Prostaglandins ( PG ) are a group of physiologically active lipid compounds called eicosanoids 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 . 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.
54-483: 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
108-402: A bound ligand is said to display "constitutive activity". The constitutive activity of a receptor may be blocked by an inverse agonist . The anti-obesity drugs rimonabant and taranabant are inverse agonists at the cannabinoid CB1 receptor and though they produced significant weight loss, both were withdrawn owing to a high incidence of depression and anxiety, which are believed to relate to
162-479: A continuous passage throughout the protein molecule. The active site iron is coordinated by N of three conserved His residues and one oxygen of the C-terminal carboxyl group. In addition, in soybean enzymes the side chain oxygen of asparagine is weakly associated with the iron. In rabbit lipoxygenase, this Asn residue is replaced with His which coordinates the iron via N atom. Thus, the coordination number of iron
216-489: A hydroxy group thereby forming hydroxylated (—OH) polyunsaturated fatty acids such as the hydroxyeicosatetraenoic acids and HODEs (i.e. hydroxyoctadecaenoic acids). Polyunsaturated fatty acids that serve as substrates for one or more of the lipoxygenases include the omega 6 fatty acids , arachidonic acid , linoleic acid , dihomo-γ-linolenic acid , and adrenic acid ; the omega-3 fatty acids , eicosapentaenoic acid , docosahexaenoic acid , and alpha-linolenic acid ; and
270-500: A key enzyme in the formation of PGE 2 . 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 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
324-419: A lipoxygenase genetic structure, possesses relatively little dioxygenation activity; rather its primary activity appears to be as an isomerase that catalyzes the conversion of hydroperoxy unsaturated fatty acids to their 1,5- epoxide , hydroxyl derivatives. Lipoxygenases are found in eukaryotes (plants, fungi, animals, protists); while the third domain of terrestrial life, the archaea , possesses proteins with
378-458: A major C-terminal catalytic domain (see Pfam database), which contains the active site . In both plant and mammalian enzymes, the N-terminal domain contains an eight-stranded antiparallel β-barrel, but in the soybean lipoxygenases this domain is significantly larger than in the rabbit enzyme. The plant lipoxygenases can be enzymatically cleaved into two fragments which stay tightly associated while
432-520: A number of lipoxygenases isozymes are involved in the metabolism of eicosanoids (such as prostaglandins , leukotrienes and nonclassic eicosanoids ). Sequence data is available for the following lipoxygenases: Plants express a variety of cytosolic lipoxygenases ( EC 1.13.11.12 ; InterPro : IPR001246 ) as well as what seems to be a chloroplast isozyme. Plant lipoxygenase in conjunction with hydroperoxide lyases are responsible for many fragrances and other signalling compounds. One example
486-557: A particular structure. This has been analogously compared to how locks will only accept specifically shaped keys . When a ligand binds to a corresponding receptor, it activates or inhibits the receptor's associated biochemical pathway, which may also be highly specialised. Receptor proteins can be also classified by the property of the ligands. Such classifications include chemoreceptors , mechanoreceptors , gravitropic receptors , photoreceptors , magnetoreceptors and gasoreceptors. The structures of receptors are very diverse and include
540-415: A receptor and produce physiological responses such as change in the electrical activity of a cell . For example, GABA , an inhibitory neurotransmitter , inhibits electrical activity of neurons by binding to GABA A receptors . There are three main ways the action of the receptor can be classified: relay of signal, amplification, or integration. Relaying sends the signal onward, amplification increases
594-410: A receptor is its binding affinity, which is inversely related to the dissociation constant K d . A good fit corresponds with high affinity and low K d . The final biological response (e.g. second messenger cascade , muscle-contraction), is only achieved after a significant number of receptors are activated. Affinity is a measure of the tendency of a ligand to bind to its receptor. Efficacy
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#1733085531512648-553: A relatively large C-terminal catalytic domain which contains the non-heme iron critical for the enzymes' catalytic activity. Most of the lipoxygenases (exception, ALOXE3) catalyze the reaction Polyunsaturated fatty acid + O 2 → fatty acid hydroperoxide in four steps: The (—OO ) residue may then be protonated to form a hydroperoxide group (—OOH) and further metabolized by the lipoxygenase to e.g. leukotrienes , hepoxilins , and various specialized pro-resolving mediators , or reduced by ubiquitous cellular glutathione peroxidases to
702-458: A slight (~20%) amino acid sequence similarity to lipoxygenases, these proteins lack iron-binding residues and therefore are not projected to possess lipoxygenase activity. Based on detailed analyses of 15-lipoxygenase 1 and stabilized 5-lipoxygenase, lipoxygenase structures consist of a 15 kilodalton N-terminal beta barrel domain, a small (e.g. ~0.6 kilodalton) linker inter-domain (see Protein domain § Domains and protein flexibility ), and
