Fe(II)-induced decomposition of epidioxides. A chemical model for prostaglandin E, prostacyclin and thromboxane biosynthesis

Turner, Jeffrey A.; Herz, Werner

doi:10.1007/bf01922283

Cited by 16 publications

(6 citation statements)

References 17 publications

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“…Sheep antiserum against 6-keto prostaglandin F 1 α was acquired from Oxford Biochemical Research. 6-Keto [5,8,9,11,12,14, H] prostaglandin F 1 α (6.88 TBq/ mmol) and [1-14 C]-linoleic acid (2.04 GBq/mmol) were acquired from Amersham Pharmacia Biotech. PGH 1 and PGH 2 were synthesized from dihomo-γ-linolenic acid and arachidonic acid, respectively, using detergent-solubilized ovine prostaglandin H synthase-1 and purified by a normal phase silica HPLC column as [21].…”

Section: Methodsmentioning

confidence: 99%

“…The prevailing reaction mechanism initially proposed by Hecker and Ullrich [8] [12,13]. Another chemical model proposed homolytic O-O bond scission using Fe(II) [14]. Although some P450s that use hydroperoxides as substrates catalyze homolytic scission to form radicals as transient intermediates [15][16][17], homolytic scission of the O-O bond has not yet been established for PGIS.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of heme environment and mechanism of peroxide bond cleavage in human prostacyclin synthase

Yeh

Hsu

Wang

et al. 2005

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Prostacyclin is a potent mediator of vasodilation and anti-platelet aggregation. It is synthesized from prostaglandin H(2) by prostacyclin synthase (PGIS), a member of Family 8 in the cytochrome P450 superfamily. Unlike most P450s, which require exogenous reducing equivalents and an oxygen molecule for mono-oxygenation, PGIS catalyzes an isomerization with an initial step of endoperoxide bond cleavage of prostaglandin H(2) (PGH(2)). The low abundance of PGIS in natural tissues necessitates heterologous expression for studies of structure/function relationships and reaction mechanism. We report here a high-yield prokaryotic system for expression of enzymatically active human PGIS. The PGIS cDNA is modified by replacing the hydrophobic amino-terminal sequence with the more hydrophilic amino-terminal sequence from P450 2C5 and by adding a four-histidine tag at the carboxyl terminus. The resulting recombinant PGIS associates with host cell membranes and was purified to electrophoretic homogeneity by nickel affinity, hydroxyapatite and CM Sepharose column chromatography. The recombinant PGIS, with a heme:protein ratio of 0.9:1, catalyzes prostacyclin formation at a K(m) of 13.3 muM PGH(2) and a V(max) of 980 per min. The dithionite-reduced PGIS binds CO with an on-rate of 5.6 x 10(5) M(-1) s(-1) and an off-rate of 15 s(-1). The ferrous-CO complex of PGIS is very short-lived and decays at a rate of 0.7 s(-1). Spectral binding assays showed that imidazole binds weakly to PGIS (K(d) approximately 0.5 mM,) but clotrimazole, a bulky and rigid imidazole derivative, binds strongly (K(d) approximately 1 microM). The transient nature of the CO complex and the weak imidazole binding seem to support an earlier proposal that PGIS active site has a limited space, but the tight binding of clotrimazole argues against this view. It appears that the heme distal pocket of PGIS is fairly adaptable to ligands of various structures. UV-visible absorption, magnetic circular dichroism and electron paramagnetic resonance spectra indicate that PGIS has a typical low-spin heme with a hydrophobic active site. PGIS catalyzes homolytic scission of the peroxide bond of a test substrate, 10-hydroperoxyoctadeca-8,12-dienoic acid, accompanied by formation of a heme intermediate with a Compound II-like optical spectrum.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterization of heme environment and mechanism of peroxide bond cleavage in human prostacyclin synthase

Yeh

Hsu

Wang

et al. 2005

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…The latter aspect needs further research eg, via radical trapping using scavenger agents. Nevertheless, others provided evidence that the cleavage of the endoperoxide bridge generates oxygen-and carboncentered radical intermediates arising from Fe(II)-induced (FeSO 4 forms Fe(II) aquo complexes in solution) degradation of ascaridole with subsequent formation of the diepoxide isoascaridole (Turner and Herz, 1977a).…”

