Feedback activation of ferrous 5-lipoxygenase during leukotriene synthesis by coexisting linoleic acid

Ferrous lipoxygenases seem to be activated through a feedback control mechanism via FA hydroperoxides generated from PUFAs by partially existing ferric lipoxygenases. However, during leukotriene synthesis, feedback activation of ferrous 5-lipoxygenase in the presence of arachidonic acid (AA) was not observed. In the present study, we examined the feedback activation of ferrous 5-lipoxygenase in the 5-lipoxygenase/AA system in the presence of linoleic aicd (LA), which is a predominant component of membrane phospholipids. When potato 5-lipoxygenase was incubated with AA and LA in the presence of nitroxyl radical, 3-carbamoyl-2,2,5,5-tetramethyl-3-pyrroline-N-oxyl (CmΔP), one-electron redox cycle reaction between ferric and ferrous 5-lipoxygenase was detected. For each revolution of the cycle, one molecule of PUFA and one molecule of its hydroperoxide were converted into PUFA-allyl radical-CmΔP adduct ([PUFA−H]·-CmΔP) and PUFA-epoxyallyl radical-CmΔP adduct ([PUFA−H+O]·-CmΔP), respectively. The ratios, [AA−H]·-CmΔP/[LA−H]·-CmΔP and [AA−H+O]·-CmΔP/[LA−H+O]·-CmΔP, were estimated to be 1.7 and 0.13, respectively. These facts indicate that ferrous 5-lipoxygenase is activated through feedback control in the presence of LA, and that resulting ferric 5-lipoxygenase catalyzes the stoichiometric synthesis of leukotrienes from AA. In conclusion, the biosynthesis of leukotrienes is remarkably efficient. Ferrous lipoxygenases seem to be activated through a feedback control mechanism via FA hydroperoxides generated from PUFAs by partially existing ferric lipoxygenases. However, during leukotriene synthesis, feedback activation of ferrous 5-lipoxygenase in the presence of arachidonic acid (AA) was not observed. In the present study, we examined the feedback activation of ferrous 5-lipoxygenase in the 5-lipoxygenase/AA system in the presence of linoleic aicd (LA), which is a predominant component of membrane phospholipids. When potato 5-lipoxygenase was incubated with AA and LA in the presence of nitroxyl radical, 3-carbamoyl-2,2,5,5-tetramethyl-3-pyrroline-N-oxyl (CmΔP), one-electron redox cycle reaction between ferric and ferrous 5-lipoxygenase was detected. For each revolution of the cycle, one molecule of PUFA and one molecule of its hydroperoxide were converted into PUFA-allyl radical-CmΔP adduct ([PUFA−H]·-CmΔP) and PUFA-epoxyallyl radical-CmΔP adduct ([PUFA−H+O]·-CmΔP), respectively. The ratios, [AA−H]·-CmΔP/[LA−H]·-CmΔP and [AA−H+O]·-CmΔP/[LA−H+O]·-CmΔP, were estimated to be 1.7 and 0.13, respectively. These facts indicate that ferrous 5-lipoxygenase is activated through feedback control in the presence of LA, and that resulting ferric 5-lipoxygenase catalyzes the stoichiometric synthesis of leukotrienes from AA. In conclusion, the biosynthesis of leukotrienes is remarkably efficient. arachidonic acid 3-carbamoyl-2,2,5,5-tetramethyl-3-pyrroline-N-oxyl fatty acid hydroperoxyeicosatetraenoic acid hydroperoxyoctadecadienoic acid linoleic acid liquid chromatography tandem mass spectrometry precursor ion scanning polyunsaturated fatty acid extracted ion chromatogram It is generally accepted that lipoxygenases exist in vivo in an inactive ferrous form (1.Schilstra M.J. Veldink G.A. Vliegenthart J.F.G. The dioxygenation rate in lipoxygenase catalysis is determined by the amount of iron (III) lipoxygenase in solution.Biochemistry. 