prostaglandin

Information about prostaglandin

A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring. They are mediators and have a variety of strong physiological effects; although they are technically hormones, they are rarely classified as such.

The prostaglandins together with the thromboxanes and prostacyclins form the prostanoid class of fatty acid derivatives; the prostanoid class is a subclass of eicosanoids.

History and name

The name prostaglandin derives from the prostate gland. When prostaglandin was first isolated from seminal fluid in 1935 by the Swedish physiologist Ulf von Euler,^[1] and independently by M.W. Goldblatt,^[2] it was believed to be part of the prostatic secretions (in actuality prostaglandins are produced by the seminal vesicles); it was later shown that many other tissues secrete prostaglandins for various functions.

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.

Biochemistry

Biosynthesis

Biosynthesis of eicosanoids. (series-2)

Prostaglandins are found in virtually all tissues and organs. These are autocrine and paracrine lipid mediators that act upon platelet, endothelium, uterine and mast cells, among others. They are synthesized in the cell from the essential fatty acids^[3] (EFAs).

Name	EFA Type	Series
Gamma-linolenic acid (GLA) via DGLA	ω-6	series-1
Arachidonic acid (AA)	ω-6	series-2
Eicosapentaenoic acid (EPA)	ω-3	series-3

An intermediate is created by phospholipase-A₂, then passed into one of either the cyclooxygenase pathway or the lipoxygenase pathway to form either prostaglandin and thromboxane or leukotriene. The cyclooxygenase pathway produces thromboxane, prostacyclin and prostaglandin D, E and F. The lipoxygenase pathway is active in leukocytes and in macrophages and synthesizes leukotrienes.

Release of prostaglandins from the cell

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 can not 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.

Cyclooxygenases

Prostaglandins are produced following the sequential oxidation of AA, DGLA or EPA by cyclooxygenases (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.

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.

Prostaglandin E synthase

Prostaglandin E₂ (PGE₂) is generated from the action of prostaglandin E synthases on prostaglandin H₂ (PGH₂). Several prostaglandin E synthases have been identified. To date, microsomal prostaglandin E synthase-1 emerges as a key enzyme in the formation of PGE₂.

Other terminal prostaglandin synthases

Terminal prostaglandin synthases 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 idenfitied. 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 crystallyzed in complex with PGD₂^[4] and bimatoprost^[5] (a synthetic analogue of PGF_2α).

Function

There are currently nine known prostaglandin receptors on various cell types. Prostaglandins ligate a subfamily of cell surface seven-transmembrane receptors, G-protein-coupled receptors. These receptors are termed DP1-2, EP1-4, FP, IP, and TP, corresponding to the receptor that ligates the corresponding prostaglandin (e.g., DP1-2 receptors bind to PGD2).

These varied receptors mean that Prostaglandins thus act on a variety of cells, and have a wide variety of actions:

cause constriction or dilatation in vascular smooth muscle cells
cause aggregation or disaggregation of platelets
sensitize spinal neurons to pain
constrict smooth muscle
regulate inflammatory mediation
regulate calcium movement
regulate hormone regulation
control cell growth

Prostaglandins are potent but have a short half-life before being inactivated and excreted. Therefore, they exert only a paracrine (locally active) or autocrine (acting on the same cell from which it is synthesized) function.

Role in pharmacology

Inhibition

See Prostaglandin antagonist

Clinical uses

Synthetic prostaglandins are used:

To induce childbirth, parturition or abortion (PGE₂ or PGF₂, with or without mifepristone, a progesterone antagonist);
To prevent closure of patent ductus arteriosus in newborns with particular cyanotic heart defects (PGE₁)
To prevent and treat peptic ulcers (PGE)
As a vasodilator in severe Raynaud's phenomenon 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)
To treat erectile dysfunction or in penile rehabilitation following surgery (PGE1 as alprostadil).^[6]

