- (alprostadil)]]
- (prostacyclin)]]
Prostaglandins ( PG) are a group of physiology active lipid compounds that have diverse hormone-like effects in animals. They are a subclass of
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 system in that they are not produced at a specific site but in many places throughout the human body.
Prostaglandins are powerful, locally-acting and inhibit the aggregation of blood .
Specific prostaglandins are named with a letter indicating the type of ring structure, followed by a number indicating the number of in the hydrocarbon structure. For example, prostaglandin E1 has the abbreviation PGE1 and prostacyclin has the abbreviation PGI2.
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 that uteri from patients who had gone through successful pregnancies responded to the fluid with relaxation, while uteri from sterile women responded with contraction.
The name
prostaglandin derives from the
prostate gland, chosen when prostaglandin was first isolated from
seminal fluid in 1935 by the Swedish
physiology Ulf von Euler,
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. Later, it was shown that many other tissues secrete prostaglandins and that they perform a variety of functions. The first
total synthesis of prostaglandin F
2α and prostaglandin E
2 were reported by Elias James Corey in 1969,
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.
Biochemistry
Biosynthesis
Prostaglandins are found in most tissues and organs. They are
biosynthesis by almost all nucleated cells. They are
autocrine and
paracrine lipid mediators that act upon
,
endothelium,
uterus and
. They are synthesized in the cell from the
fatty acid arachidonic acid.
Arachidonic acid is created from diacylglycerol via phospholipase-A2, then brought to either the Cyclooxygenase or the Lipoxygenase. The cyclooxygenase pathway produces thromboxane, prostacyclin and prostaglandin D, E and F.
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 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
(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 synthase
Prostaglandin E
2 (PGE
2) — the most abundant prostaglandin
— is generated from the action of prostaglandin E synthases on prostaglandin H
2 (prostaglandin H2, PGH
2). 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 PGE
2.
Other terminal prostaglandin synthases
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 PGD
2 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 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 hormones
-
act on thermoregulatory center of hypothalamus to produce fever
-
increase mating behaviors in goldfish
-
cause the uterus to contract
-
prevent gastrointestinal tract from self-digesting, contributing to its mucosal defence in multifactorial way.
Types
The following is a comparison of different types of prostaglandin, including
prostacyclin (prostacyclin; PGI
2), prostaglandin D
2 (PGD
2), prostaglandin E
2 (PGE
2), and prostaglandin F
2α (PGF
2α).
|
|
| PGI2 | IP | Gs protein | |
| PGD2 | PTGDR (DP1) and CRTH2 (DP2) | GPCR |
-
produced by mast cells; recruits Th2 cells, eosinophils, and basophils
-
In 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 | Gq protein | |
| EP2 | Gs protein | |
| EP3 | Gi protein |
-
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)
-
↑ autonomous ns neurotransmitters
-
↑ platelet response to their agonists
|
| EP4 | Gs protein |
-
hyperalgesia
[
]
-
Fever
-
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)
-
↓ stomach acid secretion
-
↑ stomach mucus secretion
-
Prostate cancer (↑ EP4 expression)
-
↑ corneal neovascularization
-
↑ chohlea auditory brain stem response
|
| PGF2α | FP | Gq protein |
-
uterus contraction
-
bronchoconstriction
-
urinary bladder contractions
-
vasoconstriction in cerebral circulation
|
Role in pharmacology
Inhibition
Examples of prostaglandin antagonists are:
-
(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.
Clinical uses
Synthetic prostaglandins are used:
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
-
Oxaprostaglandin, a type of prostaglandin
-
, a chemically related class of physiologically active substances
Notes
External links
