Dataset Information

Comparison of the Substrate Preferences of ?3 Fatty Acid Desaturases for Long Chain Polyunsaturated Fatty Acids.

ABSTRACT: Omega-3 long chain polyunsaturated fatty acids (?3 LC-PUFAs) such as eicosapentaenoic acid (EPA; 20:5?3) and docosahexaenoic acid (DHA; 22:6?3) are important fatty acids for human health. These ?3 LC-PUFAs are produced from their ?3 precursors by a set of desaturases and elongases involved in the biosynthesis pathway and are also converted from ?6 LC-PUFA by omega-3 desaturases (?3Ds). Here, we have investigated eight ?3-desaturases obtained from a cyanobacterium, plants, fungi and a lower animal species for their activities and compared their specificities for various C18, C20 and C22 ?6 PUFA substrates by transiently expressing them in Nicotiana benthamiana leaves. Our results showed hitherto unreported activity of many of the ?3Ds on ?6 LC-PUFA substrates leading to their conversion to ?3 LC-PUFAs. This discovery could be important in the engineering of EPA and DHA in heterologous hosts.

SUBMITTER: Shrestha P

PROVIDER: S-EPMC6627408 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Comparison of the Substrate Preferences of ω3 Fatty Acid Desaturases for Long Chain Polyunsaturated Fatty Acids.

Shrestha Pushkar P Zhou Xue-Rong XR Vibhakaran Pillai Sapna S Petrie James J de Feyter Robert R Singh Surinder S

International journal of molecular sciences 20190622 12

Omega-3 long chain polyunsaturated fatty acids (ω3 LC-PUFAs) such as eicosapentaenoic acid (EPA; 20:5ω3) and docosahexaenoic acid (DHA; 22:6ω3) are important fatty acids for human health. These ω3 LC-PUFAs are produced from their ω3 precursors by a set of desaturases and elongases involved in the biosynthesis pathway and are also converted from ω6 LC-PUFA by omega-3 desaturases (ω3Ds). Here, we have investigated eight ω3-desaturases obtained from a cyanobacterium, plants, fungi and a lower anima ...[more]

PMID: 31234541

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Project description:Docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (ARA, 20:4n-6) are the major long chain polyunsaturated fatty acids (LCPUFA) of the central nervous system. We examined the alterations in transcriptional profiles in neonate baboon cerebral cortex brain tissue using high-density Affymetrix oligonucleotide arrays ("U133 plus 2.0"). Twelve neonates were divided into 3 groups: Control (C, no DHA-ARA); 1× LCPUFA (L, 0.33%DHA-0.67%ARA); 3× LCPUFA (L3, 1.00%DHA-0.67%ARA). Significance analysis (P < 0.05) of a total of >54,000 probe sets (ps) identified changes in expression levels of 1108 ps, representing 2.05% of the total ps on the oligoarray, with most ps showing <2-fold change. Comparing L and C, 534 ps were upregulated with supplementation, and 574 ps were downregulated. For the L3/C comparisons, 666 ps were upregulated and 442 ps were downregulated. Characterization of differentially regulated genes by gene ontology assign them to diverse biological functions, notably lipid metabolism, ion channel and transport, G-protein and signal transduction, development, visual perception, membrane function, apoptosis, cytoskeleton, peptidases, cell cycle, stress response, kinases and phosphatases, transcription regulation, receptors, and ubiquitin, with about 400 transcripts having no defined function. Of differentially expressed genes involved in lipid metabolism, PLA2G6, a phospholipase recently associated with infantile neuroaxonal dystrophy, was downregulated in both LCPUFA groups. ELOVL5, a PUFA elongase, was the only enzyme in the LCPUFA biosynthetic pathway that was differentially expressed. Mitochondrial fatty acid carrier, CPT2, was among several genes associated with mitochondrial fatty acid oxidation to be downregulated, while the mitochondrial proton carrier, UCP2, was upregulated. PUFA-regulated receptor, Retinoic acid receptor alpha (RARA) was repressed in both groups, while HNF4A, a PUFA regulated factor, was downregulated in L3/C. Genes involved in neural development, TIMM8A, NRG1, SEMA3D and NUMB, were upregulated while HES1 and SIM1 showed decreased expression. LUM, EML2, TIMP3 and TTC8 which have roles in visual perception were upregulated and TIA1, a silencer of COX2 gene translation is upregulated in L3/C. Ingenuity network analysis identified a top network associated with nervous system development and function with EGFR as the outstanding interaction partner. In this network EGFR interacts with genes involved in neural or visual perception, TIMP3, NRG1, ADAM17, EDG7 and FGF7. Quantitative real time-PCR analysis on selected genes confirmed the array results. The L and L3 groups have DHA and ARA content within the ranges observed in human and baboon breastmilk, and thus these data indicate that LCPUFA concentrations within the normal range of human breastmilk induce global changes in gene expression across numerous functions including transcripts involved in neural development, visual perception, etc. Keywords: dietary dose response

