Enzymological Studies on Prostaglandin Biosynthesis

Yamamoto, Shozo; Ogino, Nobuchika; Ohki, S; Yoshimoto, Tanihiro; Bhat, Sanjay P.; Oka, Jun; Hayaishi, Osamu

doi:10.1016/b978-0-12-405850-7.50007-2

Cited by 30 publications

(55 citation statements)

References 18 publications

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“…This fraction thus contained cyclooxygenase. It has been reported before that cyclooxygenase from vesicular glands does not adsorb to DEAE-cellulose under similar conditions (19). The second enzyme component was eluted from DEAE-cellulose with 0.2 M potassium phosphate, pH 7.4.…”

Section: Discussionmentioning

confidence: 79%

“…The prostaglandin endoperoxides PGG2 and PGH2, which are intermediates in the transformation, can also be converted to prostaglandins (PGD2, PGE2, PGF2a, and PGI2) or to a C17 hydroxy fatty acid (HHT) plus malondialdehyde, as shown in this figure. An enzyme catalyzing the conversion of arachidonic acid to PGH2 has been purified to homogeneity from vesicular glands (19)(20)(21) and named prostaglandin endoperoxide synthase or fatty acid cyclooxygenase (EC 1.14.99.1). The transformation of PGH2 to thromboxane B2 occurs in two steps: (i) isomerization of the endoperoxide to thromboxane A2 and (ii) nucleophilic attack by water to form thromboxane B2 (1).…”

Section: Discussionmentioning

confidence: 99%

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Resolution of prostaglandin endoperoxide synthase and thromboxane synthase of human platelets.

Hammarström¹,

Falardeau²

1977

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

158

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Thromboxane synthase was localized to the microsomes of human platelets. The enzyme was insensitive to sulfhydryl reagents and thiols but was inhibited by 12L-hydroperoxy-5,8,10,14-eicosatetraenoic acid (concentration for 50% inhibition = 0.1 mM). Treatment of microsomes with Triton X-100 solubilized the enzymes that catalyze the conversion of arachidonic acid to thromboxane B2. The solubilized material was resolved by DEAE-cellulose chromatography into two components, one converting arachidonic acid to prostaglandins G2 and H2 and the other converting prostaglandin H2 to thromboxane B2.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Resolution of prostaglandin endoperoxide synthase and thromboxane synthase of human platelets.

Hammarström¹,

Falardeau²

1977

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

158

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“…the first two steps of the biotransformation of arachidonic acid into prostaglandins and thromboxanes (Nugteren and Hazelhof, 1973;Hamberg et al, 1974;Miyamoto et al, 1976;Van der Ouderaa et a]., 1977;Ohki et al, 1979). It first acts as a dioxygenase (cyclooxygenase) which oxidizes arachidonic acid to prostaglandin G, (PGG,), then as a peroxidase which reduces PGG, to prostaglandin H, (PGH,) Eqn(1); (Hamberg et al, 1974;Okhi et al, 1979;Hemler and Lands, 1980;Kulmacz et al, 1985;Markey et al, 1987).…”

mentioning

confidence: 99%

“…PGHS can be released from the membranes upon extraction in the presence of detergents and purified from bovine (Miyamoto et al, 1976;Hemler et al, 1976) and sheep seminal vesicles (Van der Ouderaa et al, 1977;Roth et al, 1981;Marnett et al, 1984;Jahnke et al, 1986; PGG, 'OH Lands, 1987) and from sheep (Boopathy and Balasubramanian, 1986) and human platelets (Takahashi et a]., 1992).…”

mentioning

confidence: 99%

“…The purified protein is a homodimer of 70 kDa subunits (Miyamoto et al, 1976;Hemler et al, 1976;Van der Ouderaa et al, 1977;Roth et al, 1981) that binds one heme/ subunit (Karthein et al, 1987;Kulmacz and Lands, 1984;Roth et al, 1981 ;Ruf et al, 1984;Ueno et al, 1982). Heme is required for both cyclooxygenase and peroxidase activities (Hemler et al, 1976;Roth et al, 1981 ;Van der Ouderaa et al, 1977).…”

mentioning

confidence: 99%

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Reactions of Prostaglandin H Synthase with Monosubstituted Hydrazines and Diazenes

