Biosynthetic mechanism of very long chain polyunsaturated fatty acids in Thraustochytrium sp. 26185

Thraustochytrium, a unicellular marine protist, has been used as a commercial source of very long chain PUFAs (VLCPUFAs) such as DHA (22:6n-3). Our recent work indicates coexistence of a Δ4-desaturation-dependent pathway (aerobic) and a polyketide synthase-like PUFA synthase pathway (anaerobic) to synthesize the fatty acids in Thraustochytrium sp. 26185. Heterologous expression of the Thraustochytrium PUFA synthase along with a phosphopantetheinyl transferase in Escherichia coli showed the anaerobic pathway was highly active in the biosynthesis of VLCPUFAs. The amount of Δ4 desaturated VLCPUFAs produced reached about 18% of the total fatty acids in the transformant cells at day 6 in a time course of the induced expression. In Thraustochytrium, the expression level of the PUFA synthase gene was much higher than that of the Δ4 desaturase gene, and also highly correlated with the production of VLCPUFAs. On the other hand, Δ9 and Δ12 desaturations in the aerobic pathway were either ineffective or absent in the species, as evidenced by the genomic survey, heterologous expression of candidate genes, and in vivo feeding experiments. These results indicate that the anaerobic pathway is solely responsible for the biosynthesis for VLCPUFAs in Thraustochytrium. Thraustochytrium, a unicellular marine protist, has been used as a commercial source of very long chain PUFAs (VLCPUFAs) such as DHA (22:6n-3). Our recent work indicates coexistence of a Δ4-desaturation-dependent pathway (aerobic) and a polyketide synthase-like PUFA synthase pathway (anaerobic) to synthesize the fatty acids in Thraustochytrium sp. 26185. Heterologous expression of the Thraustochytrium PUFA synthase along with a phosphopantetheinyl transferase in Escherichia coli showed the anaerobic pathway was highly active in the biosynthesis of VLCPUFAs. The amount of Δ4 desaturated VLCPUFAs produced reached about 18% of the total fatty acids in the transformant cells at day 6 in a time course of the induced expression. In Thraustochytrium, the expression level of the PUFA synthase gene was much higher than that of the Δ4 desaturase gene, and also highly correlated with the production of VLCPUFAs. On the other hand, Δ9 and Δ12 desaturations in the aerobic pathway were either ineffective or absent in the species, as evidenced by the genomic survey, heterologous expression of candidate genes, and in vivo feeding experiments. These results indicate that the anaerobic pathway is solely responsible for the biosynthesis for VLCPUFAs in Thraustochytrium. Very long chain PUFAs (VLCPUFAs), such as arachidonic acid (ARA, 20:4n-6) and DHA (22:6n-3), are essential components of cell membranes and precursors for biologically active signaling molecules in mammals. VLCPUFAs and their derived signaling molecules, such as eicosanoids and docosanoids, regulate the neurotransmission process in the brain, thereby affecting mood, cognition, and other neurological behaviors (1Bazinet R.P. Laye S. Polyunsaturated fatty acids and their metabolites in brain function and disease.Nat. Rev. Neurosci. 2014; 15: 771-785Crossref PubMed Scopus (818) Google Scholar). In addition, VLCPUFAs and their derivatives can also regulate other physiological processes, such as blood circulation, metabolic pathways, and inflammatory status in mammals (2Guichardant M. Calzada C. Bernoud-Hubac N. Lagarde M. Vericel E. Omega-3 polyunsaturated fatty acids and oxygenated metabolism in atherothrombosis.Biochim. Biophys. Acta. 2015; 1851: 485-495Crossref PubMed Scopus (32) Google Scholar, 3Wang W. Zhu J. Lyu F. Panigrahy D. Ferrara K.W. Hammock B. Zhang G. omega-3 polyunsaturated fatty acids-derived lipid metabolites on angiogenesis, inflammation and cancer.Prostaglandins Other Lipid Mediat. 2014; 113–115: 13-20Crossref PubMed Scopus (99) Google Scholar). Imbalances of different types of VLCPUFAs and their derivatives in the body have been shown to implicate various pathogeneses in humans, such as neurological disorders, cardiovascular diseases, metabolic syndrome, and inflammatory conditions (4Robinson L.E. Mazurak V.C. N-3 polyunsaturated fatty acids: relationship to inflammation in healthy adults and adults exhibiting features of metabolic syndrome.Lipids. 