References

1. ^ Von Euler US. Über die spezifische blutdrucksenkende Substanz des menschlichen Prostata- und Samenblasensekrets. Klin Wochenschr 1935;14:1182–1183.
2. ^ Goldblatt MW. Properties of human seminal plasma. J Physiol 1935;84:208-18. PMID 16994667.
3. ^ Dorlands Medical Dictionary [1] URL reference on 10/23/05.
4. ^ Komoto J, Yamada T, Watanabe K, Takusagawa F (2004). "Crystal structure of human prostaglandin F synthase (AKR1C3)". Biochemistry 43 (8): 2188-98. PMID 14979715.
5. ^ Komoto J, Yamada T, Watanabe K, Woodward D, Takusagawa F (2006). "Prostaglandin F2alpha formation from prostaglandin H2 by prostaglandin F synthase (PGFS): crystal structure of PGFS containing bimatoprost". Biochemistry 45 (7): 1987-96. PMID 16475787.
6. ^ Medscape Early Penile Rehabilitation Helps Reduce Later Intractable ED [2] URL reference on 10/23/05.

External links

MeSH Prostaglandins

• • [ e] Endocrine system: hormones/endocrine glands (Peptide hormones, Steroid hormones)
Hypothalamic-pituitary	Hypothalamus: TRH, CRH , GnRH, GHRH, somatostatin, dopamine - Posterior pituitary: vasopressin, oxytocin - Anterior pituitary: α (FSH, LH, TSH), GH, prolactin, POMC (ACTH, MSH, endorphins, lipotropin)
Adrenal axis	Adrenal medulla: epinephrine, norepinephrine - Adrenal cortex: aldosterone, cortisol, DHEA
Thyroid axis	Thyroid: thyroid hormone (T₃ and T₄) - calcitonin - Parathyroid: PTH
Gonadal axis	Testis: testosterone, AMH, inhibin - Ovary: estradiol, progesterone, inhibin/activin, relaxin (pregnancy)
Other end. glands	Pancreas: glucagon, insulin, somatostatin - Pineal gland: melatonin
Non-end. glands	Placenta: hCG, HPL, estrogen, progesterone - Kidney: renin, EPO, calcitriol, prostaglandin - Heart atrium: ANP - Stomach: gastrin, ghrelin - Duodenum: CCK, GIP, secretin, motilin, VIP - Ileum: enteroglucagon - Adipose tissue: leptin, adiponectin, resistin - Thymus: Thymosin - Thymopoietin - Liver/other: Insulin-like growth factor (IGF-1, IGF-2)
Target-derived	NGF, BDNF, NT-3

• • [ e] Autacoids, unsaturated fatty acids: Eicosanoids
Prostanoids	Prostaglandins - Thromboxanes (A2, B2)
Other	Arachidonic acids - Eicosapentaenoic acid - Leukotrienes - Lipoxins

• • [ e] Eicosanoids: prostaglandins
Endogenous/series 2	D2 - E2 (Dinoprostone) - H2 - I2 (Prostacyclin)
Prostaglandin analogues	Alprostadil - Beraprost - Bimatoprost - Carboprost - Enprostil - Iloprost - Latanoprost - Misoprostol - Travoprost - Treprostinil

Lipids can be broadly defined as any fat-soluble (hydrophobic), naturally-occurring molecules. The term is more-specifically used to refer to fatty-acids and their derivatives (including tri-, di-, and monoglycerides and phospholipids) as well as other fat-soluble sterol-containing
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Types of Fats in Food

Unsaturated fat
Monounsaturated fat
Polyunsaturated fat
Trans fat
Omega: 3, 6, 9

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4, 2
(mildly acidic oxide)
Electronegativity 2.55 (Pauling scale)
Ionization energies
(more) 1st: 1086.5 kJmol⁻¹
2nd: 2352.6 kJmol⁻¹
3rd: 4620.5 kJmol⁻¹

Atomic radius 70 pm
Atomic radius (calc.
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Physiology (from Greek: φυσις, physis, “nature, origin”; and λόγος, logos, "knowledge") is the study of the mechanical, physical, and biochemical functions of living organisms.
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hormone (from Greek όρμή - "to set in motion") is a chemical messenger that carries a signal from one cell (or group of cells) to another. All multicellular organisms produce hormones (including plants - see phytohormone).
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Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2.

