docosapentaenoic-acid and adrenic-acid

The first total synthesis of three omega-6 dihydroxylated (E,E,Z)-docosatrienes has been successfully achieved employing a flexible strategy. The key features encompass a Boland semireduction, to create the (E,E,Z)-triene via an (E,E)-ynediene, and a selective deprotection of a tris(tert-butyldimethylsilyl) ether. The main advantage of the present strategy over previous syntheses of noncyclic dihydroxylated PUFA metabolites derived from docosahexaenoic and arachidonic acids comes from the introduction of the polar head chain at the very end of the synthesis from an advanced, pivotal aldehyde. In terms of divergency this enables late-stage modification of the head group.

Topics: Arachidonic Acids; Docosahexaenoic Acids; Fatty Acids, Unsaturated; Molecular Structure; Stereoisomerism

When rat liver microsomes were incubated with [1-14C]22:4(n-6) under standard conditions for measuring acyl-CoA desaturases, it was not possible to detect the synthesis of any 22:5(n-6). When malonyl-CoA and NADPH were included in the incubation, 22:4(n-6) was chain elongated to 24:4(n-6), which was then desaturated to 24:5(n-6). Rat hepatocytes metabolized [1-14C]22:4(n-6), [3-14C]24:4(n-6), and [3-14C]24:5(n-6) to yield esterified radioactive 22:5(n-6). The results show that 22:4(n-6) is the precursor of 22:5(n-6) but the pathway is independent of an acyl-CoA-dependent 4-desaturase and probably requires intracellular communication between the endoplasmic reticulum and a site for beta-oxidation. Microsomal reaction rates for (n-6) versus (n-3) polyunsaturated fatty acid biosynthesis cannot per se be used to explain why in vivo most membrane lipids preferentially accumulate 22:6(n-3) rather than 22:5(n-6). Rates of desaturation of 24:4(n-6) and 24:5(n-3) at position 6 were similar (M. Geiger et al., Biochim. Biophys. Acta 1170, 137-142, 1993). We now show that 20:4(n-6) and 20:5(n-3) are chain elongated at the same rate as are 22:4(n-6) and 22:5(n-3). At present, no single reaction can be defined as being substrate specific or rate limiting to explain why there is an apparent selective synthesis and acylation of 22:6(n-3) rather than 22:5(n-6) into membrane lipids.

Topics: Animals; Chromatography, High Pressure Liquid; Erucic Acids; Fatty Acids, Unsaturated; Male; Microsomes, Liver; Rats; Rats, Sprague-Dawley; Signal Transduction; Substrate Specificity

The metabolism of the C22 unsaturated fatty acids erucic acid (22:1(n-9)), adrenic acid (22:4(n-6)), docosapentaenoic acid (22:5(n-3)) and docosahexaenoic acid (22:6(n-3)) was studied in cultured fibroblasts from patients with acyl-CoA oxidase deficiency, the Zellweger syndrome, X-linked adrenoleukodystrophy (X-ALD) and normal controls. [3-14C] 22:4 (n-6) and [3-14C] 22:5 (n-3) were shortened (retroconverted) to [1-14C] 20:4 (n-6) and [1-14C] 20:5 (n-3), respectively, in normal and X-ALD fibroblasts. In Zellweger and acyl-CoA oxidase deficient fibroblasts these reactions were deficient. Since the retroconversion is normal in X-ALD fibroblasts peroxisomal very long chain (lignoceryl) CoA ligase is probably not required for the activation of C22 unsaturated fatty acids. The present work with fibroblasts from patients with a specific acyl-CoA oxidase deficiency, previously shown to have a deficient peroxisomal clofibrate-inducible acyl-CoA oxidase, and which accumulate 24:0 and 26:0 fatty acids, supports the view that this enzyme is responsible for the chain-shortening of docosahexaenoic acid (22:6(n-3)), erucic acid (22:1(n-9)), docosapentaenoic acid (22:5(n-3)), and adrenic acid (22:4(n-6)) as well.

Topics: Acyl-CoA Oxidase; Adrenoleukodystrophy; Cell Line; Docosahexaenoic Acids; Erucic Acids; Esterification; Fatty Acids; Fatty Acids, Unsaturated; Fibroblasts; Humans; Microbodies; Oxidation-Reduction; Oxidoreductases; Zellweger Syndrome

