In vitro activity of the fatty acyl desaturases of human cancerous and noncancerous tissues

Nakazawa, Ichiro; Mead, James F.; Yonemoto, Robert H.

doi:10.1007/bf02532589

Cited by 23 publications

(12 citation statements)

References 11 publications

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“…Conversion of 20:2co6 to 20:3006 by A8desaturation has been shown in rat testis (16), human bladder and colon (17). If this enzyme is present in the cat, it could account for the synthesis of some arachidonate from linoleate via 20:2co6 and the A8-desaturation step as shown in the diagram.…”

Section: Resultsmentioning

confidence: 94%

Metabolism of linoleic acid in the cat

Sinclair¹,

McLean

Monger

1979

Lipids

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Cats fed a diet containing linoleate as the only polyunsaturated fatty acid showed extremely low levels of arachidonate in the plasma lipids, as well as an increase in linoleate, eicosadienoate and an unknown fatty acid. Administration of [1-14C]linoleic acid and [2-14C]eicosa-8,11,14-trienoic acid to cats showed that in the liver there was no conversion of the [1-14C] 18:2 to arachidonate, whereas there was significant metabolism of [2-14C] 20:3 to arachidonate. It was found when methyl-gamma-linolenate was fed to cats that the level of 20:3 omega 6 and 20:4 omega 6 in the erythrocytes increased significantly. These results show that there is no significant delta 6 desaturase activity in the cat, whereas chain elongation and delta 5 desaturase enzymes are operative. The unknown fatty acid was isolated from the liver lipids and shown to be a 20-carbon fatty acid with 3 double bonds and which by gas liquid chromatography could be separated from 20:3 omega 9 and 20:3 omega 6. The presence of the delta 5-desaturase activity and the results of the ozonolysis studies indicated that this unknown fatty acid was eicosa-5,11,14-trienoic acid.

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Section: Resultsmentioning

confidence: 94%

Metabolism of linoleic acid in the cat

Sinclair¹,

McLean

Monger

1979

Lipids

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“…There are many reports of D8-desaturation activity in mammalian cells (25,26), in rat and human testes (27,28), and in mouse liver (29), though it has not been verified by molecular cloning, and the existence of D8-desaturation in rat microsomes has been questioned (30). The putative substrate of the D8-desaturase, 11,14-eicosadienoic acid (20:2 n-6), is found in human plasma and red cells as well as other tissues, and its concentration has recently been associated with human genetic variation in the FADS gene cluster (31,32).…”

mentioning

confidence: 99%

An alternate pathway to long-chain polyunsaturates: the FADS2 gene product Δ8-desaturates 20:2n-6 and 20:3n-3

Park

Kothapalli

Lawrence

et al. 2009

Journal of Lipid Research

188

151

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The mammalian #6-desaturase coded by fatty acid desaturase 2 (FADS2; HSA11q12-q13.1) catalyzes the first and rate-limiting step for the biosynthesis of long-chain polyunsaturated fatty acids. FADS2 is known to act on at least five substrates, and we hypothesized that the FADS2 gene product would have #8-desaturase activity. Saccharomyces cerevisiae transformed with a FADS2 construct from baboon neonate liver cDNA gained the function to desaturate 11,14-eicosadienoic acid (20:2n-6) and 11,14,17-eicosatrienoic acid (20:3n-3) to yield 20:3n-6 and 20:4n-3, respectively. Competition experiments indicate that #8-desaturation favors activity toward 20:3n-3 over 20:2n-6 by 3-fold. Similar experiments show that #6-desaturase activity is favored over #8-desaturase activity by 7-fold and 23-fold for n-6 (18:2n-6 vs 20:2n-6) and n-3 (18:3n-3 vs 20:3n-3), respectively. In mammals, 20:3n-6 is the immediate precursor of prostaglandin E1 and thromboxane B1. 20:3n-6 and 20:4n-3 are also immediate precursors of long-chain polyunsaturated fatty acids arachidonic acid and eicosapentaenoic acid, respectively. These findings provide unequivocal molecular evidence for a novel alternative biosynthetic route to long-chain polyunsaturated fatty acids in mammals from substrates previously considered to be dead-end products.-Park, W. J., K. S. D. Kothapalli, P. Lawrence, C. Tyburczy, and J. T.Brenna. An alternate pathway to long-chain polyunsaturates: the FADS2 gene product #8-desaturates 20:2n-6 and 20:3n-3. J. Lipid Res. 2009Res. . 50: 1195Res. -1202 Supplementary key words polyunsaturated fatty acid biosynthesis • dihomo-g-linolenic acid • eicosanoid precursor biosynthesis Long-chain polyunsaturated fatty acids (LCPUFAs) are ubiquitous in mammalian tissue, achieving highest concentrations in the membranes of neural and other excitable tissue (1). LCPUFA of the n-3 and n-6 families, especially eicosapentaenoic acid (EPA; 20:5n-3), docosahexaenoic acid (22:6n-3), and arachidonic acid (20:4n-6), are bioactive components of membrane phospholipids and serve as substrates for signaling molecules (2). The degree of unsaturation of the membranes is determined by the action of enzymes involved in fatty acid biosynthesis and metabolism (3). Most organisms synthesize unsaturated fatty acids, but the pathways are specific to cell types and species.Fatty acid desaturases are enzymes that catalyze the introduction of cis double bonds at specific positions in a fatty acid chain (4). Desaturases in plants and lower animal species can introduce double bonds near the methyl end. Eukaryotic cells of higher animals, fungi, and dinoflagellates express membrane-bound acyl-CoA front-end desaturases (5, 6) catalyzing double bond introduction into the D6, D5, D8, and D4 positions. Mammalian front-end desaturases operate on diet-derived PUFA to synthesize LCPUFA, which can also be derived from the diet but possibly not in sufficient quantities to optimize health (7).The front-end desaturases are remarkable for their structural similarity and functiona...