2013; 48: 319-332Crossref PubMed Scopus (57) Google Scholar, 5Janssen C.I. Kiliaan A.J. Long-chain polyunsaturated fatty acids (LCPUFA) from genesis to senescence: the influence of LCPUFA on neural development, aging, and neurodegeneration.Prog. Lipid Res. 2014; 53: 1-17Crossref PubMed Scopus (336) Google Scholar). Appropriate dietary supplementation of these fatty acids is thus encouraged to provide protection against chronic diseases and improve performance of the brain, eyes, and immune system. There are two distinct pathways in nature for the biosynthesis of VLCPUFAs (6Qiu X. Biosynthesis of docosahexaenoic acid (DHA, 22:6-4,7,10,13,16,19): two distinct pathways.Prostaglandins Leukot. Essent. Fatty Acids. 2003; 68: 181-186Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 7Khozin-Goldberg I. Iskandarov U. Cohen Z. LC-PUFA from photosynthetic microalgae: occurrence, biosynthesis, and prospects in biotechnology.Appl. Microbiol. Biotechnol. 2011; 91: 905-915Crossref PubMed Scopus (160) Google Scholar). The aerobic pathway follows an alternating desaturation and elongation process and occurs mainly in animals and eukaryotic microorganisms (8Sprecher H. Luthria D.L. Mohammed B.S. Baykousheva S.P. Reevaluation of the pathways for the biosynthesis of polyunsaturated fatty acids.J. Lipid Res. 1995; 36: 2471-2477Abstract Full Text PDF PubMed Google Scholar, 9Harwood J.L. Guschina I.A. The versatility of algae and their lipid metabolism.Biochimie. 2009; 91: 679-684Crossref PubMed Scopus (231) Google Scholar, 10Meesapyodsuk D. Qiu X. The front-end desaturase: structure, function, evolution and biotechnological use.Lipids. 2012; 47: 227-237Crossref PubMed Scopus (108) Google Scholar, 11Graham I.A. Larson T. Napier J.A. Rational metabolic engineering of transgenic plants for biosynthesis of omega-3 polyunsaturates.Curr. Opin. Biotechnol. 2007; 18: 142-147Crossref PubMed Scopus (82) Google Scholar). The anaerobic pathway utilizes a polyketide synthase (PKS)-like PUFA synthase and takes place only in microorganisms (12Metz J.G. Roessler P. Facciotti D. Levering C. Dittrich F. Lassner M. Valentine R. Lardizabal K. Domergue F. Yamada A. et al.Production of polyunsaturated fatty acids by polyketide synthases in both prokaryotes and eukaryotes.Science. 2001; 293: 290-293Crossref PubMed Scopus (549) Google Scholar, 13Okuyama H. Orikasa Y. Nishida T. Watanabe K. Morita N. Bacterial genes responsible for the biosynthesis of eicosapentaenoic and docosahexaenoic acids and their heterologous expression.Appl. Environ. Microbiol. 2007; 73: 665-670Crossref PubMed Scopus (108) Google Scholar, 14Morita N. Tanaka M. Okuyama H. Biosynthesis of fatty acids in the docosahexaenoic acid-producing bacterium Moritella marina strain MP-1.Biochem. Soc. Trans. 2000; 28: 943-945Crossref PubMed Scopus (34) Google Scholar). In the aerobic pathway, synthesis of VLCPUFAs, such as DHA in mammals, starts from α-linolenic acid (ALA, 18:3n-3) and goes through a retro-conversion process via a controlled β-oxidation step in the peroxisome for two carbon chain shortening (15Voss A. Reinhart M. Sankarappa S. Sprecher H. 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.J. Biol. Chem. 1991; 266: 19995-20000Abstract Full Text PDF PubMed Google Scholar, 16Sprecher H. Chen Q. Yin F.Q. Regulation of the biosynthesis of 22:5n-6 and 22:6n-3: a complex intracellular process.Lipids. 1999; 34: S153-S156Crossref PubMed Google Scholar), while the synthesis of DHA in eukaryotic microorganisms starts from stearic acid (SA, 18:0) and ends with the final Δ4 desaturation step (17Qiu X. Hong H. MacKenzie S.L. Identification of a Delta 4 fatty acid desaturase from Thraustochytrium sp. involved in the biosynthesis of docosahexanoic acid by heterologous expression in Saccharomyces cerevisiae and Brassica juncea.J. Biol. Chem. 2001; 276: 31561-31566Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar). In the anaerobic pathway, the VLCPUFA synthesis catalyzed by a PUFA synthase (12Metz J.G. Roessler P. Facciotti D. Levering C. Dittrich F. Lassner M. Valentine R. Lardizabal K. Domergue F. Yamada A. et al.Production of polyunsaturated fatty acids by polyketide synthases in both prokaryotes and eukaryotes.Science. 