15‐Hydroperoxy‐PGE₂: Intermediate in Mammalian and Algal Prostaglandin Biosynthesis

Abstract

Arachidonic-acid-derived prostaglandins (PGs), specifically PGE 2 ,p lay ac entral role in inflammation and numerous immunological reactions.T he enzymes of PGE 2 biosynthesis are important pharmacological targets for antiinflammatory drugs.B esides mammals,c ertain edible marine algae possess ac omprehensive repertoire of bioactive arachidonic-acid-derived oxylipins including PGs that may account for food poisoning.D escribed here is the analysis of PGE 2 biosynthesis in the red macroalga Gracilaria vermiculophylla that led to the identification of 15-hydroperoxy-PGE 2 ,anovel precursor of PGE 2 and 15-keto-PGE 2 .Interestingly,this novel precursor is also produced in human macrophages where it represents akey metabolite in an alternative biosynthetic PGE 2 pathway in addition to the well-established arachidonic acid-PGG 2 -PGH 2 -PGE 2 route.T his alternative pathway of mammalian PGE 2 biosynthesis mayo pen novel opportunities to intervene with inflammation-related diseases.

Mammalian‐Like Inflammatory and Pro‐Resolving Oxylipins in Marine Algae

“…This hydroperoxide is the biosynthetic intermediate to PGE 2 and 15-keto-PGE 2 in algae ( Figure 2). [32] Interestingly, the hydroperoxide was previously not observed in mammals where the biosynthesis via PGH 2 is well established. It becomes clear that mammals and algae employ different major routes to the same prostaglandin ( Figure 2).…”

“…Indeed, human macrophages, key producers of lipid mediators during inflammation, contain this hydroperoxide. [32,33] 15-Hydroperoxy-PGE 2 is in fact a hitherto unidentified intermediate in an alternative route to PGE 2 in mammals, where the formation of PGE 2 proceeds along two independent pathways ( Figure 2). [31] The route via 15-hydro- Arachidonic acid is cyclized by COX-1 or COX-2 to PGG 2 , which is reduced by the peroxidase activity of the COX to PGH 2 and subsequently converted by prostaglandin E synthase to PGE 2 .…”

“…Upon re-investigation of the biosynthesis in human macrophages, the alternative route via 15-hydroperoxy-PGE 2 was established in mammals as well (thin red arrows). [32] peroxy-PGE 2 dominates in algae and renders a mixture of PGE 2 and 15-keto-PGE 2 whereas human macrophages preferentially rely on the canonical pathway via PGH 2 with the 15-hydroperoxy-PGE 2 route as a minor pathway (Figure 2). [32] The discovery of an independent route via the hydroperoxide might provide a new paradigm for treating inflammation-related diseases.…”

“…[32] peroxy-PGE 2 dominates in algae and renders a mixture of PGE 2 and 15-keto-PGE 2 whereas human macrophages preferentially rely on the canonical pathway via PGH 2 with the 15-hydroperoxy-PGE 2 route as a minor pathway (Figure 2). [32] The discovery of an independent route via the hydroperoxide might provide a new paradigm for treating inflammation-related diseases. Selective COX peroxidase inhibitors may be developed to alleviate carcinogenic effects from sideproducts formed by the COX peroxide reductase domain while still allowing PGE 2 biosynthesis to occur via the hydroperoxide pathway.…”

“…Selective COX peroxidase inhibitors may be developed to alleviate carcinogenic effects from sideproducts formed by the COX peroxide reductase domain while still allowing PGE 2 biosynthesis to occur via the hydroperoxide pathway. [32] Regarding ingestion of raw alga, 15-hydroperoxy-PGE 2 might be converted to PGE 2 inside the human stomach promoting food poisoning.…”