Prostacyclin and thromboxane synthase as P-450 enzymes

Ullrich, Volker; Graf, Hermann

doi:10.1016/0165-6147(84)90467-x

Cited by 56 publications

(17 citation statements)

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“…# synthase (PGIS), a cytochrome P450, contains 500 amino acids with a calculated molecular mass of about 57 kDa [1][2][3] and is located in the endoplasmic-reticulum (ER) membrane [4][5][6]. PGIS converts prostaglandin H # (PGH # ) into prostaglandin I # (PGI # ), a potent inhibitor of platelet aggregation, vasoconstriction and leucocyte interactions with endothelium [7,8].…”

Section: Prostaglandin Imentioning

confidence: 99%

Substrate access channel topology in membrane-bound prostacyclin synthase

Deng¹,

Huang²,

So³

et al. 2002

Biochem. J.

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Results from our molecular-modelling and site-directed-mutagenesis studies of prostaglandin I # synthase (PGIS) have suggested that the large PGIS cytoplasmic domain is anchored to the endoplasmic reticulum (ER) membrane by the N-terminal segment in a way that orients the substrate access channel opening to face the membrane. To test this hypothesis we have explored the accessibility of the PGIS substrate channel opening to site-specific antibodies. The working three-dimensional PGIS model constructed by protein homology modelling was used to predict surface portions near the substrate access channel opening. Two peptides corresponding to the surface immediately near the opening [residues 66-75 (P66-75) and 95-116 (P95-116)], and two other peptides corresponding to the surface about 10-20 A H (1 A H l 0.1 nm) away from the opening [residues 366-382 (P366-382) and 472-482 (P472-482)] were used to prepare sitespecific antibodies. All four antipeptide antibodies specifically recognized the synthetic segments of human PGIS and recombinant PGIS, as shown by binding assays and Western-blot analysis. The site-specific antibodies were used to probe the

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Section: Prostaglandin Imentioning

confidence: 99%

Substrate access channel topology in membrane-bound prostacyclin synthase

Deng¹,

Huang²,

So³

et al. 2002

Biochem. J.

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“…Dazoxiben is a thromboxane synthetase inhibitor (Tyler, 1983), there being good evidence (Ullrich & Graf, 1984) that thromboxane A2 (TXA2) synthetase is a P-450 protein. The reason why dazoxiben did not apparently inhibit tolbutamide hydroxylation is open to speculation.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of tolbutamide metabolism by substituted imidazole drugs in vivo: evidence for a structure‐activity relationship

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Tjia

1985

British J Pharmacology

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1 Tolbutamide has been used as a model drug for an examination of the effects of eleven substituted imidazole compounds on hepatic metabolism in vivo. 2 The 1-substituted compounds 1-methylimidazole, miconazole, clotrimazole and ketoconazole produced marked alterations in tolbutamide kinetics (increased half-life, decreased clearance). However, if there was substitution in the 2-position, irrespective of a substituent on N-1, then the compound did not appear to inhibit metabolism (e.g. 2-methylimidazole, 1,2-dimethylimidazole, methimazole, metronidazole). The 4-substituted compounds, 4-methylimidazole and cimetidine were inhibitors. 3 A structure-activity relationship for the inhibitory actions of the substituted imidazoles is thus evident in vivo.

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“…4 However, various extrahepatic tissues, including lung, kidney, intestine, bone marrow, and adrenal glands, contain substantial amounts of cytochrome P-450 mixed function oxidase (MFO) activity. 5 " 7 Ullrich and Graf 8 have shown the presence of cytochrome P-450 in hog aorta microsomes. In their study, they were unable to demonstrate monooxygenase activity using typical substrates for microsomal cytochrome P-450 reactions.…”

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confidence: 99%

Presence of cytochrome P-450-dependent monooxygenase in intimal cells of the hog aorta.

Abraham¹,

Pinto²,

Mullane³

et al. 1985

Hypertension

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SUMMARY Cytochrome P-450-dependent mixed function oxidase activity is present in vascular tissue; however, as far as we could determine, the distribution of monooxygenase activity across the blood vessel wall has not previously been assessed. The aryl-hydrocarbon hydroxylase activity was examined by metabolism of benzo[a]pyrene in microsomes prepared from intimal and smooth muscle cell scrapings of the hog thoracic aorta. Microsomes of intimal cells comprising 95 % endothelial cells showed an approximately 2.5-fold increase in aryl-hydrocarbon hydroxylase activity compared with that in microsomes prepared from medial smooth muscle cells. Michaelis-Mentin kinetics for the intimal enzyme yielded an apparent K m value of 11.11 /xM and an apparent V max of 3-0H benzo[a]pyrene of 40 pmol/mg protein/10 min. Aryl-hydrocarbon hydroxylase activity was dependent on nicotinamide adenine dinucleotide phosphate and was inhibited by 7,8 benzoflavone, SKF 525A, and carbon monoxide. The localization of cytochrome P-450-dependent mixed function oxidase primarily to the intimal surface of the aorta may indicate a role for this enzyme system in vasoregulation and the pathogenesis of atherosclerosis. (Hypertension 7: 899-904, 1985)

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Prostacyclin and thromboxane synthase as P-450 enzymes

Cited by 56 publications

References 0 publications

Substrate access channel topology in membrane-bound prostacyclin synthase

Substrate access channel topology in membrane-bound prostacyclin synthase

Inhibition of tolbutamide metabolism by substituted imidazole drugs in vivo: evidence for a structure‐activity relationship

Presence of cytochrome P-450-dependent monooxygenase in intimal cells of the hog aorta.

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