Cyclopentenone prostaglandins

Cyclopentenone prostaglandins are a subset of

• PGD2 is a 20 carbon
  electrophilic
  center.
• PGJ2 undergoes a spontaneous isomerization reaction in which the carbon 13,14 double bound shifts to the carbon 12,13 position to become Δ12-PGJ2 with a second electrophilic center site established at carbon 13.
• Δ12-PGJ2 undergoes a spontaneous dehydration reaction across its 15-hydroxyl-carbon 14 region to form a new double bound between carbons 14 and 15 thereby becoming 15-deoxy-Δ12,14-PGJ2 with retained electrophilic sites at carbons 9 and 13. Carbon 9 is more electrophilic than carbon 13 and therefore is more active than carbon 9 in forming covalent bonds with other molecules.

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^[2]

The

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.[1]^[2]

Mechanisms of action

G protein coupled receptors

The PGJ2 series of cyclopentenone PGs bind to and activate the

• IKK-β subunit of
  IkB kinase) to induce the transcription of genes, many of which contribute to regulating inflammatory responses.^[1] 15-deoxy-Δ12,14-PGJ2 forms an adduct with the IKK-β subunit of IκB kinase thereby inhibiting the kinases activity thereby promoting the entry of NFκB into the nucleus and stimulating the transcription of more than 15O proteins many of which regulate inflammatory responses. The net effect of this inhibition is to inhibit and/or refers inflammation.^[1][10][11]
• Nrf2 by proteasomes thereby inhibiting this transcription factor from entering the nucleus and stimulating the transcription of numerous genes that for diverse antioxidant proteins such as HMOX1 which encodes the carbon monoxide-forming and anti-inflammatory protein, HO-1 (see Carbon monoxide#Chemistry and Carbon monoxide#Physiology). 15-Deoxy-Δ12,14-PGJ2 forms adducts with KEAP1 cysteines 273 and 288 thereby blocking its ability to suppress activation of Nrf2's induction of antioxidant proteins.^[1][11] The ability of cyclopentenone prostaglandins to promote the transcription of Nrf2-dependent genes appears critical to their anti-inflammatory actions.^[8]
• TNFα, to sequester in cellular stress granules. The inhibition of protein translation can trigger programmed cell death responses while the sequestration of TRAF2 may suppress inflammatory responses. PGA1 has similar although less potent effects on protein translation and TRAF2 sequestration and therefore may also form an adduct with, and thereby inactivate, eIF4a.^[1][12]
• UCHL1: PGA1, Δ12-PGJ2, and 15-deoxy-Δ12,14-PGJ2 form adducts with the UCHL1 (Ubiquitin carboxy-terminal hydrolase L1), a protein that is found to be deposited as aggregate in the pathologically involved tissues of Parkinson's disease and well as other neurodegenerative diseases. In further studies, 15-deoxy-Δ12,14-PGJ2 was found to trigger Uch-L1 aggregate formation and suggested that this reaction may contribute to the development and/or progression of these diseases.^[9][13]
• H-Ras: 15-Deoxy-Δ12,14-PGJ2 forms a covalent bond with cysteine 184 on H-ras thereby activating this signaling protein and promoting the proliferation of cells.^[14]
• heart attack in a rat model.^[15]

Acting by inhibiting or stimulating the signaling pathways cited in the previous section, the cyclopentenone prostaglandins, principally 15-deoxy-Δ12,14-PGJ2, Δ12-PGJ2, PGJ2 and, in fewer studies, PGA2 and PGA1 have been shown to inhibit the function and/or survival of various pro-inflammatory, neurological, and other cell types.[1]^[2][9] The three PGJ2 cyclopentenone prostaglandins induce apoptosis in rodent cultured neuron cells by a mechanism that involves inhibiting the Phosphoinositide 3-kinase signaling pathway; this inhibition is independent of their ability to activate PPARγ or their prostaglandin DP2 receptor.^[9][16]

Animal Studies

15-deoxy-Δ12,14-PGJ2, Δ12-PGJ2, PGJ2 and, in fewer studies, PGA2 and PGA1 inhibit the inflammatory response and tissue damage that follow experimentally-induced pancreatitis; glomerulonephritis; arthritis; spinal cord, brain, and lung injury; injury due to ischemia in the heart, brain, kidney, and gut; and stress-induced central nervous system trauma.^[2]

Rat