On the haemoprotein character of prostaglandin endoperoxide synthetase

Ouderaa, Frans J. van der; Buytenhek, M.; Slikkerveer, F.J.; Dorp, D. A. van

doi:10.1016/0005-2760(79)90197-8

Cited by 115 publications

(32 citation statements)

References 25 publications

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“…The last one is characteristic of high spin heme species. This spectrophotometric feature was comparable with PGHS, which has the Soret ␣/␤ and charge-transfer transitions at 411, 501, and 633 nm (25,27,28). The molecular coefficient was 11.6 mM Ϫ1 cm Ϫ1 (410 nm).…”

Section: Resultssupporting

confidence: 52%

“…With the reduced form, a broad band at ϳ507 nm was evident in the ␣/␤ band, and clear peaks at 636 and 661 nm appeared in the charge-transfer transitions. The spectrophotometric properties of reduced form of rice ␣-oxygenase was totally different from those of mammalian PGHSs having peaks of 428, 530, and 558 nm for the Soret ␤ and ␣ bands, respectively (28). In short, the heme coordination state of ferrous form of the rice enzyme has a close resemblance with those of mammalian PGHSs, although that of ferric state is significantly different.…”

Section: Resultsmentioning

confidence: 81%

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Catalytic Properties of Rice α-Oxygenase

Koeduka

Matsui

Akakabe

et al. 2002

Journal of Biological Chemistry

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Long-chain fatty acids can be metabolized to C n؊1 aldehydes by ␣-oxidation in plants. The reaction mechanism of the enzyme has not been elucidated. In this study, a complete nucleotide sequence of fatty acid ␣-oxygenase gene in rice plants (Oryza sativa) was isolated. The deduced amino acid sequence showed some similarity with those of mammalian prostaglandin H synthases (PGHSs). The gene was expressed in Escherichia coli and purified to apparently homogenous state. It showed the highest activity with linoleic acid and predominantly formed 2-hydroperoxide of the fatty acid (C n ), which is then spontaneously decarboxylated to form corresponding C n؊1 aldehyde. With linoleic or linoleic acids as a substrate, rice ␣-oxygenase formed no product having a max at approximately 234 nm, which indicated that the enzyme could not oxygenize the pentadiene system in the substrate. The spectroscopic feature of the purified enzyme in its ferrous state is similar to that of mammalian PGHS, whereas that of dithionite-reduced state showed significant difference. Site-directed mutagenesis revealed that His-158, Tyr-380, and Ser-558 were essential for the ␣-oxygenase activity. These residues are conserved in PGHS and known as a heme ligand, a source of a radical species to initiate oxygenation reaction and a residue involved in substrate binding, respectively. This finding suggested that the initial step of the oxygenation reaction in ␣-oxygenase has a high similarity with that of PGHS. The rice ␣-oxygenase activity was inhibited by imidazole but hardly inhibited by nonsteroidal anti-inflammatory drugs, such as aspirin, ibuprofen, and flurbiprofen, which are known as typical PGHS inhibitors. In addition, peroxidase activity could not be detected with ␣-oxygenase when palmitic acid 2-hydroperoxide was used as a substrate. From these findings, the catalytic resemblance between ␣-oxygenase and PGHS seems to be evident, although there still are differences in their substrate recognitions and peroxidation activities.

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Section: Resultssupporting

confidence: 52%

Section: Resultsmentioning

confidence: 81%

Catalytic Properties of Rice α-Oxygenase

Koeduka

Matsui

Akakabe

et al. 2002

Journal of Biological Chemistry

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“…The discovery that protection by phenol was observed only when adequate heme was also available (Fig. 4) is consistent with the established heme requirement for the prostaglandin hydroperoxidase activity (3,5,9,10). High levels of heme may protect the vulnerable site(s) on the enzyme from destruction, or may confer increased thermal or physical stability on cyclooxygenase such as observed for hemoglobin (21).…”

