The prostaglandins (PG) are a group of
physiologically active
lipid
Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids includ ...
compounds called
eicosanoid
Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosanoids are a s ...
s having diverse
hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are require ...
-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
In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
arachidonic acid.
Every prostaglandin contains 20
carbon
Carbon () is a chemical element with the symbol C and atomic number 6. It is nonmetallic and tetravalent—its atom making four electrons available to form covalent chemical bonds. It belongs to group 14 of the periodic table. Carbon mak ...
atoms, including a
5-carbon ring. They are a subclass of
eicosanoid
Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosanoids are a s ...
s 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 Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with p ...
or
paracrine Paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over ...
factors with their target cells present in the immediate vicinity of the site of their
secretion. Prostaglandins differ from
endocrine hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are require ...
s 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
Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
. 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.
Conversely,
thromboxanes
Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring.
Thromboxane is named for i ...
(produced by platelet cells) are
vasoconstrictors and facilitate platelet aggregation. Their name comes from their role in clot formation (
thrombosis
Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (t ...
).
Specific prostaglandins are named with a letter (which indicates the type of ring structure) followed by a number (which indicates the number of
double bond
In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betwee ...
s in the
hydrocarbon
In organic chemistry, a hydrocarbon is an organic compound consisting entirely of hydrogen and carbon. Hydrocarbons are examples of group 14 hydrides. Hydrocarbons are generally colourless and hydrophobic, and their odors are usually weak or ...
structure). For example,
prostaglandin E1
Prostaglandin E1 (PGE1), also known as alprostadil, is a naturally occurring prostaglandin which is used as a medication. In infants with congenital heart defects, it is delivered by intravenous infusion, slow injection into a vein to open the d ...
is abbreviated PGE
1, and
prostaglandin I2 is abbreviated PGI
2.
History and name
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 the curious finding that uteri from patients who had gone through successful pregnancies responded to the fluid with relaxation, while uteri from sterile women responded with contraction upon addition of this seminal fluid. The name ''prostaglandin'' derives from the
prostate
The prostate is both an accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found only in some mammals. It differs between species anatomically, chemically, and phys ...
gland, chosen when prostaglandin was first isolated from
seminal fluid in 1935 by the Swedish
physiologist Ulf von Euler
Ulf Svante von Euler (7 February 1905 – 9 March 1983) was a Swedish physiologist and pharmacologist. He shared the Nobel Prize in Physiology or Medicine in 1970 for his work on neurotransmitters.
Life
Ulf Svante von Euler-Chelpin was born in ...
, and independently by the Irish-English physiologist Maurice Walter Goldblatt (1895–1967). Prostaglandins were believed to be part of the prostatic secretions, and eventually were discovered to be produced by the
seminal vesicles
The seminal vesicles (also called vesicular glands, or seminal glands) are a pair of two convoluted tubular glands that lie behind the urinary bladder of some male mammals. They secrete fluid that partly composes the semen.
The vesicles are 5� ...
. Later, it was shown that many other tissues secrete prostaglandins and that they perform a variety of functions. The first
total syntheses of
prostaglandin F2α and
prostaglandin E2 were reported by
E. J. Corey
Elias James Corey (born July 12, 1928) is an American organic chemist. In 1990, he won the Nobel Prize in Chemistry "for his development of the theory and methodology of organic synthesis", specifically retrosynthetic analysis. Regarded by many a ...
in 1969,
an achievement for which he was awarded the
Japan Prize in 1989.
In 1971, it was determined that
aspirin
Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...
-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
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...
for their research on prostaglandins.
Biochemistry
Biosynthesis
Prostaglandins are found in most tissues and organs. They are
produced by almost all nucleated cells. They are
autocrine Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with p ...
and
paracrine Paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over ...
lipid mediators that act upon
platelet
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby i ...
s,
endothelium
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vesse ...
,
uterine
The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The ...
and
mast cell
A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a par ...
s. They are synthesized in the cell from the
fatty acid
In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
arachidonic acid.
