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Cyclopentenone prostaglandins
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Cyclopentenone prostaglandins
Cyclopentenone prostaglandins are a subset of prostaglandins (PGs) or prostanoids (see Eicosanoid §§ Classic eicosanoids and Nonclassic eicosanoids) that has 15-deoxy-Δ12,14-prostaglandin J2 (15-d-Δ12,14-PGJ2), Δ12-PGJ2, and PGJ2 as its most prominent members but also including PGA2, PGA1, and, while not classified as such, other PGs. 15-d-Δ12,14-PGJ2, Δ12-PGJ2, and PGJ2 share a common mono-unsaturated cyclopentenone structure as well as a set of similar biological activities including the ability to suppress inflammation responses and the growth as well as survival of cells, particularly those of cancerous or neurological origin. Consequently, these three cyclopentenone-PGs and the two epoxyisoprostanes are suggested to be models for the development of novel anti-inflammatory and anti-cancer drugs. The cyclopenentone prostaglandins are structurally and functionally related to a subset of isoprostanes viz., two cyclopentenone isoprostanes, 5,6-epoxyisoprostane E2 and 5,6-epoxisoprostane A2.
In cells, COX-1 and COX-2 metabolize arachidonic acid to PGH2 which is then converted to PGE2 by any one of three isozymes, PTGES, PTGES2, and PTGES3 or, alternatively, to PGD2 by either of two enzymes, a glutathione-independent synthase termed lipocalin-type Prostaglandin D2 synthase (PTGDS or L-PGDS) and a glutathione-dependent hematopoietic-type H-PGDS or PTGDS2; the COX's also metabolizes dihomo-gamma-linolenic acid to PGH1 which is metabolized by one of the three PTGES isoenzymes to PGE1 (see Eicosanoid § Prostanoid pathways). PGE2, PGE1, and PGD2 undergo a dehydration reaction PGA2, PGA1, and PGJ2, respectively. PGD2 conversions form the most studied cyclopentenone PGs. These conversions are as follows:
PGE2 and PGE1 are 20 carbon metabolites of arachidonic acid and dihomo-γ-linolenic acid, respectively, with a double bond between carbons 13 and 14, a carbon-carbon bond between carbons 8 and 12 (which establishes their cyclopentanone structure), hydroxyl residues at carbons 11 and 15, and a ketol residue at carbon 9. They differ in that PGE2 has, while PGE1 lacks, a double bound between carbons 5 and 6. Both PGs undergo a dehydration reaction across their 11-hydroxyl-carbon 10 regions to form a new double bond between carbons 10 and 11 to become PGA2 and PGA1, respectively, with a cyclopentenone ring replacing the cyclopentanone rings or their precursors and a newly established electrophilic site at carbon 11. This electrophilic site is probably less electrophilic that the carbon 9 sites of Δ12-PGJ2 and 15-deoxy-Δ12-PGJ2
The cyclopentenone structures of PGA2, PGA1, PGJ2, Δ12-PGJ2, and 15-d-Δ12,14-PGJ2 possess α,β-unsaturated carbonyl groups (see α,β-Unsaturated carbonyl compounds) which serve to establish high levels of chemical reactivity at nearby carbons 9, 11, and/or 13. These carbons are electrophiles that readily form covalent bonds by acting as acceptors in Michael reactions to form covalent bonds with exposed nucleophile sites, particularly thiol residues, in diverse proteins. The reaction inactivates or reduces the activity of various functionally important target proteins and is one mechanism by which cyclopentenone PGs influence cell function.
All of the reactions undergone by the above cited PGs occur spontaneously (i.e. are enzyme-independent) in aqueous media. This biochemistry sets very important limitations on the study of the cyclopentenone PGs and to a lesser extent on PGE2, PGE1, and PGD2: a) detection of the cyclopentenone PGs in tissues may and has often reflected their formation during tissue preparation; b) detection of PGE2, PGE1, and PGD2 in tissues may be underestimated because of losses due to their conversion to cyclopentenone PGs; c) the activities, as studied in vitro or in vivo, of PGJ2 may reflect its conversion to Δ12-PGJ2 or 15-deoxy-Δ12,14-PGJ2, those of Δ12-PGJ2 may reflect its conversion to 15-deoxy-Δ12,14-PGJ2, and those of PGE2, PGE1, or PGD2 may reflect their conversion to any of the cyclopentenone PGs; and d) the attachment of these compounds, similar to that in other Michael reactions, is reversible and therefore may be underestimated or go undetected in studies.
