthases on prostaglandin H₂ (prostaglandin H2, PGH₂). Several prostaglandin E syntheses have been identified. To date, microsomal (named as misoprostol) prostaglandin E synthase-1 emerges as a key enzyme in the formation of PGE₂.Template:Citation needed

Other terminal prostaglandin synthasesEdit

Terminal prostaglandin syntheses have been identified that are responsible for the formation of other prostaglandins. For example, hematopoietic and lipocalin prostaglandin D synthases (hPGDS and lPGDS) are responsible for the formation of PGD₂ 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-PGF_2α,β from PGD₂ and PGF_2α from PGH₂ in the presence of NADPH. This enzyme has recently been crystallized in complex with PGD₂<ref>Template:Cite journal</ref> and bimatoprost<ref>Template:Cite journal</ref> (a synthetic analogue of PGF_2α).

FunctionsEdit

There are currently ten known prostaglandin 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 to PGD2).

The diversity of receptors means that prostaglandins act on an array of cells and have a wide variety of effects such as:

create eicosanoids hormones
act on thermoregulatory center of hypothalamus to produce fever
increase mating behaviors in goldfish<ref>{{#invoke:citation/CS1|citation

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cause the uterus to contractTemplate:Efn
prevent gastrointestinal tract from self-digesting, contributing to its mucosal defence in multifactorial way.<ref>Template:Cite journal</ref>

TypesEdit

The following is a comparison of different types of prostaglandin, including prostaglandin I₂ (prostacyclin; PGI₂), prostaglandin D₂ (PGD₂), prostaglandin E₂ (PGE₂), and prostaglandin F_2α (PGF_2α).<ref>Template:Cite journal</ref>

Type	Receptor	Receptor type	Function
PGI₂	IP	G_s	vasodilation inhibit platelet aggregation bronchodilation
PGD₂	PTGDR (DP1) and CRTH2 (DP2)	GPCR	produced by mast cells; recruits Th2 cells, eosinophils, and basophils In mammalian organs, large amounts of PGD2 are found only in the brain and in mast cells Critical to development of allergic diseases such as asthma
PGE₂	EP₁	G_q	bronchoconstriction GI tract smooth muscle contraction enhanced proliferation of T lymphocytes (Th1 sub-type)
	EP₂	G_s	bronchodilation GI tract smooth muscle relaxation vasodilation reduced intra-ocular pressure regulation of B cells, T cells (CD4 & CD8) & antigen presenting cell function pro-inflammatory cell development → inflammation & fever suppression of NMDA receptor related neurotoxicity (only present within the central nervous system)
	EP₃	G_i	uterus contraction (when pregnant) GI tract smooth muscle contraction lipolysis inhibition inhibitory effect on thermogenic pre-optic hypothalamus stimulate nitrix oxide synthesis → PGE2 synthesis → pyogenic ↑ mast cell release of histamine (increasing allergy response) ↑ pain perception hyperalgesia (wild type EP3 expression) ↑ autonomic neurotransmitters<ref name=Rang>Template:Cite book</ref> ↑ platelet response to their agonists<ref>Template:Cite journal</ref> and ↑ atherothrombosis in vivo<ref>Template:Cite journal</ref>
	EP₄	G_s	hyperalgesia<ref name=Rang/> pyrogenic supports regulatory T cell production stimulate dendritic cell maturation (antigen presenting cells of skin & mucosa) inhibit antibody B cell proliferation ↑ inflammatory region blood flow (pyogenic & erythema) Inhibitory effects of dorsal root ganglion (speculated reduction in allodynia & hyperalgesia) ↓ gastric acid secretion ↑ gastric mucus secretion Prostate cancer (↑ EP4 expression) ↑ corneal neovascularization ↑ chohlea auditory brain stem response
PGF_2α	FP	G_q	uterus contraction bronchoconstriction urinary bladder contractions<ref>Template:Cite journal</ref> vasoconstriction in cerebral circulation<ref>Template:Cite book</ref>

Role in pharmacologyEdit

InhibitionEdit

Template:See also

Examples of prostaglandin antagonists are:

NSAIDs (inhibit cyclooxygenase) and COX-2 selective inhibitors or coxibs
Corticosteroids (inhibit phospholipase A₂ production)
Cyclopentenone prostaglandins may play a role in inhibiting inflammation
Vitamin D₃ and vitamin K₂.<ref name="pmid34206530">Template:Cite journal</ref><ref name="pmid8240383">Template:Cite journal</ref><ref name="pmid20046582">Template:Cite journal</ref>

Clinical usesEdit

Synthetic prostaglandins are used:

To induce childbirth (parturition) or abortion (PGE₂ or PGF_{2(misoprostol)}, with or without mifepristone, a progesterone antagonist)
- Induction of labour<ref name="NCBI Bookshelf WHO">{{#invoke:citation/CS1|citation

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To prevent closure of ductus arteriosus in newborns with particular cyanotic heart defects (PGE₁)
As a vasodilator in severe Raynaud syndrome or ischemia of a limb
In pulmonary hypertension
In treatment of glaucoma (as in bimatoprost ophthalmic solution, a synthetic prostamide analog with ocular hypotensive activity) (PGF_2α)
To treat erectile dysfunction or in penile rehabilitation following surgery (PGE1 as alprostadil).<ref name="muse">Medscape Early Penile Rehabilitation Helps Reduce Later Intractable ED</ref>
To measure erect penis size in a clinical environment<ref name=veale2015>Template:Cite journal</ref>
To treat egg binding in small birds<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

SynthesisEdit

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.<ref>Template:Cite journal</ref>

Diels-Alder in the total synthesis of prostaglandin F2α by E. J. Corey