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“…Similar analysis was also carried out on WT Arabidopsis and the parental Isochrysis Δ9‐elongase line CA1‐9. By using this approach, it was hoped to gain further insights into the substrates of the Ac8 Δ8‐desaturase, in particular to determine if this enzyme utilised glycerolipids or acyl‐CoA substrates (a major factor determining the efficiency of transgenic PUFA desaturation) [2,3,13]. As can be seen in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This Δ6‐desaturase/elongase system appears to be the predominant biosynthetic pathway for these LC‐PUFAs in a wide range of organisms from microalgae to mammals. However, a few (equally diverse) organisms have been reported to possess an “alternative” pathway, in which the substrates LA and ALA are initially elongated by a specific Δ9‐elongase to yield 20:2, n − 6 and 20:3, n − 3 [3,4]. These products then undergo Δ8‐desaturation, producing substrates for “conventional” Δ5‐desaturation.…”

Section: Introductionmentioning

confidence: 99%

The alternative pathway C₂₀ Δ8‐desaturase from the non‐photosynthetic organism Acanthamoeba castellanii is an atypical cytochrome b₅‐fusion desaturase

Sayanova

Haslam

et al. 2006

FEBS Letters

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A cDNA encoding a C 20 D8-desaturase was isolated from the free-living soil amoeba, Acanthamoeba castellanii and functionally characterised by heterologous expression. The open reading frame of the A. castellanii C 20 D8-desaturase showed similarity to other microsomal front-end desaturases, but the N-terminal domain contained a variant form of the conserved heme-binding motif in which H-P-G-G is replaced by H-P-A-G. Co-expression of the A. castellani D8-desaturase with the Isochrysis galbana D9-elongase in transgenic Arabidopsis plants confirmed the activity observed in yeast and its role in the alternative pathway for C 20 polyunsaturated fatty acid synthesis. Acyl-CoA profiles of these transgenic plants revealed an unexpected accumulation of C 20 fatty acids in the acyl-CoA pool. This is the first report of an alternative pathway C 20 D8-desaturase from a non-photosynthetic organism, and also the first report of a front-end desaturase lacking the canonical cytochrome b 5 domain.

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In vitro activity of the fatty acyl desaturases of human cancerous and noncancerous tissues

Cited by 23 publications

References 11 publications

Metabolism of linoleic acid in the cat

Metabolism of linoleic acid in the cat

An alternate pathway to long-chain polyunsaturates: the FADS2 gene product Δ8-desaturates 20:2n-6 and 20:3n-3

The alternative pathway C₂₀ Δ8‐desaturase from the non‐photosynthetic organism Acanthamoeba castellanii is an atypical cytochrome b₅‐fusion desaturase

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In vitro activity of the fatty acyl desaturases of human cancerous and noncancerous tissues

Cited by 23 publications

References 11 publications

Metabolism of linoleic acid in the cat

Metabolism of linoleic acid in the cat

An alternate pathway to long-chain polyunsaturates: the FADS2 gene product Δ8-desaturates 20:2n-6 and 20:3n-3

The alternative pathway C20 Δ8‐desaturase from the non‐photosynthetic organism Acanthamoeba castellanii is an atypical cytochrome b5‐fusion desaturase

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The alternative pathway C₂₀ Δ8‐desaturase from the non‐photosynthetic organism Acanthamoeba castellanii is an atypical cytochrome b₅‐fusion desaturase