The metabolism of 7,10,13,16,19-docosapentaenoic acid to 4,7,10,13,16,19-docosahexaenoic acid in rat liver is independent of a 4-desaturase.

Voss, Anne Coble; Reinhart, Meri; Sankarappa, S. K.; Sprecher, Howard

doi:10.1016/s0021-9258(18)54882-1

Cited by 581 publications

(58 citation statements)

References 34 publications

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“…That dietary intake (Figure 6:7) influences microsomal reactions in LC-PUFA biosynthesis is clear (Voss, Reinhart, Sankarappa, & Sprecher, 1991), and loss of DHA from adult healthy brain tissues is known to induce an inability to concentrate, loss of memory, and dementia (Pawlosky & Salem, 1995). This assertion is supported by a study of polymorphisms of delta-6 desaturase (Figure 1: 7, 10), necessary for conversion of precursors into AA, n-6 docosapentaenoic acid (DPA), the estradiol-dependent precursor to DHA, with an advantage of 6.4 IQ points ( t = 6.35, p < .001) in children breastfed over those fed milk formula without LC-PUFA supplementation (Caspi et al, 2007).…”

Section: Resultsmentioning

confidence: 99%

The Systems Theory of Autistogenesis

Malone

2012

Sage Open

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The systems theory of autistogenesis accounts for genetic and environmental predisposing factors for pervasive developmental disorders. During development, regions of the brain myelinate differentially, even while neuroinflammatory events induce neurological damage. Incorrect dietary ratios of docosahexaenoic acid (DHA) to arachidonic acid (AA) promote developmental aberration characteristic of autism spectrum disorders (ASD), and commercial infant formulae possesses DHA/AA ratios unsuitable for normal brain development in those predisposed. The aromatase gene regulates DHA/AA metabolism and represents a potential biomarker for ASD. Aromatase converts testosterone to estradiol. Estradiol is neuroprotective and a modulator of oxytocin receptors deficient in autism. Neuroprotective DHA is not well synthesized in males and is regulated by estradiol. Therefore, converging evidence indicates that any disturbance to the autistogenic system linking environment to neurobiology and genetics is capable of inducing developmental disorders with gender disparity.

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Section: Resultsmentioning

confidence: 99%

The Systems Theory of Autistogenesis

Malone

2012

Sage Open

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“…Until 1991, the biosynthesis of biologically active 22:5n‐6 and 22:6n‐3 PUFAs in all organisms was thought to occur via Δ4 desaturation. However, difficulties in demonstrating Δ4 desaturation activity collected from microsomes of rats fed minimal fat diets led to the proposal of a coupled microsomal‐peroxisomal pathway (11). Classic biochemical radiotracer evidence has been presented in numerous studies in support of this pathway in tissue, primarily from rats.…”

Section: Discussionmentioning

confidence: 99%

“…Fractionated organelles, cells, or an intact animal are treated with specially labeled C or H PUFA precursors, and products are analyzed by HPLC or other methods with radioactivity detection without localization of the radioactivity within the product (11, 38‐40). For instance, the first article to introduce this pathway incubated rat liver microsomes or primary hepatocytes with 1‐ 14 C‐18:2, 1‐ 14 G‐22:5, 3‐ 14 C‐24:5 or 3‐ 14 C‐24:6 showed flow of label into 22:6 when incubated with cells but not microsomes (11). Addition of a peroxisome‐enriched fraction led to incorporation of label into 22:6n‐3 and 22:5n‐6, respectively, leading to the “coupled microsomal‐peroxisomal” pathway (pathway A).…”

Section: Discussionmentioning

confidence: 99%

“…, 3 H, 14 C) showing that the ratio of label is similar in the precursor or products, as was done in early studies that demonstrated direct chain elongation and desaturation (42), or β‐oxidation in peroxisomes (43). Finally, no studies comparing 1‐ 14 C‐24:6 to 3‐ 14 C‐24:6 labeling of product fatty acids have been reported; the C24 fatty acid labeled in the 1 position could have been synthesized by then‐available methods (11). Our labeling studies are not vulnerable to this alternative because conversion of the d5 moiety to acetate would result in the d3 COOH‐CD3, which, upon incorporation into an elongated fatty acid, would retain only 2 deuteriums, resulting in a d2‐labeled fatty acid product.…”

Section: Discussionmentioning

confidence: 99%

“…The presently accepted mammalian biochemical pathway for 22:6n‐3 and 22:5n‐6 biosynthesis worked out with rodents is presumed to operate via sequential desaturation and elongation on the ER with a final round of β‐oxidation in the peroxisomes (px) demonstrated for rat liver and other tissues (11, 12), via pathway A:

\begin{array}{l} left & n - 6 : 18 : 2 \to 18 : 3 \to 20 : 3 \to 20 : 4 \to 22 : 4 \to \\ left & [24 : 4 \to 24 : 5 \to transport to px \to] 22 : 5 n - 6 \end{array}

\begin{array}{l} left & n - 3 : 18 : 3 \to 18 : 4 \to 20 : 4 \to 20 : 5 \to 22 : 5 \to \\ left & [24 : 5 \to 24 : 6 \to transport to px \to] 22 : 6 n - 3 \end{array}

expressed as n:d where the steps that increment the double bond number (d) are desaturations (D) and those that increase the carbon number (n) are elongations (E).…”