The PGJ2 series of cyclopentenone PGs bind to and activate the G protein-coupled receptor, Prostaglandin DP2 receptor, with 15-deoxy-Δ12,14-PGJ2 and PDJ2 exhibiting potencies comparable to PGD2 (i.e. Ki equilibrium constants ~20-45 nanomolar) and Δ12-PGJ2 having 10-fold lesser potency, at least on mouse DP2 receptor. These PGJ2's also bind and activate a second G protein-coupled receptor, Prostaglandin DP1 receptor, but require high concentrations to do so; this activation is not considered physiological. DP2 and DP1 are G protein-coupled receptors, with the DP2 receptor coupled to Gi alpha subunit-dependent depression of cellular cAMP levels and causing the potentiation cell injury in neural tissue cultures and with the DP1 receptor coupled to Gs alpha subunit-dependent increases in cellular cAMP levels and the suppression of cell injury in neural tissue cultures.
PGD2, PGJ2, Δ12-PGJ2, and 15-deoxy-Δ12,14-PGJ2 activate the transcription factor, PPARγ, with 15-deoxy-Δ12,14-PGJ2 being the most potent of the four PGs. Accordingly, further studies have focused on 15-deoxy-Δ12,14-PGJ2. This PG directly binds with and activates PPARγ thereby inducing the transcription of genes containing the PPARγ response element. In consequence of this action, 15-deoxy-Δ12,14-PGJ2 causes cells to engage the pathway of Programmed cell death termed Paraptosis, a form of cell suicide that differs from apoptosis by involving cytoplasmic vacuolization and mitochondrial swelling rather than plasma membrane blebbing, nuclear condensation and fragmentation, and apoptotic bodies. 15-Deoxy-Δ12,14-PGG2's activation of PPARγ and the induction of paraptosis is responsible for inhibiting the growth of cultured human breast, colon, prostate, and perhaps other cancer cell lines. Studies indicated the anti-inflammatory actions of the cyclopentenone prostaglandins show no or little dependency on their PPARγ-activating capacity.
The electrophilic centers in the cyclopentenone ring of cyclopentenone PGs form covalent bonds with exposed nucleophilic centers, primarily the sulfur atom in the thiol residues of cysteine residues. Proteomics analyses have detected 368 proteins that are covalently modified by 15-deoxy-Δ12,14-PGJ2; these include numerous plasma membrane, cell signaling, glycolytic enzyme, cytoskeletal, and Chaperone (protein)s. This results in the addition of the PG to the protein by a Michael addition reaction and important modifications in the activity of target proteins that have key functions in cells. 15-Deoxy-Δ12,14-PGJ2 shows the greatest reactivity and has been the focus of these studies. Proteomic studies indicate that PGJs form adducts with over 358 proteins. This adduct formation has been studied with several functionally and/or clinically important proteins such as:
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Cyclopentenone prostaglandins
Cyclopentenone prostaglandins are a subset of prostaglandins (PGs) or prostanoids (see Eicosanoid §§ Classic eicosanoids and Nonclassic eicosanoids) that has 15-deoxy-Δ12,14-prostaglandin J2 (15-d-Δ12,14-PGJ2), Δ12-PGJ2, and PGJ2 as its most prominent members but also including PGA2, PGA1, and, while not classified as such, other PGs. 15-d-Δ12,14-PGJ2, Δ12-PGJ2, and PGJ2 share a common mono-unsaturated cyclopentenone structure as well as a set of similar biological activities including the ability to suppress inflammation responses and the growth as well as survival of cells, particularly those of cancerous or neurological origin. Consequently, these three cyclopentenone-PGs and the two epoxyisoprostanes are suggested to be models for the development of novel anti-inflammatory and anti-cancer drugs. The cyclopenentone prostaglandins are structurally and functionally related to a subset of isoprostanes viz., two cyclopentenone isoprostanes, 5,6-epoxyisoprostane E2 and 5,6-epoxisoprostane A2.
In cells, COX-1 and COX-2 metabolize arachidonic acid to PGH2 which is then converted to PGE2 by any one of three isozymes, PTGES, PTGES2, and PTGES3 or, alternatively, to PGD2 by either of two enzymes, a glutathione-independent synthase termed lipocalin-type Prostaglandin D2 synthase (PTGDS or L-PGDS) and a glutathione-dependent hematopoietic-type H-PGDS or PTGDS2; the COX's also metabolizes dihomo-gamma-linolenic acid to PGH1 which is metabolized by one of the three PTGES isoenzymes to PGE1 (see Eicosanoid § Prostanoid pathways). PGE2, PGE1, and PGD2 undergo a dehydration reaction PGA2, PGA1, and PGJ2, respectively. PGD2 conversions form the most studied cyclopentenone PGs. These conversions are as follows:
PGE2 and PGE1 are 20 carbon metabolites of arachidonic acid and dihomo-γ-linolenic acid, respectively, with a double bond between carbons 13 and 14, a carbon-carbon bond between carbons 8 and 12 (which establishes their cyclopentanone structure), hydroxyl residues at carbons 11 and 15, and a ketol residue at carbon 9. They differ in that PGE2 has, while PGE1 lacks, a double bound between carbons 5 and 6. Both PGs undergo a dehydration reaction across their 11-hydroxyl-carbon 10 regions to form a new double bond between carbons 10 and 11 to become PGA2 and PGA1, respectively, with a cyclopentenone ring replacing the cyclopentanone rings or their precursors and a newly established electrophilic site at carbon 11. This electrophilic site is probably less electrophilic that the carbon 9 sites of Δ12-PGJ2 and 15-deoxy-Δ12-PGJ2
The cyclopentenone structures of PGA2, PGA1, PGJ2, Δ12-PGJ2, and 15-d-Δ12,14-PGJ2 possess α,β-unsaturated carbonyl groups (see α,β-Unsaturated carbonyl compounds) which serve to establish high levels of chemical reactivity at nearby carbons 9, 11, and/or 13. These carbons are electrophiles that readily form covalent bonds by acting as acceptors in Michael reactions to form covalent bonds with exposed nucleophile sites, particularly thiol residues, in diverse proteins. The reaction inactivates or reduces the activity of various functionally important target proteins and is one mechanism by which cyclopentenone PGs influence cell function.