Thromboxane is named for its role in clot formation (thrombosis).
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Prostacyclin is a member of the family of lipid molecules known as eicosanoids. Epoprostenol (brand name Flolan) is a synthetic form of prostacyclin, approved by the FDA as a medicine in 1995.
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Prostanoid is the term used to describe a subclass of eicosanoids consisting of: the prostaglandins (mediators of inflammatory and anaphylactic reactions), the thromboxanes (mediators of vasoconstriction) and the prostacyclins (active in the resolution phase of inflammation.
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In biochemistry, eicosanoids are signaling molecules derived from omega-3 (ω-3) or omega-6 (ω-6) fats. They exert complex control over many bodily systems, mainly in inflammation or immunity, and as messengers in the central nervous system.
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The prostate is a compound tubuloalveolar exocrine gland of the male mammalian reproductive system.

The prostate differs considerably among species anatomically, chemically, and physiologically.
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Semen is an organic fluid (also known as seminal fluid) that usually contains spermatozoa. It is secreted by the gonads (sexual glands) and other sexual organs of male or hermaphroditic animals for fertilization of female ova. The process of discharge is called ejaculation.
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19th century - 20th century - 21st century
1900s 1910s 1920s - 1930s - 1940s 1950s 1960s
1932 1933 1934 - 1935 - 1936 1937 1938

Year 1935 (MCMXXXV
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Ulf Svante von Euler (February 7, 1905 – March 9, 1983) was a Swedish physiologist and pharmacologist. He won a Nobel Prize in Medicine and Physiology in 1970 for his work on neurotransmitters.

Life

Ulf S.
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The seminal vesicles are a pair of simple tubular glands posteroinferior to the urinary bladder of males.

Anatomy

They are approximately 5 cm in length, though the full length of the gland is approximately 10 cm and curled up inside of the structure.
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19th century - 20th century - 21st century
1940s 1950s 1960s - 1970s - 1980s 1990s 2000s
1968 1969 1970 - 1971 - 1972 1973 1974

Year 1971 (MCMLXXI
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Aspirin^®, or acetylsalicylic acid (IPA: /əˌsɛtɨlsælɨˌsɪlɨk ˈæsɨd/
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Sune Karl Bergström (born January 10, 1916 in Stockholm, Sweden; died August 15, 2004) was a Swedish biochemist. In 1975, he was appointed to the Nobel Foundation Board of Directors in Sweden.
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Bengt Ingemar Samuelsson (born May 21, 1934) is a Swedish biochemist.

He was born in Halmstad in southwest Sweden and studied at Stockholm University, where he became a professor in 1967. He shared with Sune K. Bergström and John R.
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Sir John Robert Vane (March 29, 1927 – November 19, 2004) was a British pharmacologist. His father was the son of Jewish immigrants from Russia and his mother came from a Worcestershire farming family.
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19th century - 20th century - 21st century
1950s 1960s 1970s - 1980s - 1990s 2000s 2010s
1979 1980 1981 - 1982 - 1983 1984 1985

Year 1982 (MCMLXXXII
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';
George Richards Minot, ';
William Parry Murphy, "for their discoveries concerning liver therapy in cases of anaemia"^[31]
1935 Hans Spemann, '' German Empire "for his discovery of the organizer effect in embryonic development"^[32]
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Autocrine signalling is a form of hormonal signalling in which a cell secretes a hormone, or chemical messenger (called the autocrine agent) that binds to autocrine receptors on the same cell, leading to changes in the cell.
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Paracrine signaling is a form of cell signaling in which the target cell is close to ("para" = alongside of or next to, but this strict prefix definition is not meticulously followed here) the signal releasing cell.

The signal chemical is called the paracrine agent.
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Platelets, or thrombocytes, are the cell fragments circulating in the blood that are involved in the cellular mechanisms of primary hemostasis leading to the formation of blood clots.
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endothelium is the thin layer of cells that line the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. Endothelial cells line the entire circulatory system, from the heart to the smallest capillary.
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uterus or womb is the major female reproductive organ of most mammals, including humans. One end, the cervix, opens into the vagina; the other is connected on both sides to the fallopian tubes.
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A mast cell (or mastocyte) is a resident cell of several types of tissues and contains many granules rich in histamine and heparin. Although best known for their role in allergy and anaphylaxis, mast cells play an important protective role as well, being intimately
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