ASPIRIN INHIBITION AND ACETYLATION OF THE PLANT CYTOCHROME-P450, ALLENE OXIDE SYNTHASE, RESEMBLES THAT OF ANIMAL PROSTAGLANDIN ENDOPEROXIDEH-SYNTHASE

The enzymatic reactions leading to octadecanoid lipid signaling interm ediates in plants are similar to those of animals and are inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) such as salicylic acid and aspirin. In animals, NSAIDs inhibit the cyclooxygenase (COX) activ ity of prostaglandin endoperoxide H synthase, which ultimately blocks the formation of prostaglandins. In plants, NSAIDs block the formation of 12-oxophytodienoic acid and jasmonates, which are the equivalent s ignaling compounds. In this study we show that NSAIDs act as competiti ve inhibitors of allene oxide synthase (AOS), the cytochrome P450 that initiates plant oxylipin synthesis. We also show that aspirin causes the time-dependent inhibition and acetylation of AOS, which leads the irreversible inactivation of this enzyme. This inhibition and acetylat ion superficially resembles that observed for the inactivation of COX in animals. In AOS, aspirin acetylates three serine residues near the C-terminal region that appear to be highly conserved among AOS sequenc es from other plants but are not conserved among ''classical'' type P4 50s. The role of these serine residues is unclear. Unlike animal COX, where acetylation of a single serine residue within the substrate chan nel leads to inactivation of prostaglandin endoperoxide H synthase, th e three serine residues in AOS are not thought to line the putative su bstrate channel. Thus, inhibition by aspirin may be by a different mec hanism. It is possible that aspirin and related NSAIDs could inhibit o ther P450s that have motifs similar to AOS and consequently serve as p otential biochemical targets for this class of drugs.