Arachidonic acid is created from
diacylglycerol
A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. DAGs can act as s ...
via
phospholipase-A2, then brought to either the
cyclooxygenase pathway or the
lipoxygenase pathway. The cyclooxygenase pathway produces
thromboxane
Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring.
Thromboxane is named for i ...
,
prostacyclin
Prostacyclin (also called prostaglandin I2 or PGI2) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator.
When used as a drug, it is also known as epoprosten ...
and prostaglandin D, E and F. Alternatively, the lipoxygenase enzyme pathway is active in
leukocytes and in
macrophages and synthesizes
leukotrienes
Leukotrienes are a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxygenase.
Leukotri ...
.
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 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
The ATP synthase, ATP-binding cassette transporters (ABC transporters) are a transport system superfamily that is one of the largest and possibly one of the oldest gene family, gene families. It is represented in all extant taxon, extant Phylum ...
superfamily. Whether MRP4 is the only transporter releasing prostaglandins from the cells is still unclear.
Cyclooxygenases
Prostaglandins are produced following the sequential oxygenation of arachidonic acid, DGLA or EPA by
cyclooxygenase
Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, ) that is responsible for formation of prostanoids, including thromboxane and prostaglandins such as pr ...
s (COX-1 and COX-2) and terminal prostaglandin synthases. The classic dogma is as follows:
*
COX-1
Cyclooxygenase 1 (COX-1), also known as prostaglandin G/H synthase 1, prostaglandin-endoperoxide synthase 1 or prostaglandin H2 synthase 1, is an enzyme that in humans is encoded by the ''PTGS1'' gene. In humans it is one of two cyclooxygenases.
...
is responsible for the baseline levels of prostaglandins.
*
COX-2
Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) (The HUGO official symbol is PTGS2; HGNC ID, HGNC:9605), also known as cyclooxygenase-2 or COX-2, is an enzyme that in humans is encoded by the ''PTGS2'' gene ...
produces prostaglandins through stimulation.
However, while COX-1 and COX-2 are both located in the
blood vessels,
stomach
The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...
and the
kidneys
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; bloo ...
, prostaglandin levels are increased by COX-2 in scenarios of
inflammation
Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
and
growth.
Prostaglandin E synthase
Prostaglandin E2 (PGE
2) — the most abundant prostaglandin — is generated from the action of
prostaglandin E synthases on prostaglandin H
2 (
prostaglandin H2
Prostaglandin H2 is a type of prostaglandin and a precursor for many other biologically significant molecules. It is synthesized from arachidonic acid in a reaction catalyzed by a cyclooxygenase enzyme. The conversion from Arachidonic acid to Pro ...
, PGH
2). Several prostaglandin E synthases have been identified. To date, microsomal prostaglandin E synthase-1 emerges as a key enzyme in the formation of PGE
2.
Other terminal prostaglandin synthases
Terminal prostaglandin synthases have been identified that are responsible for the formation of other prostaglandins. For example, hematopoietic and
lipocalin
The lipocalins are a family of proteins which transport small hydrophobic molecules such as steroids, bilins, retinoids, and lipids and most lipocalins are also able to bind to complexed iron (via siderophores or flavonoids) as well as heme. They ...
prostaglandin D synthases (hPGDS and lPGDS) are responsible for the formation of
PGD2 from PGH
2. Similarly, prostacyclin (PGI
2) synthase (PGIS) converts PGH
2 into PGI
2. A thromboxane synthase (
TxAS) has also been identified.
Prostaglandin-F synthase (PGFS) catalyzes the formation of 9α,11β-PGF
2α,β from PGD
2 and PGF
2α from PGH
2 in the presence of NADPH. This enzyme has recently been crystallized in complex with PGD
2 and bimatoprost (a synthetic analogue of PGF
2α).