1994; 33: 3974-3979Crossref PubMed Scopus (94) Google Scholar, 2.De Groot J.J.M.C. Veldink G.A. Vliegenthart J.F.G. Boldingh J. Wever R. Van Gelder B.F. Demonstration by EPR spectroscopy of the functional role of iron in soybean lipoxygenase-1.Biochim. Biophys. Acta. 1975; 377: 71-79Crossref PubMed Scopus (294) Google Scholar, 3.Ludwig P. Holzhütter H.G. Colosimo A. Silvestrini M.C. Schewe T. Rapoport S.M. A kinetic model for lipoxygenases based on experimental data with the lipoxygenase of reticulocytes.Eur. J. Biochem. 1987; 168: 325-337Crossref PubMed Scopus (97) Google Scholar). In earlier reports, it was demonstrated that, in the reaction of soybean lipoxygenase (15-lipoxygenase) with linoleic acid (LA), accumulation of hydroperoxides started just after a specific time lag. Interestingly, the kinetics of soybean lipoxygenase reactions with PUFA was altered by supplementation with exogenous hydroperoxides, which reduced the initial lag phase of the reaction. Namely, the lipoxygenase reactions in vivo appear to be regulated through feedback control system dependent on resulting hydroperoxides, which were produced by partially existing ferric lipoxygenase (4.Haining J.L. Axelrod B. Induction period in the lipoxidase-catalyzed oxidation of linoleic acid and its abolition by substrate peroxide.J. Biol. Chem. 1958; 232: 193-202Abstract Full Text PDF PubMed Google Scholar, 5.Finazzi-Agro A. Avigliano L. Veldink G.A. Vliegenthart J.F. Boldingh J. The influence of oxygen on the fluorescence of lipoxygenase.Biochim. Biophys. Acta. 1973; 326: 462-470Crossref PubMed Scopus (128) Google Scholar, 6.Schilstra M.J. Veldink G.A. Verhagen J. Vliegenthart J.F.G. Effect of lipid hydroperoxide on lipoxygenase kinetics.Biochemistry. 1992; 31: 7692-7699Crossref PubMed Scopus (77) Google Scholar). 5-Lipoxygenase, which catalyzes leukotriene synthesis from arachidonic acid (AA), also exists in an inactive ferrous form in vivo. However, ferrous 5-lipoxygenase is hardly activated by feedback control mechanisms during reactions with AA (7.Maclouf J. De Laclos B.F. Borgeat P. Stimulation of leukotriene biosynthesis in human blood leukocytes by platelet-derived 12-hydroperoxy-icosatetraenoic acid.Proc. Natl. Acad. Sci. USA. 1982; 79: 6042-6046Crossref PubMed Scopus (147) Google Scholar, 8.Rouzer C.A. Samuelsson B. The importance of hydroperoxide activation for the detection and assay of mammalian 5-lipoxygenase.FEBS Lett. 1986; 204: 293-296Crossref PubMed Scopus (109) Google Scholar, 9.Riendeau D. Denis D. Choo L.Y. Nathaniel D.J. Stimulation of 5-lipoxygenase activity under conditions which promote lipid peroxidation.Biochem. J. 1989; 263: 565-572Crossref PubMed Scopus (42) Google Scholar). In addition, the pseudoperoxidase (lipohydroperoxidase) reaction of ferrous 5-lipoxygenase using 5-hydroperoxyeicosatetraenoic acid (5-HpETE) as a substrate wastes a part of AA that must be stoichiometrically converted to leukotrienes. Namely, feedback control of 5-lipoxygenase activation in the 5-lipoxygenase/AA system may be inefficient for the biosynthesis of the physiologically functional molecule. In contrast, PUFAs, which are essential components of phospholipids in biological membranes, consist of not only AA but also LA (10.Fisher M. Johnson M.H. Natale A.M. Levine P.H. Linoleic acid levels in white blood cells, platelets, and serum of multiple sclerosis patients.Acta Neurol. Scand. 