756-440: A stretch of 40 amino acids. This region contains two of the three zinc-ligands; the other histidines have been shown to be important for the activity of lipoxygenases. The two long central helices cross at the active site; both helices include internal stretches of π-helix that provide three histidine (His) ligands to the active site iron. Two cavities in the major domain of soybean lipoxygenase-1 (cavities I and II) extend from
810-526: Is cis-3-hexenal , the odor of freshly cut grass . With the exception of the gene encoding 5-LOX ( ALOX5 ), which is located on chromosome 10q11.2, all six human LOX genes are located on chromosome 17.p13 and code for a single chain protein of 75–81 kilodaltons that consists of 662–711 amino acids. Mammalian LOX genes contain 14 ( ALOX5 , ALOX12 , ALOX15 , ALOX15B ) or 15 ( ALOX12B , ALOXE3 ) exons with exon/ intron boundaries at highly conserved positions. The 6 human lipoxygenases along with some of
864-537: Is a common model to examine lipoxygenase function. However, there are some key differences between the lipoxygenases between mice and men that make extrapolations from mice studies to humans difficult. In contrast to the 6 functional lipoxygenases in humans, mice have 7 functional lipoxygenases and some of the latter have different metabolic activities than their human orthologs . In particular, mouse Alox15, unlike human ALOX15, metabolizes arachidonic acid mainly to 12-HpETE and mouse Alox15b, in contrast to human ALOX15b,
918-464: Is a locally acting feedback mechanism. The ligands for receptors are as diverse as their receptors. GPCRs (7TMs) are a particularly vast family, with at least 810 members. There are also LGICs for at least a dozen endogenous ligands, and many more receptors possible through different subunit compositions. Some common examples of ligands and receptors include: Some example ionotropic (LGIC) and metabotropic (specifically, GPCRs) receptors are shown in
972-579: Is as follows: 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 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 synthases have been identified. To date, microsomal (named as misoprostol ) prostaglandin E synthase-1 emerges as
1026-426: Is either five or six, with a hydroxyl or water ligand to a hexacoordinate iron. Details about the active site feature of lipoxygenase were revealed in the structure of porcine leukocyte 12-lipoxygenase catalytic domain complex In the 3D structure, the substrate analog inhibitor occupied a U-shaped channel open adjacent to the iron site. This channel could accommodate arachidonic acid without much computation, defining
1080-505: Is not responding sufficiently to the hormone. The main receptors in the immune system are pattern recognition receptors (PRRs), toll-like receptors (TLRs), killer activated and killer inhibitor receptors (KARs and KIRs), complement receptors , Fc receptors , B cell receptors and T cell receptors . Lipoxygenase Lipoxygenases ( EC 1.13.11.- ) ( LOX ) are a family of (non- heme ) iron -containing enzymes , more specifically oxidative enzymes , most of which catalyze
1134-414: Is primarily an 8-lipoxygenase, metabolizing arachdionic acid to 8-HpETE; there is no comparable 8-HpETE-forming lipoxygenase in humans. There are several lipoxygenase structures known including: soybean lipoxygenase L1 and L3, coral 8-lipoxygenase, human 5-lipoxygenase, rabbit 15-lipoxygenase and porcine leukocyte 12-lipoxygenase catalytic domain. The protein consists of a small N-terminal PLAT domain and
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#17330855315121188-411: Is referred to as its endogenous ligand. E.g. the endogenous ligand for the nicotinic acetylcholine receptor is acetylcholine , but it can also be activated by nicotine and blocked by curare . Receptors of a particular type are linked to specific cellular biochemical pathways that correspond to the signal. While numerous receptors are found in most cells, each receptor will only bind with ligands of
1242-513: Is shown below. It involves a Diels–Alder reaction which establishes the relative stereochemistry of three contiguous stereocenters on the prostaglandin cyclopentane core. Cold exposure and IUDs may ↑ prostaglandin production. Receptor (biochemistry) In biochemistry and pharmacology , receptors are chemical structures, composed of protein , that receive and transduce signals that may be integrated into biological systems. These signals are typically chemical messengers which bind to
1296-411: Is the measure of the bound ligand to activate its receptor. Not every ligand that binds to a receptor also activates that receptor. The following classes of ligands exist: Note that the idea of receptor agonism and antagonism only refers to the interaction between receptors and ligands and not to their biological effects. A receptor which is capable of producing a biological response in the absence of
1350-530: The dioxygenation of polyunsaturated fatty acids in lipids containing a cis,cis-1,4- pentadiene into cell signaling agents that serve diverse roles as autocrine signals that regulate the function of their parent cells, paracrine signals that regulate the function of nearby cells, and endocrine signals that regulate the function of distant cells. The lipoxygenases are related to each other based upon their similar genetic structure and dioxygenation activity. However, one lipoxygenase, ALOXE3, while having
