Prostaglandins Proteins

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Prostaglandins Proteins

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Prostaglandins Proteins Background

Prostaglandins were discovered in 1930s by von Euler US (von Euler 1936), who found that a substance from seminal fluid increases uterine constrictions in rabbit, dilates blood vessels in frog and reduces blood pressure in rabbit, cat and dog. This substance was named prostaglandin because it was originally thought to be secreted by the prostate gland.

Prostaglandins (PG) are hormonally active oxygenated fatty acids that are formed within living cells in several enzymatically regulated reactions. Arachidonic acid is the major precursor of prostaglandin biosynthesis that is released from cell-membrane phospholipids via hydrolysis of ester bonds mediated by phospholipase A2 (PLA2). The PLA2-derived arachidonate undergoes the ratelimiting step in prostaglandin biosynthesis catalyzed by prostaglandin synthases (PTGS) that exhibits two distinct but complementary enzymatic activities, including cyclooxygenase and peroxidase. Arachidonate is first oxygenated by cyclooxygenase into prostaglandin G2 and then reduced by peroxidase to unstable prostaglandin H2 (PGH2). PGH2 is sequentially metabolized to five primary active prostaglandins, including prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), prostaglandin F2α (PGF2α), prostacyclin (PGI2) and thromboxane A2 (TxA2) via cell-specific prostaglandin isomerases and synthases. Levels of PGE2 and PGF2α can be locally modulated by prostaglandin 9-ketoreductase (CBR) that converts PGE2 to PGF2α. Finally, the half-life of PG within cells is regulated by 15-hydroxyprostaglandin dehydrogenase (HPGD) that converts PG into their biologically inactive 15-hydroxy metabolites.

Prostaglandin synthases (PTGS) are rate-limiting enzymes in prostaglandin biosynthesis and exist in two isoforms, PTGS1 and PTGS2, both encoded by distinct genes. PTGS1 is expressed at relatively constant level in most tissues, perhaps, due to few cis-acting response elements and no TATA box in the 5’ flanking region. By contrast, PTGS2 can be induced by several cytokines, growth factors and mechanical stress. Indeed, PTGS2 promoter region contains numerous regulatory elements, including CCAAT motif, two AP- 2 (activator protein-2) sites, three Sp1 sites, two NFƙβ sites, a cAMP response element and a TATA box. Immunoreactive PTGS1 and PTGS2 proteins are located in the endoplasmic reticulum and nuclear envelope, but PTGS2 is more abundant in the nuclear envelope. PTGS1 and PTGS2 share high similarity with respect to the primary structure of the active site and kinetic properties. However, there are differences between PTGS1 and PTGS2 that have important pharmacological and biological consequences.

PTGS2 competes more effectively for newly released arachidonate when both isoenzymes are co-expressed in the same cell because PTGS1 exhibits negative allosterism at low arachidonate concentrations. The cyclooxygenase active site of PTGS2 is approximately 20% larger than that of PTGS1, which has been exploited in developing PTGS2–specific non-steroidal anti-inflammatory drugs (NSAIDs). Currently, modern NSAIDs compete with arachidonate for binding to the cyclooxygenase active site of PTGS2 in a time-dependent and reversible manner. Modern NSAIDs include NS-398, DuP-697, meloxicam, SC52125 and L-745-337. Further, there is a number of NSAIDs that exhibit intermediate inhibitory activity towards both PTGS isoforms, such as indomethacin, flurbiprofen and meclofenamate. Of particular note, aspirin causes irreversible inhibition of PTGS isoforms by covalent modification of serine 530, which then protrudes into the cyclooxygenase active site and interferes with arachidonate binding. Collectively, presented information indicate that PG biosynthesis is complex process mediated by multiple enzymes, and that PG production in vivo can be altered by pharmacological agents.


Prostaglandin Receptors and Signaling

Prostaglandins elicit divert cellular responses by interacting with cell surface G-protein coupled receptors or with nuclear receptors. These receptors have been named as PTGER1–4, PTGFR, PTGDR, PTGIR and PTGTR for PGE2, PGF2α, PGD2, PGI2 and TxA2, respectively. In addition, 15ΔPGJ2, a PGD2 metabolite, and PGI2 act via nuclear peroxisome proliferator activated receptor gamma (PPARG) and delta PPARD, respectively.

PGE2 can activate multiple PTGER receptor subtypes that activate diverse signaling pathways. PTGER1 is coupled to phospholipase C (PLC), generating two second messengers, inositol trisphosphate (IP3), which is involved in the liberation of intracellular calcium (Ca2+), and diacylglycerol (DAG), an activator of the protein kinase C (PKC) signaling pathway. PTGER2 and PTGER4 are coupled to adenylate cyclase (AC) and generate cyclic adenosine monophosphate (cAMP) that activates the protein kinase A (PKA) signaling pathway, but can also regulate genes expression via β-catenin-mediated Wnt signaling. The signaling of PTGER3 is more complex because of the multiple isoforms with a wide range of actions from inhibition of AC via G protein Gi to activation of the PKA pathway via Gs and activation of the PLC pathway via Gq. PGF2α activates PTGFR receptor and induces PLC signaling pathway. PGI2 binding to PTGIR receptor stimulates primarily AC/cAMP/PKA signaling but activation of PLC/Ca2+/PKC pathway is also evident. Activation of PTGDR increases cAMP and activates PKA pathway. There are two splice variants of thromboxane receptor (TBXARα and TBXARβ) and both, upon ligand binding, induce the PLC-and PKA-mediated signaling responses. Of note, isoforms of PTGTR have opposing effects on AC activity because PTGTRα inhibits while PTGTRβ increases cAMP synthesis. In addition, binding of PGI2 to PPARD and 15ΔPGJ2 to PPARG engenders formation of heterodimers with the retinoic acid X receptor (RXR) that translocate to the nucleus and interact with PPAR response elements to enhance or inhibit transcription of target genes.

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