Alkoxy Lipids

Once an alkoxy derivahve of dihydroxyacetone is formed, reduchon fo fhe 2-OH form, further acylation, and conversion to various alkyl phospholipids and neutral lipids can occur. The pathways (Eq. 21-12, steps b-f) are closely akin to those of Fig. 21-4. The conversion of alkoxy lipids fo plasmalogens occurs by oxidative desaturation (Eq. 21-12, step/). ° The initial steps in the S5mthesis of efher-linked lipids take place principally in the peroxisomes. Enzymes catalyzing both the acylation of dihydroxyacetone phosphate and the S5mthesis of alkyl-dihydroxyacetone-P (step a, Eq. 

The higher alcohols, 16 0, 18 0 and 18 1 (9), form mono- and diethers with glycerol. Such alkoxy-lipids are widely distributed in small amounts in mammals and sea animals. Examples of confirmed structures are shown in Formula 3.48. 

Common names of some deacylated alkoxy lipids (1-0-alkyIglycerol) are the following ... 

The free higher alcohols described under 3.6.2 and the deacylated alkoxy-lipids belong to this class. 

A synthesis of these results has been presented, and evidence presented for the role of alkoxy radicals generated during lipid oxidation (Bogan and Lamar 1995 Tatarko and Bumpus 1993). 

LOO, the peroxyl radical LH, the lipid substrate L, the lipid-derived alkyl radical AH, a chain-breaking antioxidant A, the antioxidant-derived radical. Copper is the catalyst in this reaction and would also form the alkoxy radical as shown in Reaction 2.9 (see text), which is omitted here for the sake of clarity. 

Figure 17.2 Lipid peroxidation scheme. LH, a polyunsaturated fatty acid LOOM, lipid hydroperoxide LOH, lipid alcohol L, lipid radical LOO, lipid hydroperoxyl radical LO, lipid alkoxyl radical. Initiation the LH hydrogen is abstracted by reactive oxygen (e.g. lipid alkyl radical, lipid alkoxy radical, lipid hydroperoxyl radical, hydroxy radical, etc.) to produce a new lipid alkyl radical, L. Propagation the lipid alkyl, alkoxyl or hydroperoxyl radical abstracts hydrogen from the neighbouring LH to generate a new L radical.

In the presence of traces of transition-metal ions, lipid hydroperoxides are a continuous source for the formation of new alkoxy and peroxy radicals which initiate new chain reactions and therefore act as amplifiers for the initial free radical event. 

Lipid alkoxy radicals (LO ) decompose in chain scission reaction to a great variety of reactive aldehydes such as malonaldehyde, hydroxyalkenals, 2-alkenals, 2,4-alkadienals and alkanals. Lipid alkoxy radicals also cause the degradation of the apolipoprotein B (apoB) to smaller peptide fragments. 

The most widely used antioxidants are free radical scavengers that remove reactive radicals formed in the initiation and propagation steps of autoxidation. A number of natural or synthetic phenols can compete, even at low concentrations, with lipid molecules as hydrogen donors to hydroperoxy and alkoxy radicals, producing hydroperoxides and alcohols and an unreactive radical. (3-carotene reacts with per-oxy radicals, producing a less-reactive radical. These stabilized radicals do not initiate or propagate the chain reaction. 

Scheme 1. Possible reactions of the autoxidation process. R is an alkyl group of an unsaturated lipid molecule. H is an a-methylenic hydrogen atom easily detachable because of the activating influence of the neighboring double bond or bonds. RO is alkoxy radical, ROO" is peroxy radical, and is an initiator.

The antioxidant radical produced because of donation of a hydrogen atom has a very low reactivity toward the unsaturated lipids or oxygen therefore, the rate of propagation is very slow. The antioxidant radicals are relatively stable so that they do not initiate a chain or free radical propagating autoxidation reaction unless present in very large quantities. These free radical interceptors react with peroxy radicals (ROO ) to stop chain propagation thus, they inhibit the formation of peroxides (Equation 13). Also, the reaction with alkoxy radicals (RO ) decreases the decomposition of hydroperoxides to harmful degradation products (Equation 14). 

Several inhibitors of lipases have been described (for a review see Patkar et al. [45]). HSL was first described in 1964, but it was not until 2000 that the first inhibitors were reported. Several companies have recently investigated HSL inhibitors to treat diabetes and lipid disorders. In 2000 Alteon [46] published a patent on eu-desmannolides, a natural product isolated from Ivoa microcephala nut. One year later Aventis [47] reported a series of natural products from Streptomyces called cy-clipostines. In the same year Aventis [48] and Novo Nordisk [49] published the first synthetic HSL inhibitors (3,4-dihydro-lH-isoquinolin-2-yl)carbamates, Novo Nordisk, and 3-phenyl-5-alkoxy-l,3,4-oxadiazol-2-ones, Aventis. In 2003, Ontogene [50] described pyrrolopyrazinediones and Novo Nordisk [51] reported another class... 

Closely related to both the triacylglycerols and phospholipids, the ether-linked lipids contain in place of one ester group an alkoxy (-OR) or alkenyl (-0-CH = CH-R) group.Phospholipids containing the alk-... 

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