Divergent cyclooxygenase responses to fatty acid structure and peroxide level in fish and mammalian prostaglandin H synthases.
Prostanoid synthesis in mammalian tissues is regulated at the level of prostaglandin H synthase (PGHS) cyclooxygenase catalysis by the availability and structure of substrate fatty acid and the availability of peroxide activator. Two major PGHS isoforms, with distinct pathophysiological functions and catalytic regulation, have been characterized in mammals; a functionally homologous PGHS isoform pair has been cloned from an evolutionarily distant vertebrate, brook trout. The cyclooxygenase activities of recombinant brook trout PGHS-1 and -2 were characterized to test the generality of mammalian regulatory paradigms for substrate specificity, peroxide activation, and product shifting by aspirin. Both trout cyclooxygenases had much more restrictive substrate specificities than their mammalian counterparts, with pronounced discrimination toward arachidonate (20:4n-6) and against eicosapentaenoate (20:5n-3) and docosahexaenoate (22:6n-3), the latter two prominent in trout tissue lipids. Aspirin treatment did not increase lipoxygenase-type catalysis by either trout enzyme. Both trout enzymes had higher requirements for peroxide activator than their mammalian counterparts, though the preferential peroxide activation of PGHS-2 over PGHS-1 seen in mammals was conserved in the fish enzymes. The divergence in cyclooxygenase characteristics between the trout and mammalian PGHS proteins may reflect accomodations to differences among vertebrates in tissue lipid composition and general redox state.
Liu
Wen
W
Department of Internal Medicine, University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, Texas 77030, USA.
Cao
Dazhe
D
Oh
Sungwhan F
SF
Serhan
Charles N
CN
Kulmacz
Richard J
RJ
D000818:Animals; D016718:Arachidonic Acid / Q000737:chemistry / Q000378:metabolism*; D001241:Aspirin / Q000494:pharmacology; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D029941:Fish Proteins / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D010545:Peroxides / Q000378:metabolism*; D012756:Sheep; D013045:Species Specificity; D013379:Substrate Specificity; D013696:Temperature; D014337:Trout / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; D029941:Fish Proteins; D010545:Peroxides; D016718:Arachidonic Acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D001241:Aspirin