Implications of the Molecular Basis of Prostacyclin Biosynthesis and Signaling in Pharmaceutical Designs
University of Liège, Luik, Walloon, Belgium Current Pharmaceutical Design
(Impact Factor: 3.45).
02/2006; 12(8):925-41. DOI: 10.2174/138161206776055994
Prostacyclin (PGI(2)) is one of the major vascular protectors against thrombosis and vasoconstriction, caused by thromboxane A(2). Understanding the molecular mechanisms of PGI(2) biosynthesis and signaling is crucial to the development of therapeutic approaches to regulate PGI(2) functions. This review provides information regarding the most current advances in the findings of the molecular mechanisms for PGI(2) biosynthesis in the endoplasmic reticulum (ER) membrane through the coordination between PGI(2) synthase and its upstream enzymes, cyclooxygenase-1 (COX-1) or -2 (COX-2), and for PGI(2) signaling through its cell membrane receptors and nuclear peroxisome proliferator-activated receptors. The substrate presentation from the COXs to PGI(2) synthase and its cell membrane receptor/G protein coupling sites, as characterized by our group, are discussed in detail. The association between the regulation of the biosynthesis and signaling of PGI(2) with the pathophysiological processes of PGI(2)-related diseases is also discussed. The molecular knowledge of PGI(2) biosynthesis and signaling will help to design the next generation of drugs, specifically targeting the regulation of PGI(2) functions, which will undoubtedly provide advances in cardiovascular protection and the treatment of PGI(2)-related diseases.
Available from: Raymond N DuBois
- "These PG synthases include various isoforms of prostaglandin D 2 (PGD 2 ) synthases (PGDS) , prostaglandin E 2 (PGE 2 ) synthases (PGES)     , and prostaglandin F 2α (PGF 2α ) synthase (PGFS) . PGH 2 can also be synthesized into prostacyclin (PGI 2 ) by its own separate synthase   (PGIS) or thromboxane A 2 (TxA 2 ) by its synthase (TXS) . In the case of inflammatory and carcinogenic activity, increased expression of COX-2 and microsomal PGE synthase-1 (mPGES-1) both occur to amplify the accumulation of PGE 2 in tumors      . "
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ABSTRACT: Prostaglandins exert a profound influence over the adhesive, migratory, and invasive behavior of cells during the development and progression of cancer. Cyclooxygenase-2 (COX-2) and microsomal prostaglandin E(2) synthase-1 (mPGES-1) are upregulated in inflammation and cancer. This results in the production of prostaglandin E(2) (PGE(2)), which binds to and activates G-protein-coupled prostaglandin E(1-4) receptors (EP(1-4)). Selectively targeting the COX-2/mPGES-1/PGE(2)/EP(1-4) axis of the prostaglandin pathway can reduce the adhesion, migration, invasion, and angiogenesis. Once stimulated by prostaglandins, cadherin adhesive connections between epithelial or endothelial cells are lost. This enables cells to invade through the underlying basement membrane and extracellular matrix (ECM). Interactions with the ECM are mediated by cell surface integrins by "outside-in signaling" through Src and focal adhesion kinase (FAK) and/or "inside-out signaling" through talins and kindlins. Combining the use of COX-2/mPGES-1/PGE(2)/EP(1-4) axis-targeted molecules with those targeting cell surface adhesion receptors or their downstream signaling molecules may enhance cancer therapy.
International Journal of Cell Biology 02/2012; 2012(3):723419. DOI:10.1155/2012/723419
Available from: ncbi.nlm.nih.gov
- "In fact, the biosynthesis of PGI2 through the coupling reaction of COXs with PGIS in the ER membrane, without other molecule involvement, was not directly proven until recently, when we showed that the engineered hybrid enzymes linking COX-1 to PGIS (COX-1-10aa- PGIS) and COX-2 to PGIS (COX-2-10aa-PGIS) could perform triple catalytic reactions and effectively convert AA into PGG2, PGH2 and then PGI2 (Ruan et al. 2006, 2008a). The purified COX-2-10aa-PGIS, without the presence of any other molecules, showed identical triple catalytic activity with that of the hybrid enzymes in cells (Ruan et al. 2008b). "
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ABSTRACT: Our aim is to understand the molecular mechanisms of the selective nonsteroidal anti-inflammatory drugs (NSAID), cyclooxygenase-2 (COX-2) inhibitors', higher "priority" to reduce synthesis of the vascular protector, prostacyclin (PGI2), compared to that of nonselective NSAIDs.
COX-1 or COX-2 was co-expressed with PGI2 synthase (PGIS) in COS-7 cells. The Km and initial velocity (½t Vmax) of the coupling reaction between COX-1 and COX-2 to PGIS were established. The experiment was further confirmed by a kinetics study using hybrid enzymes linking COX-1 or COX-2 to PGIS. Finally, COX-1 or COX-2 and PGIS were respectively fused to red (RFP) and cyanic (CFP) fluorescence proteins, and co-expressed in cells. The distances between COXs and PGIS were compared by FRET.
The Km for converting arachidonic acid (AA) to PGI2 by COX-2 coupled to PGIS is ~2.0μM; however, it was 3-fold more (~6.0μM) for COX-1 coupled to PGIS. The Km and ½t Vmax for COX-2 linked to PGIS were ~2.0μM and 20s, respectively, which were 2-5 folds faster than that of COX-1 linked to PGIS. The FRET study found that the distance between COX-2-RFP and PGIS-CFP is shorter than that between COX-1-RFP and PGIS-CFP.
The study provided strong evidence suggesting that the low Km, faster ½t Vmax, and closer distance are the basis for COX-2 dominance over COX-1 (coupled to PGIS) in PGI2 synthesis, and further demonstrated the mechanisms of selective COX-2 inhibitors with higher potential to reduce synthesis of the vascular protector, PGI2.
Life sciences 10/2010; 88(1-2):24-30. DOI:10.1016/j.lfs.2010.10.017 · 2.70 Impact Factor
Available from: Rania Nasrallah
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ABSTRACT: There are five major PGs (prostaglandins/prostanoids) produced from arachidonic acid via the COX (cyclo-oxygenase) pathway: PGE(2), PGI(2) (prostacyclin), PGD(2), PGF(2alpha) and TXA(2) (thromboxane A(2)). They exert many biological effects through specific G-protein-coupled membrane receptors, namely EP (PGE(2) receptor), IP (PGI(2) receptor), DP (PGD(2) receptor), FP (PGF(2alpha) receptor) and TP (TXA(2) receptor) respectively. PGs are implicated in physiological and pathological processes in all major organ systems, including cardiovascular function, gastrointestinal responses, reproductive processes, renal effects etc. This review highlights recent insights into the role of each prostanoid in regulating various aspects of renal function, including haemodynamics, renin secretion, growth responses, tubular transport processes and cell fate. A thorough review of the literature since Y2K (year 2000) is provided, with a general overview of PGs and their synthesis enzymes, and then specific considerations of each PG/prostanoid receptor system in the kidney.
Clinical Science 11/2007; 113(7):297-311. DOI:10.1042/CS20070089 · 5.60 Impact Factor
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