Phosphorylation of Elovl5 changes its substrate preference to synthesize Mead acid in response to essential fatty acid deficiency

2020 ◽  
Author(s):  
Yuri Hayashi ◽  
Misato Yamano ◽  
Nozomu Kono ◽  
Hiroyuki Arai ◽  
Yoko Fujiwara ◽  
...  

ABSTRACTPolyunsaturated fatty acids (PUFAs) of the n-6 and n-3 series cannot be synthesized in mammals and therefore are called essential fatty acids (EFAs). Mead acid (20:3n-9) is an unusual n-9 PUFA, endogenously synthesized from oleic acid (18:1n-9) in an EFA-deficient state. Although Elovl5, a fatty acid elongase, has long been known to selectively elongate C18 and C20 PUFAs, it can use 18:1n-9 as a substrate for the synthesis of Mead acid under C20 PUFA-deficient, but not-sufficient, conditions. We found, by an in vitro enzyme assay, that the microsomal fraction obtained from PUFA-deficient, but not -sufficient, cells showed significant Elovl5 activity toward 18:1n-9, with no effect on its constitutive activity toward 18:3n-6, implying that Elovl5 acquires the activity toward 18:1n-9 under the PUFA-deficient conditions at the enzyme level. Further biochemical analysis revealed that Elovl5 was phosphorylated in the C20 PUFA-supplemented cells, and that treatment with an inhibitor of glycogen synthase kinase 3 (GSK3) completely abolished the phosphorylation of Elovl5 and retained the Elovl5 activity toward 18:1n-9, even in the presence of C20 PUFA. Finally, mutation of putative phosphorylation sites (T281A/S283A/S285A) on Elovl5 did not decrease the activity of Elovl5 toward 18:1n-9 by supplementation with C20 PUFA, suggesting that the phosphorylation of Elovl5 contributed to a change in substrate preference. Thus, by changing its substrate specificity in an EFA-deficient state, Elovl5 is able to regulate the synthesis of Mead acid to maintain levels of long-chain PUFAs.

1959 ◽  
Vol 197 (4) ◽  
pp. 893-896 ◽  
Author(s):  
Takuya Hayashida ◽  
Oscar W. Portman

The effect of feeding diets deficient in essential fatty acids on the composition of adrenal lipids and on the secretory activity of adrenocortical hormones was studied. Rats which were fed diets devoid of fat had lower levels of tetraenoic and pentaenoic acids and higher levels of trienoic acids in both the total lipid and cholesterol ester fraction than did rats receiving a supplement of corn oil. There was a greater accumulation of cholesterol esterified with saturated and monounsaturated fatty acids in the adrenals of the rats fed essential fatty acid-deficient diets. The adrenals of the essential fatty acid-deficient rats secreted smaller quantities of steroid hormones in vitro under the stimulation of ACTH.


1987 ◽  
Vol 33 (10) ◽  
pp. 1869-1873 ◽  
Author(s):  
E N Siguel ◽  
K M Chee ◽  
J X Gong ◽  
E J Schaefer

Abstract To develop criteria for deficiency of essential fatty acids (EFA), we used capillary-column gas-liquid chromatography to determine fatty acids (percentage of total fatty acids) in plasma obtained in the fasting state from 56 reference subjects and from 10 patients with intestinal fat malabsorption and suspected EFA deficiency. Fatty acid evaluations (percentage of total fatty acids) that allowed for a clear distinction (P less than 0.01) between reference subjects and patients, based on values two standard deviations below or above the reference mean, included values for linoleic acid (18:2w6) below 27%, and values for palmitic acid (16:0), palmitoleic acid (16:1w7), oleic acid (18:1w9), vaccenic acid (18:1w7), and Mead acid (20:3w9) exceeding 21%, 2.6%, 23.3%, 2.1%, and 0.21%, respectively. Ratios of total EFA to total non-EFA of less than 0.60 and of Mead acid to arachidonic acid of greater than 0.025 also served to identify patients, and were not found in reference subjects. Significant inverse correlations between percentages of plasma EFA and plasma mono-unsaturated fatty acids were noted. Our reference-interval data can be used to assess normality of plasma EFA status.


2017 ◽  
Vol 10 (1) ◽  
pp. 92-99 ◽  
Author(s):  
Hércules Rezende Freitas

Polyunsaturated fatty acids (PUFAs) comprise about 35-40% of the total lipid content from green algaeChlorella, reaching up to 24% linoleic acid and 27% α-linolenic acid inC. vulgaris. Also, microalgae nutrient composition may be modulated by changes in the culture medium, increasing fatty acid and microelement concentrations in the algae biomass. PUFAs, such as α-linolenic (n-3) and linoleic (n-6) acids, as well as its derivatives, are considered essential for dietary consumption, and their ability to regulate body chemistry has been recently explored in depth. A balanced fatty acid consumption is shown to counteract the negative effects of western diets, such as chronic inflammation and glucose intolerance. In this brief commentary, technological and practical uses ofC. vulgarisare explored as means to improve dietary quality and, ultimately, human health.