Functions
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 receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
s. 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
eicosanoid
Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosanoids are a s ...
s hormones
* acts on thermoregulatory center of
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
to produce
fever
Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...
* increases mating behaviors in goldfish
* Prostaglandins are released during
menstruation, due to the destruction of the
endometrial cells, and the resultant release of their contents. Release of prostaglandins and other inflammatory mediators in the
uterus
The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The ...
cause the uterus to contract. These substances are thought to be a major factor in primary
dysmenorrhea.
Types
The following is a comparison of different types of prostaglandin, including
prostaglandin I2 (prostacyclin; PGI
2),
prostaglandin D2 (PGD
2),
prostaglandin E2 (PGE
2), and
prostaglandin F2α (PGF
2α).
Role in pharmacology
Inhibition
Examples of prostaglandin antagonists are:
*
NSAID
Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...
s (inhibit
cyclooxygenase
Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, ) that is responsible for formation of prostanoids, including thromboxane and prostaglandins such as pr ...
) and
COX-2 selective inhibitors or coxibs
*
Corticosteroids (inhibit
phospholipase A2 production)
*
Cyclopentenone prostaglandins may play a role in inhibiting
inflammation
Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
Clinical uses
Synthetic prostaglandins are used:
* To induce
childbirth
Childbirth, also known as labour and delivery, is the ending of pregnancy where one or more babies exits the internal environment of the mother via vaginal delivery or caesarean section. In 2019, there were about 140.11 million births glob ...
(parturition) or
abortion
Abortion is the termination of a pregnancy by removal or expulsion of an embryo or fetus. An abortion that occurs without intervention is known as a miscarriage or "spontaneous abortion"; these occur in approximately 30% to 40% of pre ...
(PGE
2 or PGF
2, with or without
mifepristone
Mifepristone, also known as RU-486, is a medication typically used in combination with misoprostol to bring about a medical abortion during pregnancy and manage early miscarriage. This combination is 97% effective during the first 63 days of ...
, a progesterone antagonist)
**
Induction of labour
* To prevent closure of
ductus arteriosus
The ''ductus arteriosus'', also called the ''ductus Botalli'', named after the Italian physiologist Leonardo Botallo, is a blood vessel in the developing fetus connecting the trunk of the pulmonary artery to the proximal descending aorta. It a ...
in newborns with particular
cyanotic heart defects (PGE
1)
* As a
vasodilator in severe
Raynaud syndrome or
ischemia of a limb
* In
pulmonary hypertension
* In treatment of
glaucoma
Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye rem ...
(as in
bimatoprost ophthalmic solution, a synthetic prostamide analog with ocular hypotensive activity) (PGF2α)
* To treat
erectile dysfunction or in penile rehabilitation following surgery (PGE1 as
alprostadil
Prostaglandin E1 (PGE1), also known as alprostadil, is a naturally occurring prostaglandin which is used as a medication. In infants with congenital heart defects, it is delivered by slow injection into a vein to open the ductus arteriosus unt ...
).
[Medscape ]
Early Penile Rehabilitation Helps Reduce Later Intractable ED
'
* To measure erect
penis size
Human penises vary in size on a number of measures, including length and circumference when flaccid and erect. Besides the natural variability of human penises in general, there are factors that lead to minor variations in a particular male, ...
in a clinical environment
* To treat
egg binding in small
bird
Birds are a group of warm-blooded vertebrates constituting the class Aves (), characterised by feathers, toothless beaked jaws, the laying of hard-shelled eggs, a high metabolic rate, a four-chambered heart, and a strong yet lightweig ...
s
Synthesis
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.
Prostaglandin stimulants
Cold exposure and IUDs may increase prostaglandin production.
See also
*
Prostamide
Prostamides are a class of physiology, physiologically active, lipid-like substances chemically related to prostaglandins. They occur naturally in humans and other animals. The first prostamide, called prostamide E2, was discovered in 1997.
Bioche ...
s, a chemically related class of physiologically active substances
References
External links
*
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