1987; 76: 241-245Crossref PubMed Scopus (17) Google Scholar). LA is a suitable substrate for 5-lipoxygenase. Conclusively, we hypothesized that LA plays a role in the feedback activation of 5-lipoxygenase for efficient leukotriene synthesis. In our previous reports (11.Koshiishi I. Tsuchida K. Takajo T. Komatsu M. Radical scavenger can scavenge lipid allyl radicals complexed with lipoxygenase at lower oxygen content.Biochem. J. 2006; 395: 303-309Crossref PubMed Scopus (19) Google Scholar, 12.Koshiishi I. Tsuchida K. Takajo T. Komatsu M. Quantification of lipid alkyl radicals trapped with nitroxyl radical via HPLC with postcolumn thermal decomposition.J. Lipid Res. 2005; 46: 2506-2513Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar), we established a novel method for converting ferric lipoxygenase into its ferrous form. When soybean ferric lipoxygenase was incubated with PUFAs in the presence of nitroxyl radical, which selectively traps carbon-centered radicals, FA allyl radical on the ferrous lipoxygenase (13.Nelson M.J. Seitz S.P. Cowling R.A. Enzyme-bound pentadienyl and peroxyl radicals in purple lipoxygenase.Biochemistry. 1990; 29: 6897-6903Crossref PubMed Scopus (76) Google Scholar, 14.Nelson M.J. Cowling R.A. Seitz S.P. Structural characterization of alkyl and peroxyl radicals in solutions of purple lipoxygenase.Biochemistry. 1994; 33: 4966-4973Crossref PubMed Scopus (80) Google Scholar, 15.Nelson M.J. Chase D.B. Seitz S.P. Photolysis of “purple” lipoxygenase: implications for the structure of the chromophore.Biochemistry. 1995; 34: 6159-6163Crossref PubMed Scopus (34) Google Scholar) was trapped by nitroxyl radical, generating ferrous lipoxygenase. This one-electron reduction of ferric lipoxygenase appeared to be linked to one-electron oxidation of ferrous lipoxygenase (pseudoperoxidase reaction), which converts hydroperoxy FA into FA alkoxyl radical. Subsequently, the FA alkoxyl radical immediately changes into epoxyallyl radical through intramolecular rearrangement (16.Iwahashi H. Parker C.E. Mason R.P. Tomer K.B. Radical adducts of nitrosobenzene and 2-methyl-2-nitrosopropane with 12,13-epoxylinoleic acid radical, 12,13-epoxylinolenic acid radical and 14,15-epoxyarachidonic acid radical: Identification by h.p.l.c.-e.p.r. and liquid chromatography-thermospray-m.s.Biochem. J. 1991; 276: 447-453Crossref PubMed Scopus (46) Google Scholar, 17.Garssen G.J. Veldink G.A. Vliegenthart J.F.G. Boldingh J. The formation of threo-11-hydroxy-trans-12:13-epoxy-9-cis-octadecanoic acid by enzymatic isomerization of 13-L-hydroperoxy-9-cis,11-trans-octadecadienoic acid by soybean lipoxygenase-1.Eur. J. Biochem. 1976; 62: 33-36Crossref PubMed Scopus (89) Google Scholar), and this carbon-centered radical is also trapped by nitroxyl radical. Therefore, each revolution of the one-electron redox cycle reaction produces a FA allyl radical-nitroxyl radical adduct and a FA epoxyallyl radical-nitroxyl radical adduct. These adducts are able to be quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) using the precursor ion scanning (PIS) technique (18.Takajo T. Tsuchida K. Murahashi T. Ueno K. Koshiishi I. Intramolecular rearrangement of linolenate peroxyl radicals in lipoxygenase reactions at lower oxygen content.J. Lipid Res. 2007; 48: 855-862Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar). In the present study, we evaluated a function of LA in the feedback control of leukotriene synthesis, by using potato 5-lipoxygenase and the nitroxyl radical spin-trapping method. Potato tuber 5-lipoxygenase and 9-hydroperoxyoctadecadienoic acid (9-HpODE) were obtained from Cayman Chemical (Ann Arbor, MI). Rabbit reticulocyte 15-lipoxygenase was obtained from BIOMOL Research Lab. Inc. Soybean lipoxygenase-1 (Type I-b), LA, and AA were obtained from Sigma Co. (St. Louis, MO). 13-Hydroperoxy-(9Z,11E)-octadecadienoic acid (13-HpODE) was obtained from Wako Pure Chemical Industries Ltd. (Osaka, Japan). 