Microbiology ◽  
2011 ◽  
Vol 157 (6) ◽  
pp. 1589-1601 ◽  
Author(s):  
Yoshihiro Agari ◽  
Kazuko Agari ◽  
Keiko Sakamoto ◽  
Seiki Kuramitsu ◽  
Akeo Shinkai

In the extremely thermophilic bacterium Thermus thermophilus HB8, one of the four TetR-family transcriptional regulators, which we named T. thermophilus FadR, negatively regulated the expression of several genes, including those involved in fatty acid degradation, both in vivo and in vitro. T. thermophilus FadR repressed the expression of the target genes by binding pseudopalindromic sequences covering the predicted −10 hexamers of their promoters, and medium-to-long straight-chain (C10–18) fatty acyl-CoA molecules were effective for transcriptional derepression. An X-ray crystal structure analysis revealed that T. thermophilus FadR bound one lauroyl (C12)-CoA molecule per FadR monomer, with its acyl chain moiety in the centre of the FadR molecule, enclosed within a tunnel-like substrate-binding pocket surrounded by hydrophobic residues, and the CoA moiety interacting with basic residues on the protein surface. The growth of T. thermophilus HB8, with palmitic acid as the sole carbon source, increased the expression of FadR-regulated genes. These results indicate that in T. thermophilus HB8, medium-to-long straight-chain fatty acids can be used for metabolic energy under the control of FadR, although the major fatty acids found in this strain are iso- and anteiso-branched-chain (C15 and 17) fatty acids.


2012 ◽  
Vol 66 (2) ◽  
pp. 207-209 ◽  
Author(s):  
Boris Pejin ◽  
Ljubodrag Vujisic ◽  
Marko Sabovljevic ◽  
Vele Tesevic ◽  
Vlatka Vajs

The fatty acid composition of the moss species Atrichum undulatum (Hedw.) P. Beauv. (Polytrichaceae) and Hypnum andoi A.J.E. Sm. (Hypnaceae) collected in winter time were analyzed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) as a contribution to their chemistry. Eight fatty acids were identified in the chloroform/methanol extract 1:1 of A. undulatum (linoleic acid 26.80%, palmitic acid 22.17%, ?-linolenic acid 20.50%, oleic acid 18.49%, arachidonic acid 6.21%, stearic acid 3.34%, cis-5,8,11,14,17-eicosapentaenoic acid 1.52% and behenic acid 1.01%), while six fatty acids were found in the same type of extract of H. andoi (palmitic acid 63.48%, erucic acid 12.38%, stearic acid 8.08%, behenic acid 6.26%, lignoceric acid 5.16% and arachidic acid 4.64%). According to this study, the moss A. undulatum can be considered as a good source of both essential fatty acids for humans (linoleic acid and ?-linolenic acid) during the winter.


2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Carmen J. E. Pee ◽  
Vera Pader ◽  
Elizabeth V. K. Ledger ◽  
Andrew M. Edwards

ABSTRACT Daptomycin is a treatment of last resort for serious infections caused by drug-resistant Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus. We have shown recently that S. aureus can evade daptomycin by releasing phospholipid decoys that sequester and inactivate the antibiotic, leading to treatment failure. Since phospholipid release occurs via an active process, we hypothesized that it could be inhibited, thereby increasing daptomycin efficacy. To identify opportunities for therapeutic interventions that block phospholipid release, we first determined how the host environment influences the release of phospholipids and the inactivation of daptomycin by S. aureus. The addition of certain host-associated fatty acids to the growth medium enhanced phospholipid release. However, in serum, the sequestration of fatty acids by albumin restricted their availability to S. aureus sufficiently to prevent their use in the generation of released phospholipids. This finding implies that in host tissues S. aureus may be completely dependent upon endogenous phospholipid biosynthesis to generate lipids for release, providing a target for therapeutic intervention. To test this, we exposed S. aureus to AFN-1252, an inhibitor of the staphylococcal FASII fatty acid biosynthetic pathway, together with daptomycin. AFN-1252 efficiently blocked daptomycin-induced phospholipid decoy production, even in the case of isolates resistant to AFN-1252, which prevented the inactivation of daptomycin and resulted in sustained bacterial killing. In turn, daptomycin prevented the fatty acid-dependent emergence of AFN-1252-resistant isolates in vitro. In summary, AFN-1252 significantly enhances daptomycin activity against S. aureus in vitro by blocking the production of phospholipid decoys, while daptomycin blocks the emergence of resistance to AFN-1252.


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