This study has investigated the metabolic modification of [3-14C]docosatetraenoate (22:4(n-6)) and [3-14C]docosapentaenoate (22:5(n-3)) by human cells in culture. Fetal skin fibroblasts converted as much as 20% of the incorporated [14C]22:4(n-6) to [14C]20:4(n-6) within 6 h and 41% within 48 h. Retroconversion of incorporated [14C]22:5(n-3) was less than 13% at all time points. Chain shortening of [14C]22:4(n-6) was also 2-6-fold greater than that of [14C]22:5(n-3) in retinoblastoma and vascular endothelial cells. Fibroblasts, vascular endothelial cells and retinoblastoma cells all elongated substantially more [14C]eicosapentaenoate than [14C]arachidonate to the respective C22 fatty acids. Within 3-4 days, fibroblasts incubated with either [14C]20:5(n-3) or [14C]22:5(n-3) had the same ratio of radiolabeled C22:C20 fatty acids in cellular glycerolipids. By contrast, the cells incubated with [14C]22:4(n-6) or [14C]20:4(n-6) did not reach a common C22/C20 equilibrium by 5 days. Although fibroblasts were found to desaturate [14C]22:5(n-3), a substantial lag time was observed; [14C]22:6(n-3) was 2% at 48 h and 20% at 96 h. By contrast, synthesis of [14C]22:6(n-3) by retinoblastoma cells was 51% within 6 h and greater than 90% at 96 h. Desaturation of [14C]22:4(n-6) was observed in retinoblastoma cells, but not in fibroblasts. These results thus suggest that the ratio of C22C20 polyunsaturated fatty acids in cells is regulated by the relative rates of retroconversion and chain elongation, with the net effect of the two processes favoring C20 for n-6 and C22 for the n-3 fatty acids. Furthermore, although fibroblasts desaturate [14C]22:5(n-3), the process appears to be qualitatively different from that of retinoblastoma cells.

Topics: Animals; Carbon Radioisotopes; Cattle; Cell Line; Cells, Cultured; Chromatography, Gas; Endothelium, Vascular; Erucic Acids; Fatty Acids, Unsaturated; Fetus; Fibroblasts; Humans; Kinetics; Skin; Umbilical Veins

Starting three weeks before mating, 12 groups of female rats were fed different amounts of linoleic acid (18:2n-6). Their male pups were killed when 21-days-old. Varying the dietary 18:2n-6 content between 150 and 6200 mg/100 g food intake had the following results. Linoleic acid levels remained very low in brain, myelin, synaptosomes, and retina. In contrast, 18:2n-6 levels increased in sciatic nerve. In heart, linoleic acid levels were high, but were not related to dietary linoleic acid intake. Levels of 18:2n-6 were significantly increased in liver, lung, kidney, and testicle and were even higher in muscle and adipose tissue. On the other hand, in heart a constant amount of 18:2n-6 was found at a low level of dietary 18:2n-6. Constant levels of arachidonic acid (20:4n-6) were reached at 150 mg/100 g diet in all nerve structures, and at 300 mg/100 g diet in testicle and muscle, at 800 mg/100 g diet in kidney, and at 1200 mg/100 g diet in liver, lung, and heart. Constant adrenic acid (22:4n-6) levels were obtained at 150, 900, and 1200 mg/100 g diet in myelin, sciatic nerve, and brain, respectively. Minimal levels were difficult to determine. In all fractions examined accumulation of docosapentaenoic acid (22:5n-6) was the most direct and specific consequence of increasing amounts of dietary 18:2n-6. Tissue eicosapentaenoic acid (20:5n-3) and 22:5n-3 levels were relatively independent of dietary 18:2n-6 intake, except in lung, liver, and kidney. In several organs (muscle, lung, kidney, liver, heart) as well as in myelin, very low levels of dietary linoleic acid led to an increase in 20:5n-3.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adipose Tissue; Animals; Arachidonic Acid; Arachidonic Acids; Brain; Dietary Fats; Eicosapentaenoic Acid; Erucic Acids; Fatty Acids, Unsaturated; Female; Kidney; Linoleic Acid; Linoleic Acids; Lung; Male; Muscles; Myocardium; Nerve Tissue; Nutritional Requirements; Rats; Rats, Inbred Strains; Testis

Human platelets metabolize 7,10,13,16-docosatetraenoic acid and 4,7,10,13,16-docosapentaenoic acid into 22-carbon thromboxanes 19-carbon HHT analogs and 14-hydroxy fatty acids via the lipoxygenase pathway. Conversely the two analogous (n-3) acids, 7,10,13,16,19-docosapentaenoic acid and 4,7,10,13,16,19-docosahexaenoic acid, are metabolized only into a pair of isomeric 11- and 14-hydroxy fatty acids. These findings suggest that platelets may contain more than one lipoxygenase.

Topics: Blood Platelets; Chromatography, High Pressure Liquid; Docosahexaenoic Acids; Erucic Acids; Fatty Acids, Unsaturated; Humans; Indomethacin; Isomerism; Lipoxygenase; Prostaglandin-Endoperoxide Synthases