3-Carbamoyl-2,2,5,5-tetramethyl-3-pyrroline-N-oxyl (CmΔP) was obtained from Aldrich Chemical Co., Inc. (Milwaukee, WI). The nitroxyl radical was recrystallized in ethanol before use. TSKgel ODS-80Ts QA and TSKguardgel ODS-80Ts were obtained from Tosoh Co. (Tokyo, Japan). Chelex® 100 Resin (100–200 mesh) was obtained from Bio-Rad Lab (Hercules, CA). All other chemicals were reagent grade. LA and AA were chromatographically purified as follows: 2 ml of 50 mM FA in 50% acetonitrile were passed through two Sep-Pak Plus C18 columns (Waters Co., Milford, MA). FA on the columns was eluted by water-acetonitrile gradient elution. These operations were performed in a nitrogen atmosphere. Contaminant hydroperoxide was eluted before FA. The FA fraction was evaporated, and the residue was dissolved in ethanol. The concentration was adjusted to 100 mM, and the solution was stored at −80°C. FA-derived carbon-centered radicals generated in the PUFA/lipoxygenase system were trapped by nitroxyl radical, CmΔP, as follows: 20 μl of 2 mM PUFA emulsion in 0.1 M phosphate buffer (pH 7.4, treated with Chelex 100) containing 2% ethanol was mixed with 10 μl of 4 mM nitroxyl radical in 0.1 M phosphate buffer (pH 7.4, treated with Chelex 100) and 10 μl of lipoxygenase in 0.1 M phosphate buffer (pH 7.4, treated with Chelex 100) in a glass vial tube with screw cap (inner volume, 0.5 ml), which was incubated at 25°C for 10 min. The reaction solution was mixed with 160 μl of cold acetonitrile and centrifuged at 10,000 g for 1 min. The supernatant was subjected to LC-MS/MS-PIS. The chromatographic conditions for the quantification of FA-derived carbon-centered radical-nitroxyl radical adducts are as follows: column, TSKgel ODS-80Ts QA 4.6 mm i.d. × 150 mm with guard column, TSKguardgel ODS-80Ts (3.2 mm i.d. × 15 mm); eluent, 75% acetonitrile containing 0.05% formic acid; flow rate, 1.0 ml/min; column temperature, 25–28°C. The on-line LC-MS/MS system consisted of the Agilent1100 HPLC system and API 4000® Triple Quadrupole LC-MS/MS system (Applied Biosystems/MDS Sciex; Concord, ON, Canada) equipped with an electrospray ion source (ESI). MS/MS conditions for API-4000 were as follows: polarity, positive; curtain gas, 50 psi; ion source gas 1, 30 psi; ion source gas 2, 70 psi; ion spray voltage, 5500 V; temperature, 600°C; collision gas, 1.00; eclistering potential, 81 V; entrance potential, 10 V; collision cell exit potential, 15 V; collision energy, 30 V; channel electron multiplier, 2000 V; deflector, −100 V. Arachidonate allyl radicals generated in the 5-lipoxygenase/AA system containing HpODE were trapped with the nitroxyl radical, CmΔP, as follows: 10 μl of 4 mM AA emulsion in 0.1 M phosphate buffer (pH 7.4, treated with Chelex 100) containing 4% ethanol was mixed with 10 μl of HpODE in 0.1 M phosphate buffer (pH 7.4, treated with Chelex 100), 10 μl of 4 mM CmΔP in 0.1 M phosphate buffer (pH 7.4, treated with Chelex 100) and 10 μl of 5-lipoxygenase solution in a glass vial tube with screw cap (inner volume, 0.5 ml), which was incubated at 25°C for 10 min. The reaction solution was mixed with 160 μl of cold acetonitrile and centrifuged at 10,000 g for 1 min at 0°C. The supernatant was subjected to HPLC with ultraviolet (UV)-detection at 234 nm. When 0.1 M phosphate buffer solution (pH 7.4; 200–250 μM soluble oxygen) containing a concentrated suspension of PUFA and ferric lipoxygenase was incubated in a sealed glass vial, the ratio of residual FA content to its hydroperoxide content reached 6:4. At the end of the reaction, lipoxygenase may exist in the form of FA allyl radical-ferrous lipoxygenase complex. As shown in Fig. 1, coexisting nitroxyl radical (CmΔP) scavenges the FA allyl radical on the lipoxygenase, producing FA allyl radical-nitroxyl radical adducts and ferrous