Project description:Background:In randomized trials, supplementation of n-3 (?-3) long-chain polyunsaturated fatty acids (LC-PUFAs) during pregnancy has resulted in increased size at birth, which is attributable to longer gestation. Objective:We examined this finding by using a Mendelian randomization approach utilizing fatty acid desaturase (FADS) gene variants affecting LC-PUFA metabolism. Design:As part of a tri-ethnic mother-offspring cohort in Singapore, 35 genetic variants in FADS1, FADS2, and FADS3 were genotyped in 898 mothers and 1103 offspring. Maternal plasma n-3 and n-6 PUFA concentrations at 26-28 wk of gestation were measured. Gestation duration was derived from an ultrasound dating scan in early pregnancy and from birth date. Birth length and weight were measured. Eight FADS variants were selected through a tagging-SNP approach and examined in association with PUFA concentrations, gestation duration among spontaneous labors, and birth size with the use of ethnicity-adjusted linear regressions and survival models that accounted for the competing risks of induced labor and prelabor cesarean delivery. Results:Maternal FADS1 variant rs174546, tagging for 8 other variants located on FADS1 and FADS2, was strongly related to plasma n-6 but not n-3 LC-PUFA concentrations. Offspring and maternal FADS3 variants were associated with gestation duration among women who had spontaneous labor: each copy of rs174450 minor allele C was associated with a shorter gestation by 2.2 d (95% CI: 0.9, 3.4 d) and 1.9 d (0.7, 3.0 d) for maternal and offspring variants, respectively. In survival models, rs174450 minor allele homozygotes had reduced time to delivery after spontaneous labor compared with major allele homozygotes [HR (95% CI): 1.51 (1.18, 1.95) and 1.51 (1.20, 1.89) for mothers and offspring, respectively]. Conclusions:With the use of a Mendelian randomization approach, we observed associations between FADS variants and gestation duration. This suggests a potential role of LC-PUFAs in gestation duration. This trial was registered at http://www.clinicaltrials.gov as NCT01174875.

Project description:In the last decades, the development of new technologies applied to lipidomics has revitalized the analysis of lipid profile alterations and the understanding of the underlying molecular mechanisms of lipid metabolism, together with their involvement in the occurrence of human disease. Of particular interest is the study of omega-3 and omega-6 long chain polyunsaturated fatty acids (LC-PUFAs), notably EPA (eicosapentaenoic acid, 20:5n-3), DHA (docosahexaenoic acid, 22:6n-3), and ARA (arachidonic acid, 20:4n-6), and their transformation into bioactive lipid mediators. In this sense, new families of PUFA-derived lipid mediators, including resolvins derived from EPA and DHA, and protectins and maresins derived from DHA, are being increasingly investigated because of their active role in the "return to homeostasis" process and resolution of inflammation. Recent findings reviewed in the present study highlight that the omega-6 fatty acid ARA appears increased, and omega-3 EPA and DHA decreased in most cancer tissues compared to normal ones, and that increments in omega-3 LC-PUFAs consumption and an omega-6/omega-3 ratio of 2-4:1, are associated with a reduced risk of breast, prostate, colon and renal cancers. Along with their lipid-lowering properties, omega-3 LC-PUFAs also exert cardioprotective functions, such as reducing platelet aggregation and inflammation, and controlling the presence of DHA in our body, especially in our liver and brain, which is crucial for optimal brain functionality. Considering that DHA is the principal omega-3 FA in cortical gray matter, the importance of DHA intake and its derived lipid mediators have been recently reported in patients with major depressive and bipolar disorders, Alzheimer disease, Parkinson's disease, and amyotrophic lateral sclerosis. The present study reviews the relationships between major diseases occurring today in the Western world and LC-PUFAs. More specifically this review focuses on the dietary omega-3 LC-PUFAs and the omega-6/omega-3 balance, in a wide range of inflammation disorders, including autoimmune diseases. This review suggests that the current recommendations of consumption and/or supplementation of omega-3 FAs are specific to particular groups of age and physiological status, and still need more fine tuning for overall human health and well being.

Dataset Information

Comparison of the Substrate Preferences of ?3 Fatty Acid Desaturases for Long Chain Polyunsaturated Fatty Acids.

Publications

Comparison of the Substrate Preferences of ω3 Fatty Acid Desaturases for Long Chain Polyunsaturated Fatty Acids.

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