Chemical stability of prostacyclin (PGI2) in aqueous solutions

Cho, M.J.; Allen, Meredith

doi:10.1016/0090-6980(78)90037-0

Cited by 208 publications

(52 citation statements)

References 7 publications

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“…Initial rate determinations were carried out in 200 l of 20 mM NaP i , pH 7.4, and 0.2% Lubrol PX by incubating 10 pmol of zPGIS with an appropriate amount of PGH 2 for 20 s at 23°C. Formation of 6-keto-prostaglandin F 1␣ (6-keto-PGF 1␣ ), the stable hydration product of PGI 2 (16), was measured by radioimmunoassay (17). Ligand binding affinity was determined by monitoring the absorbance changes of the Soret band as described (12).…”

Section: Methodsmentioning

confidence: 99%

Structures of Prostacyclin Synthase and Its Complexes with Substrate Analog and Inhibitor Reveal a Ligand-specific Heme Conformation Change

Chiang

Yeh

et al. 2008

Journal of Biological Chemistry

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Prostacyclin synthase (PGIS) is a cytochrome P450 (P450) enzyme that catalyzes production of prostacyclin from prostaglandin H 2 . PGIS is unusual in that it catalyzes an isomerization rather than a monooxygenation, which is typical of P450 enzymes. To understand the structural basis for prostacyclin biosynthesis in greater detail, we have determined the crystal structures of ligand-free, inhibitor (minoxidil)-bound and substrate analog U51605-bound PGIS. These structures demonstrate a stereo-specific substrate binding and suggest features of the enzyme that facilitate isomerization. Unlike most microsomal P450s, where large substrate-induced conformational changes take place at the distal side of the heme, conformational changes in PGIS are observed at the proximal side and in the heme itself. The conserved and extensive heme propionate-protein interactions seen in all other P450s, which are largely absent in the ligand-free PGIS, are recovered upon U51605 binding accompanied by water exclusion from the active site. In contrast, when minoxidil binds, the propionate-protein interactions are not recovered and water molecules are largely retained. These findings suggest that PGIS represents a divergent evolution of the P450 family, in which a heme barrier has evolved to ensure strict binding specificity for prostaglandin H 2 , leading to a radicalmediated isomerization with high product fidelity. The U51605-bound structure also provides a view of the substrate entrance and product exit channels.

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Section: Methodsmentioning

confidence: 99%

Structures of Prostacyclin Synthase and Its Complexes with Substrate Analog and Inhibitor Reveal a Ligand-specific Heme Conformation Change

Chiang

Yeh

et al. 2008

Journal of Biological Chemistry

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“…Although native PGI 2 is inherently unstable at room temperature with a t 1/2 of seconds to minutes (6), continuous infusions of a highly alkaline solution (pH 10.2 to 10.8) are approved by the U.S. Food and Drug Administration (FDA) in the treatment of PAH. To combat the technical difficulties associated with administering epoprostenol, more stable synthetic analogs of PGI 2 have been developed and approved for use in PAH.…”

Section: Synthetic Prostacyclin Analogs Differentially Regulate Macromentioning

confidence: 99%

Synthetic Prostacyclin Analogs Differentially Regulate Macrophage Function via Distinct Analog-Receptor Binding Specificities