lipoxygenase (11.Koshiishi I. Tsuchida K. Takajo T. Komatsu M. Radical scavenger can scavenge lipid allyl radicals complexed with lipoxygenase at lower oxygen content.Biochem. J. 2006; 395: 303-309Crossref PubMed Scopus (19) Google Scholar). Subsequently, the ferrous lipoxygenase should be reoxidized to ferric one by cycling hydroperoxides through a pseudoperoxidase reaction, generating a FA alkoxyl radical, which may be intramolecularly rearranged by the addition of a double bond to form the FA epoxyallyl radical (carbon-centered radical) (16.Iwahashi H. Parker C.E. Mason R.P. Tomer K.B. Radical adducts of nitrosobenzene and 2-methyl-2-nitrosopropane with 12,13-epoxylinoleic acid radical, 12,13-epoxylinolenic acid radical and 14,15-epoxyarachidonic acid radical: Identification by h.p.l.c.-e.p.r. and liquid chromatography-thermospray-m.s.Biochem. J. 1991; 276: 447-453Crossref PubMed Scopus (46) Google Scholar, 17.Garssen G.J. Veldink G.A. Vliegenthart J.F.G. Boldingh J. The formation of threo-11-hydroxy-trans-12:13-epoxy-9-cis-octadecanoic acid by enzymatic isomerization of 13-L-hydroperoxy-9-cis,11-trans-octadecadienoic acid by soybean lipoxygenase-1.Eur. J. Biochem. 1976; 62: 33-36Crossref PubMed Scopus (89) Google Scholar). Nitroxyl radical can trap FA epoxyallyl radical to the FA epoxyallyl radical-nitroxyl radical adduct through radical-radical conjunction (12.Koshiishi I. Tsuchida K. Takajo T. Komatsu M. Quantification of lipid alkyl radicals trapped with nitroxyl radical via HPLC with postcolumn thermal decomposition.J. Lipid Res. 2005; 46: 2506-2513Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). Namely, each revolution of the redox cycle reaction between ferrous lipoxygenase and ferric one produces one FA allyl radical-nitroxyl radical adduct and one FA epoxyallyl radical-nitroxyl radical adduct. FA-derived carbon-centered radical-CmΔP adducts are commonly cleaved into a hydroxylamine form of CmΔP (molecular mass, 184) and residual cationic FA derivatives (12.Koshiishi I. Tsuchida K. Takajo T. Komatsu M. Quantification of lipid alkyl radicals trapped with nitroxyl radical via HPLC with postcolumn thermal decomposition.J. Lipid Res. 2005; 46: 2506-2513Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). Therefore, it is possible to selectively detect adducts by LC-MS/MS with PIS for m/z 185. The intermediate carbon-centered E/Z-pentadiene radical on lipoxygenase undergoes resonance stabilization into two positionally isomeric pentadiene radicals; −CH = CH−CH = CH−·CH− and −·CH−CH = CH−CH = CH−. Nitroxyl radical can bind to both sides of the pentadiene moiety, generating two regioisomers of FA allyl radical-nitroxyl radical adduct. For example, in the lipoxygenase/LA/nitroxyl radical system, octadecadienoic acid substituted by nitroxyl radical at the C-9 or C-13 position should be generated. In the present study, we used soybean lipoxygenase-1 and rabbit reticulocyte lipoxygenase as 15-lipoxygenase and 12/15-lipoxygenase isozymes, respectively. LA was incubated with soybean 15-lipoxygenase or rabbit reticulocyte 12/15-lipoxygenase in the presence of CmΔP in phosphate buffer solution (pH 7.4), and the reaction solution was then subjected to LC-MS/MS-PIS. The extracted ion chromatograms (XIC) of m/z 463 corresponding to [LA−H]·-CmΔP are shown in Fig. 2A , C. These results indicate that allyl and allyl were generated for both soybean 15-lipoxygenase and rabbit reticulocyte It is of that predominant hydroperoxide produced in the or system is it was that the ferrous and to ferric through pseudoperoxidase reaction. In a AA was incubated with soybean 15-lipoxygenase or rabbit reticulocyte 