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confidence: 99%

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The fatty acid desaturase 2 (FADS2) gene product catalyzes Δ4 desaturation to yield n-3 docosahexaenoic acid and n-6 docosapentaenoic acid in human cells

Park¹,

Park²,

Kothapalli³

et al. 2015

The FASEB Journal

119

115

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Docosahexaenoic acid (DHA) is a Δ4-desaturated C22 fatty acid and the limiting highly unsaturated fatty acid (HUFA) in neural tissue. The biosynthesis of Δ4-desaturated docosanoid fatty acids 22:6n-3 and 22:5n-6 are believed to proceed via a circuitous biochemical pathway requiring repeated use of a fatty acid desaturase 2 (FADS2) protein to perform Δ6 desaturation on C24 fatty acids in the endoplasmic reticulum followed by 1 round of β-oxidation in the peroxisomes. We demonstrate here that the FADS2 gene product can directly Δ4-desaturate 22:5n-3→22:6n-3 (DHA) and 22:4n-6→22:5n-6. Human MCF-7 cells lacking functional FADS2-mediated Δ6-desaturase were stably transformed with FADS2, FADS1, or empty vector. When incubated with 22:5n-3 or 22:4n-6, FADS2 stable cells produce 22:6n-3 or 22:5n-6, respectively. Similarly, FADS2 stable cells when incubated with d5-18:3n-3 show synthesis of d5-22:6n-3 with no labeling of 24:5n-3 or 24:6n-3 at 24 h. Further, both C24 fatty acids are shown to be products of the respective C22 fatty acids via elongation. Our results demonstrate that the FADS2 classical transcript mediates direct Δ4 desaturation to yield 22:6n-3 and 22:5n-6 in human cells, as has been widely shown previously for desaturation by fish and many other organisms.

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Phospholipid incorporation and metabolic conversion of n-3 polyunsaturated fatty acids in the Y79 retinoblastoma cell line

Goustard-Langelier¹,

Alessandri²,

Raguénez

et al. 2000

J. Neurosci. Res.

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The metabolic conversion of n-3 fatty acids was studied in the human Y79 retinoblastoma cell line. Cultured cells were exposed to increasing concentrations of either 18:3n-3, 22:5n-3, or 22:6n-3, and their phospholipid fatty acid composition was analyzed after 72 hr. Cells internalized the supplemental fatty acids and proceeded to their metabolic conversion. Supplemental 22:6n-3 was directly esterified into cell phospholipids, at levels typical for normal neural retinas (41% by weight of phosphatidylethanolamine fatty acids, and 24% of phosphatidylcholine fatty acids). In contrast, 18:3n-3 was mainly converted to 20:5n-3 and 22:5n-3, both of which appeared in cell phospholipids after exposure to low external concentrations of 18:3n-3 (10 microg/ml). Y79 cells can proceed to the metabolic conversion of 18:3n-3 through elongation and Delta6- and Delta5-desaturation. When cells were exposed to high external concentrations of 18:3n-3 (30 microg/ml), the supplemental fatty acid was directly incorporated, and its relative content increased in both phospholipid classes to the detriment of all other n-3 fatty acids. Cells cultured in the presence of 22:5n-3 did not incorporate 22:6n-3 into their phospholipids but did incorporate 20:5n-3 and 22:5n-3. The data suggest that Y79 cells can proceed to the microsomal steps of n-3 metabolism, involving elongation, desaturation, and chain shortening of 22C fatty acids. Although Y79 cells avidly used supplemental 22:6n-3 for phospholipid incorporation at levels typical for normal photoreceptor cells, they failed to match such levels through metabolic conversion of n-3 parent fatty acids. The terminal step of the very long-chain polyunsaturated fatty acid synthesis, consisting in Delta6-desaturation followed by peroxisomal chain shortening of 24C-fatty acids, could be rate-limiting in Y79 cells.

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The metabolism of 7,10,13,16,19-docosapentaenoic acid to 4,7,10,13,16,19-docosahexaenoic acid in rat liver is independent of a 4-desaturase.

Cited by 581 publications

References 34 publications

The Systems Theory of Autistogenesis

The Systems Theory of Autistogenesis

The fatty acid desaturase 2 (FADS2) gene product catalyzes Δ4 desaturation to yield n-3 docosahexaenoic acid and n-6 docosapentaenoic acid in human cells

Phospholipid incorporation and metabolic conversion of n-3 polyunsaturated fatty acids in the Y79 retinoblastoma cell line

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