Aronoff

Peres

Serezani

et al. 2007

The Journal of Immunology

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PGI2 (prostacyclin) is a lipid mediator with vasodilatory and antithrombotic effects used in the treatment of vasoconstrictive/ischemic diseases including pulmonary artery hypertension. However, emerging research supports a role for PGs, including PGI2, in the regulation of both innate and acquired immunity. As PGI2 is unstable, we sought to define the effects of various PGI2 analogs on resident alveolar macrophage (AM) and peritoneal macrophage (PM) innate immune functions. The effects of iloprost, carbaprostacyclin, and treprostinil on the regulation of phagocytosis, bacterial killing, and inflammatory mediator production were determined in both macrophage populations from rats. Iloprost failed to suppress AM functions to the same degree that it did in PMs, a characteristic shared by carbaprostacyclin. This difference reflected greater expression of the Gαs protein-coupled I prostanoid receptor and greater cAMP generation in PMs than AMs. Treprostinil inhibited phagocytosis, bacterial killing, and cytokine generation in AMs to a much greater degree than the other PGI2 analogs and more closely resembled the effects of PGE2. Studies with the E prostanoid (EP) 2 receptor antagonist AH-6809 and EP2-null macrophages indicated that this was due in part to the previously unknown ability of treprostinil to stimulate the EP2 receptor. The present investigation for the first time identifies differences in immunoregulatory properties of clinically administered PGI2 analogs. These studies are the first to explore the capacity of PGI2 to regulate bacterial killing and phagocytosis in macrophages, and our findings may hold important consequences regarding the risk of infection for patients receiving such agents.

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“…In solution, prostacyclin is rapidly hydrolyzed to 6-keto-PGF 1␣ (28). To determine if PGIS can catalyze the isomerization of endocannabinoidderived PGH 2 -like lipids to the corresponding prostacyclins, microsomal PGIS was prepared from mature bovine aorta.…”

Section: Fig 11 Concentration-and Time-dependent Isomerization Of Pmentioning

confidence: 99%

Metabolism of the Endocannabinoids, 2-Arachidonylglycerol and Anandamide, into Prostaglandin, Thromboxane, and Prostacyclin Glycerol Esters and Ethanolamides

Kozak¹,

Crews²,

Morrow³

et al. 2002

Journal of Biological Chemistry

335

265

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Cyclooxygenase-2 (COX-2) action on the endocannabinoids, 2-arachidonylglycerol (2-AG) and anandamide (AEA), generates prostaglandin glycerol esters (PG-G) and ethanolamides (PG-EA), respectively. The diversity of PG-Gs and PG-EAs that can be formed enzymatically following COX-2 oxygenation of endocannabinoids was examined in cellular and subcellular systems. In cellular systems, glycerol esters and ethanolamides of PGE 2 , PGD 2 , and PGF 2␣ were major products of the endocannabinoid-derived COX-2 products, PGH 2 -G and PGH 2 -EA. The sequential action of purified COX-2 and thromboxane synthase on AEA and 2-AG provided thromboxane A 2 ethanolamide and glycerol ester, respectively. Similarly, bovine prostacyclin synthase catalyzed the isomerization of the intermediate endoperoxides, PGH 2 -G and PGH 2 -EA, to the corresponding prostacyclin derivatives. Quantification of the efficiency of prostaglandin and thromboxane synthase-directed endoperoxide isomerization demonstrated that PGE, PGD, and PGI synthases catalyze the isomerization of PGH 2 -G at rates approaching those observed with PGH 2 . In contrast, thromboxane synthase was far more efficient at catalyzing PGH 2 isomerization than at catalyzing the isomerization of PGH 2 -G. These results define the in vitro diversity of endocannabinoid-derived prostanoids and will permit focused investigations into their production and potential biological actions in vivo.

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Chemical stability of prostacyclin (PGI2) in aqueous solutions

Cited by 208 publications

References 7 publications

Structures of Prostacyclin Synthase and Its Complexes with Substrate Analog and Inhibitor Reveal a Ligand-specific Heme Conformation Change

Structures of Prostacyclin Synthase and Its Complexes with Substrate Analog and Inhibitor Reveal a Ligand-specific Heme Conformation Change

Synthetic Prostacyclin Analogs Differentially Regulate Macrophage Function via Distinct Analog-Receptor Binding Specificities

Metabolism of the Endocannabinoids, 2-Arachidonylglycerol and Anandamide, into Prostaglandin, Thromboxane, and Prostacyclin Glycerol Esters and Ethanolamides

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