12/15-lipoxygenase in the presence of CmΔP in phosphate buffer solution (pH and the reaction solution was then subjected to LC-MS/MS-PIS. The of m/z corresponding to allyl radical-CmΔP adducts are shown in Fig. D. As shown in Fig. two regioisomers corresponding to acid substituted by CmΔP at the or position were produced in the In contrast, in the system, regioisomers corresponding to acid substituted by CmΔP at the or position were 12/15-lipoxygenase at the C-13 or on ferrous and 12/15-lipoxygenase are activated to the ferric form via through a pseudoperoxidase reaction during feedback In the present study, we used potato tuber 5-lipoxygenase as a 5-lipoxygenase. LA at the but not the C-13 position T. from potato and of an that the of linoleic J. PubMed Scopus Google Scholar). ion chromatograms When the reaction solution of the system was subjected to allyl and allyl adducts were at and min In contrast, in the system, acid substituted by CmΔP at the or C-9 position should be generated. allyl radical-CmΔP adducts were not in the system at not However, purified LA was to the system, not only allyl radical-CmΔP adducts but also allyl radical-CmΔP adducts were generated in the reaction solution The of FA-derived carbon-centered radical-CmΔP adducts eluted the period of min and the of m/z are shown in Fig. 4 Interestingly, the content of epoxyallyl radical-CmΔP adducts was that of epoxyallyl radical-CmΔP The ratio of was estimated to be 0.13, the ratio of [AA−H]·-CmΔP/[LA−H]·-CmΔP was estimated to be regioisomers corresponding to acid substituted by CmΔP at the or C-9 position were at and min. on it was that ferrous 5-lipoxygenase is not activated to ferric 5-lipoxygenase by through a pseudoperoxidase reaction but is dependent on of corresponding to of fatty acid radical-CmΔP adducts eluted from to 30 and the extracted ion chromatogram from the ion chromatogram in LC-MS/MS with precursor ion scanning for m/z 185. buffer solution (pH containing polyunsaturated fatty acid mM linoleic aicd and 0.5 mM 1 mM CmΔP, and 5-lipoxygenase was incubated at 25°C for 10 min. extracted ion It is generally that the predominant resulting hydroperoxides in the system and the system are and T. from potato and of an that the of linoleic J. PubMed Scopus Google Scholar). The epoxyallyl radical-CmΔP adducts produced in the system should be two regioisomers corresponding to acid substituted by CmΔP at the or C-9 In contrast, the epoxyallyl radical-CmΔP adducts produced in the system should be two regioisomers corresponding to acid substituted by CmΔP at the or C-13 The of both regioisomers should on the in the of corresponding the of carbon-centered radical-CmΔP This that epoxyallyl radical-CmΔP adducts from are eluted at and from are eluted at min. the activation of ferrous 5-lipoxygenase by HpODE but not we examined supplementation of the system with HpODE the of allyl radical-CmΔP are shown in Fig. and appeared to ferrous 5-lipoxygenase into its ferric adducts in an HpODE 20 μM HpODE to be through oxidation of ferrous lipoxygenase as as in the It should be that the HpODE content was to ferrous 5-lipoxygenase into the ferric Therefore, 200–250 μM which to the oxygen content in the reaction should be generated in the system containing These facts indicate that promote the one-electron redox cycle reaction between ferrous 5-lipoxygenase and ferric It is generally accepted that soybean ferrous lipoxygenase is converted into its ferric form through pseudoperoxidase reaction using hydroperoxide as a This is the hydroperoxide content in the soybean system after a time lag. In the present study, we alkoxyl radical in the reaction of ferrous