Mahy

Gaspard

Delaforge

et al. 1994

European Journal of Biochemistry

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The reaction of p‐chlorophenylhydrazine with prostaglandin H synthase (PGHS) Fe(III) under aerobic conditions leads to a partial destruction of the heme and to a new complex absorbing at 436 nm. This complex is also obtained by reaction of p‐chlorophenyldiazene (pClPhN = NH) with PGHS Fe(III) under anaerobic conditions and by oxidation of the PGHS Fe(II)(pClPhN = NH) diazene complex by Fe(CN)6K3. The similarity between those reactions and those of arylhydrazines and aryldiazenes with other hemoproteins such as cytochrome P450 and hemoglobin and myoglobin, as well as the similarities between the spectroscopic and chemical properties of this complex and those of the σ‐aryl complexes of other hemoproteins such as hemoglobin and myoglobin, strongly suggested a PGHS Fe(III)‐pClPh structure for this complex. It was completely established after the extraction of its heme, by butan‐2‐one at 0°C under neutral or acidic conditions, which led to the σ‐aryl PGHS‐Fe(III)‐pClPh complex and to N‐phenylprotoporphyrin IX, respectively. A mechanism is proposed for the formation of the PGHS Fe(III) pClPh complex; it includes the reduction of PGHS Fe(III) into PGHS Fe(II) with formation of the diazene pClPhN = NH. This diazene can bind to PGHS Fe(II) or be oxidized with formation of pClPh free radicals. These radicals can react with PGHS Fe(II) to form the PGHS Fe(III)‐pClPh complex or with the protein, or may initiate free radical oxidations which could lead to destruction of the heme or of the protein. Other alkylhydrazines or arylhydrazines also react with PGHS Fe(III) under aerobic conditions with the formation of PGHS Fe(III)‐R or aryl (Ar) complexes and heme destruction. Alkylhydrazines such as methylhydrazine, which lead to very reactive alkyl radicals, lead to very low amounts of PGHS Fe(III)‐R complex and high amounts of heme destruction, whereas arylhydrazines bearing electron‐withdrawing substituents such as 3,4‐dichlorophenylhydrazine, which lead to stabilized aryl radicals, lead to a high amounts of PGHS Fe(III)‐Ar complex and low amounts of heme destruction. Some information concerning the structure of the active site of PGHS has been drawn from those studies as follows: (a) the formation of σ‐aryl PGHS Fe(III)‐Ar and PGHS Fe(II)(ArN = NH) complexes bearing bulky ligands on the iron is in agreement with a large hydrophobic active site with an easily accessible iron atom and, (b) a comparison of the UV‐visible characteristics of PGHS Fe(III)‐R or Ar complexes with those of other hemoprotein‐Fe(III)‐R or hemoprotein‐Fe(III)‐Ar complexes is in agreement with a histidine as the axial proximal ligand of the iron of PGHS. Finally, the formation of iron(III)‐R or iron (III)‐Ar complexes and the free radical oxidative degradation of the heme could both explain why monosubstituted hydrazines are powerful inhibitors of PGHS and very bad reducing cosubstrates of the peroxidase function of PGHS.

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QSAR and conformational analysis of the antiinflammatory agent amfenac and analogues

Ruiz

Lopez

Milà

et al. 1993

J Computer-Aided Mol Des

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The new nonsteroidal antiinflammatory drug (NSAID) arylacetic amfenac (2-amino-3-benzoylphenylacetic acid) and 19 substituted derivatives were studied in order to correlate the biological activities with the structure-related parameters. The geometry of amfenac in neutral and anionic form was totally optimized, starting from standard geometries and crystallographic data, using semiempirical AM1 and MNDO quantum-mechanical methods. Conformational analysis shows the existence of a rigid structure for rotations of the acetic acid chain (alpha degrees) and the central carbonyl group (gamma degrees) around the bonds with the phenylamine ring, whereas the carboxyl group (beta degrees) and the phenyl ring of the benzoyl group (delta degrees) can rotate almost freely. Electrostatic potential maps were analyzed and showed that the electrostatic orientation effect seems to make an important contribution to the binding of the active compounds to prostaglandin synthase. An electrostatic orientation model of the binding site is proposed. The frontier orbital charge distribution was also described for each compound. On the other hand, steric, electronic and hydrophobic (log P) parameters were calculated and QSAR analysis showed that the most significant parameter for the antiinflammatory activity was the pi-electron density of the HOMO orbital in the second aromatic ring. These results suggest a possible electronic charge transfer between the aromatic fragments and the receptor.

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Enzymological Studies on Prostaglandin Biosynthesis

Cited by 30 publications

References 18 publications

Resolution of prostaglandin endoperoxide synthase and thromboxane synthase of human platelets.

Resolution of prostaglandin endoperoxide synthase and thromboxane synthase of human platelets.

Reactions of Prostaglandin H Synthase with Monosubstituted Hydrazines and Diazenes

QSAR and conformational analysis of the antiinflammatory agent amfenac and analogues

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