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Prostaglandin H synthase-2-catalyzed oxygenation of 2-arachidonoylglycerol is more sensitive to peroxide tone than oxygenation of arachidonic acid.
J Biol Chem. 2012 Oct 26; 287(44):37383-94.JB

Abstract

The endocannabinoid, 2-arachidonoylglycerol (2-AG), is a selective substrate for the inducible isoform of prostaglandin H synthase (PGHS), PGHS-2. Its turnover leads to the formation of glyceryl esters of prostaglandins (PG-Gs), a subset of which elicits agonism at unique, as yet unidentified, receptors. The k(cat)/K(m) values for oxygenation of arachidonic acid (AA) and 2-AG by PGHS-2 are very similar, but the sensitivities of the two substrates to peroxide-dependent activation have not been compared. 15-Hydroperoxy derivatives of AA and 2-AG were found to be comparable in their ability to serve as substrates for the peroxidase activities of PGHS-2, PGHS-1, and glutathione peroxidase (GPx). They also were comparable in the activation of AA oxygenation by cyanide-inhibited PGHS-2. However, oxygenation of 2-AG was significantly suppressed relative to AA by the presence of GPx and GSH. Furthermore, 2-AG oxygenation by peroxidase-deficient H388YmPGHS-2 was much less efficient than AA oxygenation. Wild-type rates of 2-AG oxygenation were restored by treatment of H388YmPGHS-2 with hydroperoxide derivatives of AA or 2-AG. RNAi silencing of phospholipid hydroperoxide-specific GPx (GPx4) in NIH/3T3 cells led to increases in cellular peroxidation and in the levels of the isoprostane product, 8-epi-PGF(2α). GPx4 silencing led to 2-4-fold increases in PG-G formation but no change in PG formation. Thus, cellular peroxide tone may be an important determinant of the extent of endocannabinoid oxygenation by PGHS-2.

Authors+Show Affiliations

A. B. Hancock Jr. Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

22942274

Citation

Musee, Joel, and Lawrence J. Marnett. "Prostaglandin H Synthase-2-catalyzed Oxygenation of 2-arachidonoylglycerol Is More Sensitive to Peroxide Tone Than Oxygenation of Arachidonic Acid." The Journal of Biological Chemistry, vol. 287, no. 44, 2012, pp. 37383-94.
Musee J, Marnett LJ. Prostaglandin H synthase-2-catalyzed oxygenation of 2-arachidonoylglycerol is more sensitive to peroxide tone than oxygenation of arachidonic acid. J Biol Chem. 2012;287(44):37383-94.
Musee, J., & Marnett, L. J. (2012). Prostaglandin H synthase-2-catalyzed oxygenation of 2-arachidonoylglycerol is more sensitive to peroxide tone than oxygenation of arachidonic acid. The Journal of Biological Chemistry, 287(44), 37383-94. https://doi.org/10.1074/jbc.M112.381202
Musee J, Marnett LJ. Prostaglandin H Synthase-2-catalyzed Oxygenation of 2-arachidonoylglycerol Is More Sensitive to Peroxide Tone Than Oxygenation of Arachidonic Acid. J Biol Chem. 2012 Oct 26;287(44):37383-94. PubMed PMID: 22942274.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Prostaglandin H synthase-2-catalyzed oxygenation of 2-arachidonoylglycerol is more sensitive to peroxide tone than oxygenation of arachidonic acid. AU - Musee,Joel, AU - Marnett,Lawrence J, Y1 - 2012/09/01/ PY - 2012/9/4/entrez PY - 2012/9/4/pubmed PY - 2013/1/8/medline SP - 37383 EP - 94 JF - The Journal of biological chemistry JO - J Biol Chem VL - 287 IS - 44 N2 - The endocannabinoid, 2-arachidonoylglycerol (2-AG), is a selective substrate for the inducible isoform of prostaglandin H synthase (PGHS), PGHS-2. Its turnover leads to the formation of glyceryl esters of prostaglandins (PG-Gs), a subset of which elicits agonism at unique, as yet unidentified, receptors. The k(cat)/K(m) values for oxygenation of arachidonic acid (AA) and 2-AG by PGHS-2 are very similar, but the sensitivities of the two substrates to peroxide-dependent activation have not been compared. 15-Hydroperoxy derivatives of AA and 2-AG were found to be comparable in their ability to serve as substrates for the peroxidase activities of PGHS-2, PGHS-1, and glutathione peroxidase (GPx). They also were comparable in the activation of AA oxygenation by cyanide-inhibited PGHS-2. However, oxygenation of 2-AG was significantly suppressed relative to AA by the presence of GPx and GSH. Furthermore, 2-AG oxygenation by peroxidase-deficient H388YmPGHS-2 was much less efficient than AA oxygenation. Wild-type rates of 2-AG oxygenation were restored by treatment of H388YmPGHS-2 with hydroperoxide derivatives of AA or 2-AG. RNAi silencing of phospholipid hydroperoxide-specific GPx (GPx4) in NIH/3T3 cells led to increases in cellular peroxidation and in the levels of the isoprostane product, 8-epi-PGF(2α). GPx4 silencing led to 2-4-fold increases in PG-G formation but no change in PG formation. Thus, cellular peroxide tone may be an important determinant of the extent of endocannabinoid oxygenation by PGHS-2. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/22942274/Prostaglandin_H_synthase_2_catalyzed_oxygenation_of_2_arachidonoylglycerol_is_more_sensitive_to_peroxide_tone_than_oxygenation_of_arachidonic_acid_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)62535-2 DB - PRIME DP - Unbound Medicine ER -