soybean 15-lipoxygenase with via the nitroxyl radical spin-trapping method. In addition, we that mammalian ferrous 12/15-lipoxygenase was activated in the system through feedback we feedback activation in both the soybean system and rabbit reticulocyte system, in which or as a substrate for the pseudoperoxidase reaction. These facts indicate that of ferrous or 12/15-lipoxygenase hydroperoxides is In contrast, feedback activation in the potato 5-lipoxygenase/AA system was not in the present reports that a amount of was produced mammalian 5-lipoxygenase was incubated with AA (7.Maclouf J. De Laclos B.F. Borgeat P. Stimulation of leukotriene biosynthesis in human blood leukocytes by platelet-derived 12-hydroperoxy-icosatetraenoic acid.Proc. Natl. Acad. Sci. USA. 1982; 79: 6042-6046Crossref PubMed Scopus (147) Google Scholar, 8.Rouzer C.A. Samuelsson B. The importance of hydroperoxide activation for the detection and assay of mammalian 5-lipoxygenase.FEBS Lett. 1986; 204: 293-296Crossref PubMed Scopus (109) Google Scholar, 9.Riendeau D. Denis D. Choo L.Y. Nathaniel D.J. Stimulation of 5-lipoxygenase activity under conditions which promote lipid peroxidation.Biochem. J. 1989; 263: 565-572Crossref PubMed Scopus (42) Google Scholar). In contrast, demonstrated that supplementation of the 5-lipoxygenase/AA system with exogenous in a in content C.A. Samuelsson B. The importance of hydroperoxide activation for the detection and assay of mammalian 5-lipoxygenase.FEBS Lett. 1986; 204: 293-296Crossref PubMed Scopus (109) Google Scholar, 9.Riendeau D. Denis D. Choo L.Y. Nathaniel D.J. Stimulation of 5-lipoxygenase activity under conditions which promote lipid peroxidation.Biochem. J. 1989; 263: 565-572Crossref PubMed Scopus (42) Google Scholar). that this is to a reduced of 5-lipoxygenase for and Samuelsson C.A. Samuelsson B. The importance of hydroperoxide activation for the detection and assay of mammalian 5-lipoxygenase.FEBS Lett. 1986; 204: 293-296Crossref PubMed Scopus (109) Google Scholar) that the reaction of human ferrous 5-lipoxygenase with was lower and De and Borgeat (7.Maclouf J. De Laclos B.F. Borgeat P. Stimulation of leukotriene biosynthesis in human blood leukocytes by platelet-derived 12-hydroperoxy-icosatetraenoic acid.Proc. Natl. Acad. Sci. USA. 1982; 79: 6042-6046Crossref PubMed Scopus (147) Google Scholar) demonstrated that coexisting in remarkably the of and leukotrienes in the that which was produced in via the reaction, a role not only in feedback activation but also in of through of the lipoxygenase is by PUFA a of that the bond in phospholipids. In the predominant PUFAs at position of phospholipids are LA and AA (10.Fisher M. Johnson M.H. Natale A.M. Levine P.H. Linoleic acid levels in white blood cells, platelets, and serum of multiple sclerosis patients.Acta Neurol. Scand. 1987; 76: 241-245Crossref PubMed Scopus (17) Google Scholar). Therefore, it is to feedback control in the It should be that potato 5-lipoxygenase was used as an of the mammalian potato 5-lipoxygenase is to mammalian 5-lipoxygenase in of both lipoxygenase and leukotriene T. Samuelsson B. with lipoxygenase catalyzes leukotriene synthesis from arachidonic acid.Proc. Natl. Acad. Sci. USA. PubMed Scopus Google Scholar). When 5-lipoxygenase was incubated with AA in the presence of amount of purified LA, the of ferric 5-lipoxygenase for AA was LA, the of ferrous 5-lipoxygenase for was As in Fig. partially existing ferric 5-lipoxygenase catalyzes and from LA and respectively. converts ferrous 5-lipoxygenase into ferric and this results in the of the of leukotrienes from AA.

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