J Biol Chem, Vol. 274, Issue 33, 22901-22901, August 13, 1999

MINIREVIEW PROLOGUE
A Thematic Series on Oxidation of Lipids as a Source of Messengers^*

From the Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112

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Donleavy described "the black smell of grease ..." in The Ginger Man (1). The importance of the addition of oxygen to lipids has been recognized in literature, paint technology, the food industry, and the biochemistry of lipid messengers, both within and between cells. Biological systems developed enzymatic processes to generate specific oxidized lipids, but even so, the spectrum of compounds is remarkably broad.

Why focus on lipids? After all, other molecules also are oxidized. First, it seems likely that oxidation of lipids precedes that of other biomolecules, at least in the usual in vivo settings. Second, oxidized lipids have in some cases been adopted as regulated second messengers and as such serve the needs of the organism, unlike oxidized proteins, for example, which are destined for destruction. Why are lipids such good candidates for oxidation? Many biologically relevant oxidants prefer a hydrophobic environment, which results in their concentration in membranes. This also brings them into close proximity to the olefinic bonds in the unsaturated fatty acids, which also are in high concentration in membranes, an almost two-dimensional world.

Studies of prostaglandins yielded the first detailed structural and mechanistic insights into such pathways, and the number of products exceeds several score. Prostaglandins derive from arachidonic acid (and close relatives) in a reaction catalyzed by cyclooxygenase (or, more accurately, prostaglandin G/H synthase). Research in this area is a growth industry as the isoforms (two now are recognized) are the culprits in inflammation and cancer and are the targets for nonsteroidal anti-inflammatory drugs. In the first article of this series Marnett and co-authors review the structure and function of these isoenzymes in "Arachidonic Acid Oxygenation by COX-1 and COX-2: Mechanisms of Catalysis and Inhibition." Alan R. Brash follows in the second article of the series with an analysis of another family of oxidases, lipoxygenase, whose members also target arachidonic acid although not as selectively as cyclooxygenase ("Lipoxygenase: Occurrence, Functions, Catalysis, and Acquisition of Substrate"). Some of the lipoxygenases have the interesting property of being able to use as a substrate arachidonic acid (or other polyunsaturated fatty acids) that remains esterified at the sn-2 position of the glycerol backbone in phospholipids; this contrasts with cyclooxygenase, which recognizes only the free fatty acid.

John A. Lawson, Joshua Rokach, and Garret A. FitzGerald continue the theme with the third article of the series, "Isoprostanes: Formation, Analysis, and Use as Indices of Lipid Peroxidation in Vivo," which explores the nonenzymatic generation of another family derived from arachidonic acid, the isoprostanes. These are such close relatives of the prostaglandins that they exert their actions by capturing the receptors for prostaglandins. The key difference is that the lack of enzymatic controls allows excessive amounts of these products to accumulate and provoke (patho)physiological responses. The generation of isoprostanes begins with a free radical-catalyzed attack on esterified arachidonate, and the release from the complex lipid follows; this is the inverse sequence of the prostaglandin synthetic pathway but the same as presumably happens with the lipoxygenase reactions mentioned above. From a medical perspective, this mechanism presents challenges because it circumvents the therapeutic effects of anti-inflammatory drugs. This may be a situation in which antioxidant therapy would be ideal, and the recent detailed structural studies provide new assays for assessing the efficacy of such approaches. The same initial process (peroxidation of arachidonate esterified in phospholipids) also can yield another family of lipid mediators, phospholipids that mimic platelet-activating factor. This is strictly analogous to the isoprostane-prostaglandin relationship in that the free radical-catalyzed process yields a product that is structurally similar to the enzymatically generated one and the receptor is usurped. In this case, the oxidation process proceeds to heterolytic cleavage of the acyl chain, rather than release of the peroxidized fatty acid, and the bioactivity resides in the unusual phospholipid product. As with the isoprostanes, the risk is that excessive amounts will be generated, for example by exposure to cigarette smoke, and lead to a pathological result. This process is reviewed by Thomas M. McIntyre, Guy A. Zimmerman, and myself in "Biologically Active Oxidized Phospholipids," the fourth article in the series.

The final article in the series addresses an area of lipid oxidation that has received the most attention in studies of a disease mechanism, the alteration of low density lipoprotein (LDL). In experimental and clinical studies of atherosclerosis it has been shown that LDL undergoes modifications that result in marked changes in its physicochemical properties and that these changes make the particle a much more effective inducer of pathological events. One of the changes, and perhaps the earliest, is oxidation of various lipids in LDL; this process and its potential role in early stages of atherogenesis are reviewed by Guy M. Chisolm III and co-authors in "The Oxidation of Lipoproteins by Monocyte-Macrophages: Biochemical and Biological Mechanisms."

	FOOTNOTES

^* This minireview will be reprinted in the 1999 Minireview Compendium, which will be available in December, 1999. 

	REFERENCES

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1.	Donleavy, J. P. (1968) The Ginger Man , p. 80, The Atlantic Monthly Press, New York