Section: Protection Of Cyclooxygenase Acetonesupporting

confidence: 82%

Protection of cyclooxygenase activity during heme-induced destabilization

Hemler

Lands

1980

Archives of Biochemistry and Biophysics

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“…COX exists in at least two isoforms with similar molecular weights ("'70 kDa). COX-1 is expressed constitutively and was first characterized, purified, and cloned from sheep vesicular glands (2)(3)(4)(5)(6)(7). Activation of COX-1 leads, for instance, to the production of prostacyclin, which when released by the endothelium is antithrombogenic (8) and by the gastric mucosa is cytoprotective (9).…”

mentioning

confidence: 99%

Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase.

Mitchell

Akarasereenont²,

Thiemermann³

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

1,466

896

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Constitutive cyclooxygenase (COX-1; prostaglandin-endoperoxide synthase, EC 1.14.99.1) is present in cells under physiological conditions, whereas COX-2 is induced by some cytokines, mitogens, and endotoxin presumably in pathological conditions, such as inflammation. Therefore, we have assessed the relative inhibitory effects of some nonsteroidal antiinflammatory drugs on the activities of COX-1 (in bovine aortic endothelial cells) and COX-2 (in endotoxinactivated J774.2 macrophages) in intact ceils, broken cells, and purified enzyme preparations (COX-1 in sheep seminal vesicles; COX-2 in sheep placenta). Similar potencies of aspfrin, indomethacin, and ibuprofen against the broken cell and purified enzyme preparations indicated no influence of species. Aspirin, indomethacin, and ibuprofen were more potent inhibitors of COX-1 than COX-2 in all models used. The relative potencies of aspirin and indomethacin varied only slightly between models, although the IC50 values were different.Ibuprofen was more potent as an inhibitor of COX-2 in intact cells than in either broken cells or purified enzymes. Sodium salicylate was a weak inhibitor of both COX isoforms in intact cells and was inactive against COX in either broken cells or purified enzyme preparations. Diclofenac, BW755C, acetaminophen, and naproxen were approximately equipotent inhibitors of COX-1 and COX-2 in intact cells. BF 389, an experimental drug currently being tested in humans, was the most potent and most selective inhibitor of COX-2 in intact cells. Thus, there are clear pharmacological differences between the two enzymes. The use of such models of COX-1 and COX-2 activity will lead to the identification of selective inhibitors of COX-2 with presumably less side effects than present therapies. Some inhibitors had higher activity in intact cells than against purified enzymes, suggesting that pure enzyme preparations may not be predictive of therapeutic action.Cyclo-oxygenase (COX; prostaglandin-endoperoxide synthase, EC 1.14.99.1) converts arachidonic acid to prostaglandin (PG) H2, which is then further metabolized by other enzymes to various PGs, prostacyclin, and thromboxanes (1). COX exists in at least two isoforms with similar molecular weights ("'70 kDa). COX-1 is expressed constitutively and was first characterized, purified, and cloned from sheep vesicular glands (2-7). Activation of COX-1 leads, for instance, to the production of prostacyclin, which when released by the endothelium is antithrombogenic (8) and by the gastric mucosa is cytoprotective (9). COX-2 is induced in cells exposed to proinflammatory agents, including cytokines (10), mitogens (11) and endotoxin (12,13 COX-2 may well explain their therapeutic utility as antiinflammatory drugs, whereas inhibition of COX-1 may explain their unwanted side effects, such as gastric and renal damage.After establishing that bovine aortic endothelial cells in culture contain COX-1 and that endotoxin-activated J774.2 macrophages contain COX-2, we have investigated the inhibitory effects of s...

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On the haemoprotein character of prostaglandin endoperoxide synthetase

Cited by 115 publications

References 25 publications

Catalytic Properties of Rice α-Oxygenase

Catalytic Properties of Rice α-Oxygenase

Protection of cyclooxygenase activity during heme-induced destabilization

Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase.

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