1404-458: 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. Prostaglandins are produced following the sequential oxygenation of arachidonic acid, DGLA or EPA by cyclooxygenases (COX-1 and COX-2) and terminal prostaglandin synthases. The classic dogma
1458-431: The omega-9 fatty acid , mead acid . Certain types of the lipoxygenases, e.g. human and murine 15-lipoxygenase 1, 12-lipoxygenase B, and ALOXE3, are capable of metabolizing fatty acid substrates that are constituents of phospholipids, cholesterol esters, or complex lipids of the skin. Most lipoxygenases catalyze the formation of initially formed hydroperoxy products that have S chirality . Exceptions to this rule include
1512-422: The receptor theory of pharmacology stated that a drug's effect is directly proportional to the number of receptors that are occupied. Furthermore, a drug effect ceases as a drug-receptor complex dissociates. Ariëns & Stephenson introduced the terms "affinity" & "efficacy" to describe the action of ligands bound to receptors. In contrast to the accepted Occupation Theory , Rate Theory proposes that
1566-448: The 12R-lipoxygenases of humans and other mammals (see below). Lipoxygenases depend on the availability of their polyunsaturated fatty acid substrates which, particularly in mammalian cells, is normally maintained at extremely low levels. In general, various phospholipase A2s and diacylglycerol lipases are activated during cell stimulation, proceed to release these fatty acids from their storage sites, and thereby are key regulators in
1620-443: The activation of receptors is directly proportional to the total number of encounters of a drug with its receptors per unit time. Pharmacological activity is directly proportional to the rates of dissociation and association, not the number of receptors occupied: As a drug approaches a receptor, the receptor alters the conformation of its binding site to produce drug—receptor complex. In some receptor systems (e.g. acetylcholine at
1674-488: The cell from the fatty acid arachidonic acid . Arachidonic acid is created from diacylglycerol via phospholipase-A 2 , 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 . Prostaglandins were originally believed to leave
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1728-405: The cell, and include cytoplasmic receptors and nuclear receptors . A molecule that binds to a receptor is called a ligand and can be a protein, peptide (short protein), or another small molecule , such as a neurotransmitter , hormone , pharmaceutical drug, toxin, calcium ion or parts of the outside of a virus or microbe. An endogenously produced substance that binds to a particular receptor
1782-411: The cell. 4 examples of intracellular LGIC are shown below: Many genetic disorders involve hereditary defects in receptor genes. Often, it is hard to determine whether the receptor is nonfunctional or the hormone is produced at decreased level; this gives rise to the "pseudo-hypo-" group of endocrine disorders , where there appears to be a decreased hormonal level while in fact it is the receptor that
1836-401: 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
1890-403: The dynamic behavior of receptors have been used to gain understanding of their mechanisms of action. Ligand binding is an equilibrium process. Ligands bind to receptors and dissociate from them according to the law of mass action in the following equation, for a ligand L and receptor, R. The brackets around chemical species denote their concentrations. One measure of how well a molecule fits
1944-399: The effect of a single ligand , and integration allows the signal to be incorporated into another biochemical pathway. Receptor proteins can be classified by their location. Cell surface receptors , also known as transmembrane receptors, include ligand-gated ion channels , G protein-coupled receptors , and enzyme-linked hormone receptors . Intracellular receptors are those found inside
1998-475: The enzyme remains active; separation of the two domains leads to loss of catalytic activity. The C-terminal (catalytic) domain consists of 18-22 helices and one (in rabbit enzyme) or two (in soybean enzymes) antiparallel β-sheets at the opposite end from the N-terminal β-barrel. The iron atom in lipoxygenases is bound by four ligands, three of which are histidine residues. Six histidines are conserved in all lipoxygenase sequences, five of them are found clustered in
2052-507: 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 physiologist Ulf von Euler , and independently by the Irish-English physiologist Maurice Walter Goldblatt (1895–1967). Prostaglandins were believed to be part of
2106-414: The following major categories, among others: Membrane receptors may be isolated from cell membranes by complex extraction procedures using solvents , detergents , and/or affinity purification . The structures and actions of receptors may be studied by using biophysical methods such as X-ray crystallography , NMR , circular dichroism , and dual polarisation interferometry . Computer simulations of
2160-495: 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 ). 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
