title: Formation of prostaglandin A analogues via an allene oxide.
abstract: One potential biosynthetic route to the prostaglandins involves the participation of lipoxygenase and allene oxide synthase enzymes, giving a hydroxylated allene oxide, which then might cyclize to form prostaglandin A or a close analogue. We have tested a model of this type of transformation using 8-hydroxy-15S-hydroperoxy eicosanoids as substrates for the dehydrase (allene oxide synthase) in flaxseed. Four of these substrates, each with a 9E,11Z,13E-conjugated triene, gave an observable rate of reaction. The two derived from eicosapentaenoic acid reacted more rapidly than the corresponding arachidonic acid analogues. Also, the 8S-hydroxy-15S-hydroperoxy diastereomers reacted more rapidly than their 8R-hydroxy analogues. Products were characterized by high pressure liquid chromatography, UV, gas chromatography-mass specrometry, 1H NMR, and CD. Reaction of the (8S)-hydroxy-(15S)-hydroperoxy-eicosapentaenoic acid gave two alpha-ketols [8S),15-dihydroxy-14-oxoeicosa-5Z,9E,11Z,17Z+ ++-tetraenoic acid and the corresponding 11E isomer in a 2:1 ratio), together with four prostaglandin A3 analogues which differed in the configurations of the side chains. Oxygen 18 labeling fully supported the intermediacy of an allene oxide in the biosynthesis. The corresponding "8R" substrate was converted to the enantiomers of these products plus three 13-hydroxy-14,15-epoxy derivatives. The arachidonate analogues formed the epoxy-hydroxy derivatives, the alpha-ketols, and two prostaglandin A2 analogues with trans configuration of the side chains. These results demonstrate (i) a feasible route of metabolism of lipoxygenase products to hydroxy allene oxide, (ii) the potential for the resulting allene oxide to cyclize to a prostaglandin A analogue, and (iii) the marked influence of the hydroxyl configuration of the rate of reaction and resulting profile of products. Some of these reactions may occur in a natural pathway of prostanoid biosynthesis in corals and other organisms.
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232.
authors.forename: A R
authors.initials: AR
authors.lastname: Brash
authors.forename: S W
authors.initials: SW
authors.lastname: Baertschi
authors.forename: T M
authors.initials: TM
authors.lastname: Harris
mesh_terms: D002851:Chromatography, High Pressure Liquid; D007202:Indicators and Reagents; D019746:Intramolecular Oxidoreductases; D007535:Isomerases / Q000378:metabolism*; D007700:Kinetics; D008968:Molecular Conformation; D015394:Molecular Structure; D011454:Prostaglandins A / Q000138:chemical synthesis*; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D007202:Indicators and Reagents; D011454:Prostaglandins A; D007535:Isomerases; D019746:Intramolecular Oxidoreductases; C021377:hydroperoxide isomerase