All of the reactions undergone by the above cited PGs occur spontaneously (i.e. are enzyme-independent) in aqueous media. This biochemistry sets very important limitations on the study of the cyclopentenone PGs and to a lesser extent on PGE2, PGE1, and PGD2: a) detection of the cyclopentenone PGs in tissues may and has often reflected their formation during tissue preparation; b) detection of PGE2, PGE1, and PGD2 in tissues may be underestimated because of losses due to their conversion to cyclopentenone PGs; c) the activities, as studied in vitro or in vivo, of PGJ2 may reflect its conversion to Δ12-PGJ2 or 15-deoxy-Δ12,14-PGJ2, those of Δ12-PGJ2 may reflect its conversion to 15-deoxy-Δ12,14-PGJ2, and those of PGE2, PGE1, or PGD2 may reflect their conversion to any of the cyclopentenone PGs; and d) the attachment of these compounds, similar to that in other Michael reactions, is reversible and therefore may be underestimated or go undetected in studies.
The PGJ2 series of cyclopentenone PGs bind to and activate the G protein-coupled receptor, Prostaglandin DP2 receptor, with 15-deoxy-Δ12,14-PGJ2 and PDJ2 exhibiting potencies comparable to PGD2 (i.e. Ki equilibrium constants ~20-45 nanomolar) and Δ12-PGJ2 having 10-fold lesser potency, at least on mouse DP2 receptor. These PGJ2's also bind and activate a second G protein-coupled receptor, Prostaglandin DP1 receptor, but require high concentrations to do so; this activation is not considered physiological. DP2 and DP1 are G protein-coupled receptors, with the DP2 receptor coupled to Gi alpha subunit-dependent depression of cellular cAMP levels and causing the potentiation cell injury in neural tissue cultures and with the DP1 receptor coupled to Gs alpha subunit-dependent increases in cellular cAMP levels and the suppression of cell injury in neural tissue cultures.
PGD2, PGJ2, Δ12-PGJ2, and 15-deoxy-Δ12,14-PGJ2 activate the transcription factor, PPARγ, with 15-deoxy-Δ12,14-PGJ2 being the most potent of the four PGs. Accordingly, further studies have focused on 15-deoxy-Δ12,14-PGJ2. This PG directly binds with and activates PPARγ thereby inducing the transcription of genes containing the PPARγ response element. In consequence of this action, 15-deoxy-Δ12,14-PGJ2 causes cells to engage the pathway of Programmed cell death termed Paraptosis, a form of cell suicide that differs from apoptosis by involving cytoplasmic vacuolization and mitochondrial swelling rather than plasma membrane blebbing, nuclear condensation and fragmentation, and apoptotic bodies. 15-Deoxy-Δ12,14-PGG2's activation of PPARγ and the induction of paraptosis is responsible for inhibiting the growth of cultured human breast, colon, prostate, and perhaps other cancer cell lines. Studies indicated the anti-inflammatory actions of the cyclopentenone prostaglandins show no or little dependency on their PPARγ-activating capacity.
The electrophilic centers in the cyclopentenone ring of cyclopentenone PGs form covalent bonds with exposed nucleophilic centers, primarily the sulfur atom in the thiol residues of cysteine residues. Proteomics analyses have detected 368 proteins that are covalently modified by 15-deoxy-Δ12,14-PGJ2; these include numerous plasma membrane, cell signaling, glycolytic enzyme, cytoskeletal, and Chaperone (protein)s. This results in the addition of the PG to the protein by a Michael addition reaction and important modifications in the activity of target proteins that have key functions in cells. 15-Deoxy-Δ12,14-PGJ2 shows the greatest reactivity and has been the focus of these studies. Proteomic studies indicate that PGJs form adducts with over 358 proteins. This adduct formation has been studied with several functionally and/or clinically important proteins such as: