Selective oxygenation of N-arachidonylglycine by cyclooxygenase-2.
Nonsteroidal anti-inflammatory drugs prevent hyperalgesia and inflammation by inhibiting the cyclooxygenase-2 (COX-2) catalyzed oxygenation of arachidonic acid to prostaglandin (PG) H(2). The lipoamino acid N-arachidonylglycine (NAGly) has also been shown to suppress tonic inflammatory pain and is naturally present at significant levels in many of the same mammalian tissues that express COX-2. Here, we report that COX-2 selectively metabolizes NAGly to PGH(2) glycine (PGH(2)-Gly) and hydroxyeicosatetraenoic glycine (HETE-Gly). Site-directed mutagenesis experiments identify the side pocket residues of COX-2, especially Arg-513, as critical determinants of the COX-2 selectivity towards NAGly. This is the first report of a charged arachidonyl derivative that is a selective substrate for COX-2. These results suggest a possible role for COX-2 in the regulation of NAGly levels and the formation of a novel class of eicosanoids from NAGly metabolism.
Prusakiewicz
Jeffery J
JJ
Department of Biochemistry, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Kingsley
Philip J
PJ
Kozak
Kevin R
KR
Marnett
Lawrence J
LJ
D000818:Animals; D001095:Arachidonic Acids / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D051546:Cyclooxygenase 2; D005998:Glycine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D008958:Models, Molecular; D010100:Oxygen / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry / Q000378:metabolism*; D011453:Prostaglandins / Q000096:biosynthesis; D013379:Substrate Specificity
D001095:Arachidonic Acids; D006893:Hydroxyeicosatetraenoic Acids; D007527:Isoenzymes; C465623:N-arachidonylglycine; D011453:Prostaglandins; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D010100:Oxygen; D005998:Glycine