2214-540: The formation of lipoxygenase-dependent metabolites. In addition, cells, when so activated, may transfer their released polyunsaturated fatty acids to adjacent or nearby cells which then metabolize them through their lipoxygenase pathways in a process termed transcellular metabolism or transcellular biosynthesis. These enzymes are most common in plants where they may be involved in a number of diverse aspects of plant physiology including growth and development, pest resistance, and senescence or responses to wounding. In mammals
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2268-424: 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
2322-577: The inhibition of the constitutive activity of the cannabinoid receptor. The GABA A receptor has constitutive activity and conducts some basal current in the absence of an agonist. This allows beta carboline to act as an inverse agonist and reduce the current below basal levels. Mutations in receptors that result in increased constitutive activity underlie some inherited diseases, such as precocious puberty (due to mutations in luteinizing hormone receptors) and hyperthyroidism (due to mutations in thyroid-stimulating hormone receptors). Early forms of
2376-914: The major products that they make, as well as some of their associations with genetic diseases, are as follows: Two lipoxygenases may act in series to make di-hydroxy or tri-hydroxy products that have activities quite different than either lipoxyenases' products. This serial metabolism may occur in different cell types that express only one of the two lipoxygenases in a process termed transcellular metabolism. For example, ALOX5 and ALOX15 or, alternatively, ALOX5 and ALOX12 can act serially to metabolize arachidonic acid into lipoxins (see 15-Hydroxyeicosatetraenoic acid §§ Further metabolism and Activities of 15(S)-HpETE, 15(S)-HETE, 15(R)-HpETE, 15(R)-HETE, and 15-oxo-ETE and Lipoxin § Synthesis ) while ALOX15 and possibly ALOX15B can act with ALOX5 to metabolize eicosapentaenoic acid to resolvin D's (see Resolvin § Biochemistry and production ). The mouse
2430-472: The neuromuscular junction in smooth muscle), agonists are able to elicit maximal response at very low levels of receptor occupancy (<1%). Thus, that system has spare receptors or a receptor reserve. This arrangement produces an economy of neurotransmitter production and release. Cells can increase ( upregulate ) or decrease ( downregulate ) the number of receptors to a given hormone or neurotransmitter to alter their sensitivity to different molecules. This
2484-473: 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 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
2538-596: 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: The following is a comparison of different types of prostaglandin, including prostaglandin I 2 (prostacyclin; PGI 2 ), prostaglandin D 2 (PGD 2 ), prostaglandin E 2 (PGE 2 ), and prostaglandin F 2α (PGF 2α ). Examples of prostaglandin antagonists are: Synthetic prostaglandins are used: The original synthesis of prostaglandins F2α and E2
2592-437: The substrate binding details for the lipoxygenase reaction. In addition, a plausible access channel, which intercepts the substrate binding channel and extended to the protein surface could be counted for the oxygen path. Soybean Lipoxygenase 1 exhibits the largest H/D kinetic isotope effect (KIE) on kcat (kH/kD) (81 near room temperature) so far reported for a biological system. Recently, an extremely elevated KIE of 540 to 730
2646-421: The surface to the active site. The funnel-shaped cavity I may function as a dioxygen channel; the long narrow cavity II is presumably a substrate pocket. The more compact mammalian enzyme contains only one boot-shaped cavity (cavity II). In soybean lipoxygenase-3 there is a third cavity which runs from the iron site to the interface of the β-barrel and catalytic domains. Cavity III, the iron site and cavity II form
2700-597: The table below. The chief neurotransmitters are glutamate and GABA; other neurotransmitters are neuromodulatory . This list is by no means exhaustive. Enzyme linked receptors include Receptor tyrosine kinases (RTKs), serine/threonine-specific protein kinase, as in bone morphogenetic protein and guanylate cyclase, as in atrial natriuretic factor receptor. Of the RTKs, 20 classes have been identified, with 58 different RTKs as members. Some examples are shown below: Receptors may be classed based on their mechanism or on their position in
2754-521: The type of ring structure, followed by a number indicating the number of double bonds in the hydrocarbon structure. For example, prostaglandin E 1 has the abbreviation PGE 1 and prostaglandin I 2 has the abbreviation PGI 2 . 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
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#17330855315122808-411: 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 (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
2862-577: 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. 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
2916-497: Was found in a double mutant Soybean Lipoxygenase 1. Because of the large magnitude of the KIE, Soybean Lipoxygenase 1 has served as the prototype for enzyme-catalyzed hydrogen-tunneling reactions. Human proteins expressed from the lipoxygenase family include ALOX12 , ALOX12B , ALOX15 , ALOX15B , ALOX5 , and ALOXE3 . While humans also possess the ALOX12P2 gene, which is an ortholog of
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