Eicosanoids and related compounds: structures, nomenclature and biosynthetic pathways

Hartmut Kühn and Sabine Borngräber

Institute of Biochemistry, University Clinics (Charité), Humboldt University, Hessische Str. 3-4, 10115 Berlin, Germany

Introduction

Eicosanoids and oxylipins comprise a family of structurally related lipid mediators that exhibit in teresting biological activities in animals and in the plant kingdom, respectively. Eicosanoids are synthesized from arachidonic acid (AA) that is released upon cell stimulation from membrane phospholipids. However, AA is not the only substrate for eicosanoid synthesis. Even in mammals, where it is one of the major polyenoic fatty acids, other fatty acids with different chain lengths and different degrees of unsaturation may be used as substrate (Fig. I). In higher plants, AA only occurs in small amounts and thus eicosanoids are usually not formed. In stead, the C-18 fatty acids (linoleic acid and α-linolenic acid) which occur in plants in large amounts are converted into oxylipins via several oxidative pathways. In the early days of eicosanoid research only a small number of bioactive lipids were known and there was no need for a systematic classification. How ever, during the last 20 years a large variety of eicosanoids and structurally related lipid mediators have been identified and for most of them the biosynthetic route has been investigated. To manage this structural multiplicity, a systematic classification and a comprehensive nom enclature for eicosanoids and related com pounds is required.

In this introductory chapter the basic rules for the currently used classification and nomenclature of eicosanoids and related compounds are summarized. For more detailed information the reader is referred to several reviews in which the nomenclature of Hcosanoids and oxylipins is explained. Moreover, the recommendations of the Committee on Eicosanoid Nomenclature may be consulted. In this paper suggestions for the nomenclature of enzymes involved in eicosanoid metabolism are also provided. These suggestions have been considered for revision of the recommendations of the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology on the Nomenclature and Classification of Enzymes.

Eicosanoids and related compounds in animals

The arachidonic acid cascade

As indicated above, the major source of eicosanoids and related com pounds in animals is the AA cascade (Fig. 2). Upon cell stimulation, AA, or under certain circumstances other precursor fatty acids, are liberated from the membrane phospholipids via activation of lipid-cleaving enzymes, such as phospholipase A 2 The free fatty acids are subsequently metabolized via three different pathways (Fig. 2). (i) The cyclooxygenase (COX) pathway, forming prostaglandins, thromboxanes or prostacyclins, (ii) the lipoxygenase (LOX) pathway, forming leukotrienes, lipoxins, hepoxilins and hydro(pero)xy fatty acids and (iii) the cytochrome P-450 (cyt P-450) pathway, forming hydroxylated fatty acids and epoxy derivatives. In these metabolic routes the initial reaction is an oxygenation of the fatty acid substrate. During the COX reaction two molecules of dioxygen are introduced, one at C11 and the second at C15 of the AA backbone. In contrast, the LOX reaction involves the introduction of one molecule of dioxygen at different positions of the substrate molecule, which are determined by the positional specificity of the enzymes. During cyt P-450-catalysed oxygenation, atomic oxygen is introduced, leading to fatty acid hydroxylation or to epoxidation of double bonds. Both the COX and LOX reactions are initiated by hydrogen abstractions from doubly allylic methylene groups, forming fatty acid radicals. This radical formation may be regarded as fatty acid activation. In contrast, the cyt-P-450-catalysed oxygenation involves activation of atmospheric dioxygen, destabilizing the O-O bond. After this, one oxygen atom is transferred to the fatty acid substrate, the other one is reduced, forming water.

The cyclooxygenase pathway

More than 50 years ago a com pound was discovered in the seminal fluid and in the prostate which caused contraction of smooth muscle cells. Although the chemical structure of this factor remained unclear for many years, it was named prostaglandin because of its organ source. Since then the chemical structures of a variety of prostanoids have been identified, and we also know that the prostate is not the only, and not even the major, source of prostaglandin (PG) formation. Moreover, most enzymes involved in prostaglandin biosynthesis have been well characterized.

The initial enzyme for prostagland information is prostaglandin endoperoxide synthase which, for simplicity, is called cyclooxygenase. This enzyme, the three-dimensional structure of which has been reported is a haemoprotein and exhibits both cyclooxygenase and peroxidase activity. It introduces two molecules of dioxygen into the fatty acid substrate, forming the cyclic endoperoxide PGG2 which is subsequently reduced to the m ore stable PGH2 (Scheme 1). PGH2 serves as substrate for the formation of the classical prostaglandins PGD2, PGE2 and PGF2α which exhibit interesting bioactivities.

Two isoenzymes of COX have been shown to exist: COX-1 is constitutively expressed in many mammalian cells and tissues and appears to be responsible for the formation of prostaglandins involved in the regulation of physiological events. COX-2 is an inducible form of the enzyme that is low-level expressed in inflammatory cells under basal conditions but is strongly induced in response to inflammatory stimuli. This induction suggested an involvement of the enzyme in the pathogenesis of inflammation and suggested COX-2 as a major target for the development of non-steroidal anti-inflammatory drugs.

AA, which contains four double bonds (Fig. 1), is converted via the COX...