HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brash, A. R. Articles by Harris, T. M. Search for Related Content PubMed PubMed Citation Articles by Brash, A. R. Articles by Harris, T. M. Social Bookmarking                      What's this?

J. Biol. Chem., Vol. 265, Issue 12, 6705-6712, Apr, 1990

Formation of prostaglandin A analogues via an allene oxide

AR Brash, SW Baertschi and TM Harris
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232.

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.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				B. Zhao, F. P. Guengerich, A. Bellamine, D. C. Lamb, M. Izumikawa, L. Lei, L. M. Podust, M. Sundaramoorthy, J. A. Kalaitzis, L. M. Reddy, et al. Binding of Two Flaviolin Substrate Molecules, Oxidative Coupling, and Crystal Structure of Streptomyces coelicolor A3(2) Cytochrome P450 158A2 J. Biol. Chem., March 25, 2005; 280(12): 11599 - 11607. [Abstract] [Full Text] [PDF]