Section: Discussionmentioning

confidence: 99%

Activation of the endoperoxide ascaridole modulates its sensitizing capacity

et al. 2015

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The monoterpene ascaridole, a fairly stable endoperoxide found in essential oils such as tea tree oil can provoke allergic contact dermatitis which has been evidenced under patch test conditions. However, concomitantly we observed irritative skin reactions that demand further data underlining the sensitization potential of ascaridole. Here, we studied the effects of ascaridole on dendritic cell (DC) activation and protein reactivity, 2 key steps of chemical-induced skin sensitization. Treatment of human monocyte-derived DC with ascaridole found support for full DC maturation, a capability of sensitizers but not irritants. It induced significant upregulation of the expression of the costimulatory molecules CD86, CD80, CD40, and the adhesion molecule CD54 in a time-dependent manner. Maturation was accompanied by release of proinflammatory cytokines interleukin (IL)-1ß, tumor necrosis factor-a, IL-6, and IL-8. Similar to other chemical skin sensitizers including hydroperoxides, we observed a certain reactivity of ascaridole toward cysteine-but not lysinecontaining peptides. During recent years, evidence accumulated for a radical mechanism as trigger for protein reactivity of peroxides. Treatment of the fairly stable endoperoxide ascaridole with iron as radical inducer ("activated ascaridole") resulted in cysteine peptide reactivity exceeding by far that of ascaridole itself. Furthermore, activated ascaridole showed increased potential for induction of the Nrf2 target gene heme oxygenase 1 and upregulation of CD86 and CD54 on THP-1 cells, an established DC surrogate. These results indicate that radical formation could be involved in the steps leading to skin sensitization induced by the endoperoxide ascaridole.

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Section: Introductionmentioning

confidence: 99%

“…Since TXA 2 was discovered to be a potent mediator for platelet aggregation,11 many studies on TXA 2 and TXAS have been conducted,12 and hypothetical mechanisms were reported 13–15. One is an Fe II ‐catalyzed mechanism proposed by Turner and Herz,13 and another is an ionic OO bond cleavage mechanism by a proton proposed by Diczfalusy and Hammarström 14. However, at that time, there had been little information about what TXAS was, until it became clear that TXAS was a member of the cytochrome P450 superfamily, and that TXA 2 biosynthesis was not catalyzed by Fe II but by Fe III ‐porphyrin 15.…”

Section: Introductionmentioning

confidence: 99%

Effect of co‐promoter and secondary monomer on shrinkage control of unsaturated polyester (UP)/styrene (St)/low‐profile additive (LPA) systems cured at low temperatures

Cao

Lee

2001

J of Applied Polymer Sci

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ABSTRACT:A series of linear functionalized polyorganosiloxanes of the type Me 3 SiO[MeSiO(CH 2 ) n R] x (Me 2 SiO) y SiMe 3 , where n ϭ 2, R ϭ O(CH 2 )NMe 2 ; n ϭ 1, R ϭ O(CH 2 )OEt; n ϭ 4, R ϭ O(CH 2 )COOEt; n ϭ 3, R ϭ O(CH 2 )Me, have been prepared and characterized. Functional group loadings of ϳ4 mol % (x ϭ 1, y ϭ 25), ϳ11 mol % (x ϭ 3, y ϭ 23), and ϳ30 mol % (x ϭ 8, y ϭ 18) were obtained by reacting commercially available copolymers Me 3 SiO(MeSi{H} O) x (Me 2 SiO) y SiMe 3 with the appropriate ratios of x : y , with the required quantities of HO(CH 2 ) n R, using dichloro(1,5-cyclooctadiene)-platinum(II) as catalyst. Amine, ether, ester, and alkyl functionalized siloxanes were obtained in good yields after purification, and each fluid polymer has been characterized by 1 H and 13 C-nuclear magnetic resonance (NMR), and Fourier transform infrared (FTIR) spectral measurements, elemental analysis, viscosity, surface tension, and density measurements. The functionalized polymers exhibit Newtonian behavior over the range of shear rates 0.4 -79.4 s Ϫ1 , and significant viscosity enhancements were observed for all functionalized polymers compared with poly(dimethylsiloxane) fluids of similar chain lengths. The functionalized siloxanes exhibited in almost all cases an increase in both viscosity and density as the functional group loading increased. The surface tensions of the polymers have also been determined and lie within the range 18.8 -22.3 mN m Ϫ1 .

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Fe(II)-induced decomposition of epidioxides. A chemical model for prostaglandin E, prostacyclin and thromboxane biosynthesis

Cited by 16 publications

References 17 publications

Characterization of heme environment and mechanism of peroxide bond cleavage in human prostacyclin synthase

Characterization of heme environment and mechanism of peroxide bond cleavage in human prostacyclin synthase

Activation of the endoperoxide ascaridole modulates its sensitizing capacity

Effect of co‐promoter and secondary monomer on shrinkage control of unsaturated polyester (UP)/styrene (St)/low‐profile additive (LPA) systems cured at low temperatures

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