2001; 293: 290-293Crossref PubMed Scopus (549) Google Scholar) from the aerobic pathway in that desaturation to are the process of fatty acid as in the biosynthesis of fatty acids in Escherichia coli J. Bacterial fatty acid synthesis and with polyketide 2009; PubMed Scopus Google Scholar). is that biosynthesis of VLCPUFAs occurs only in types of while animals and plants the PUFA synthase and of the aerobic pathway, and thus are to synthesize these fatty marine that can synthesize VLCPUFAs, the process goes through either an aerobic pathway and to and carbon of fatty acids for the final or an anaerobic pathway a PUFA synthase to for of to VLCPUFAs. Thraustochytrium sp. is a unicellular marine that can than of total fatty acids as VLCPUFAs in and Our indicates that is an aerobic pathway in for the biosynthesis of VLCPUFAs and DHA can through the final step of Δ4 desaturation (17Qiu X. Hong H. MacKenzie S.L. Identification of a Delta 4 fatty acid desaturase from Thraustochytrium sp. involved in the biosynthesis of docosahexanoic acid by heterologous expression in Saccharomyces cerevisiae and Brassica juncea.J. Biol. Chem. 2001; 276: 31561-31566Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar). recent of an pathway a PUFA synthase for the biosynthesis of VLCPUFAs in species, as in a of the Thraustochytrium sp. (12Metz J.G. Roessler P. Facciotti D. Levering C. Dittrich F. Lassner M. Valentine R. Lardizabal K. Domergue F. Yamada A. et al.Production of polyunsaturated fatty acids by polyketide synthases in both prokaryotes and eukaryotes.Science. 2001; 293: 290-293Crossref PubMed Scopus (549) Google Scholar, A. J. B. D. S. J.G. Fatty acid production in of a polyunsaturated fatty acid synthase and a fatty acid PubMed Scopus Google Scholar, J.G. J. B. Roessler P. R. of polyunsaturated fatty acid synthesis in of the as fatty 2009; 47: PubMed Scopus Google Scholar). The of to the function and of the two pathways for the biosynthesis of VLCPUFAs in the Thraustochytrium sp. was from the and on of and at The E. coli was from of the Thraustochytrium genes the PUFA synthase were In to the genes, the genomic from Thraustochytrium was used as a for were to the from the Thraustochytrium as in The of the PUFA synthase the of for and the of both and and of for to synthesize a was to and a with and to a and and and a with The was two by a with and to a and from with The was with from with and at both were by were to the In to the of and were by the was from and with the and was from and with and The was to the of and were at showed that E. coli phosphopantetheinyl transferase were to the of PUFA synthases A. J. B. D. S. J.G. Fatty acid production in of a polyunsaturated fatty acid synthase and a fatty acid PubMed Scopus Google Scholar). gene from sp. was by and The were by and and the of with the genes from Thraustochytrium and S. from was used as a to Thraustochytrium sp. and S. genes were from the two The gene from Thraustochytrium was by genomic as The was acids with a of The gene from was a of acids and was at of Thraustochytrium cells was in of at with The cells were with the and at two cells were by at and two The was used for total fatty acid and the for the total to the was by with The was from of the total by genes, and were as were The was to were on a with the for for for for with were with from the was used to the expression of and with expression were the E. coli transformant cells and either or or were in or with and at The was to of the The were at to was by of The cells to at with and were for lipid and total fatty acid at the time course to the expression level by fatty acids in E. coli were to fatty acid by at for the the was at of and of The was by and at for for The was and the was in and used for of total derivatives were on an with a with The was at for and to at a of the was conditions an of at the biosynthesis and of VLCPUFAs in Thraustochytrium sp. the of the in the aerobic pathway for the biosynthesis of for Δ9 front-end and Δ4 and for as as at for fatty acid In addition, a a of and for the synthesis of and of a PUFA highly to of for the biosynthesis of VLCPUFAs A. J. B. D. S. J.G. Fatty acid production in of a polyunsaturated fatty acid synthase and a fatty acid PubMed Scopus Google Scholar), were also These indicate that both aerobic and anaerobic pathways in the both pathways were for the VLCPUFA biosynthesis, to genes in the two pathways that were and in or E. coli for the In the aerobic pathway, genes front-end and been and from the desaturase and Δ4 desaturase a acid and acid and (17Qiu X. Hong H. MacKenzie S.L. Identification of a Delta 4 fatty acid desaturase from Thraustochytrium sp. involved in the biosynthesis of docosahexanoic acid by heterologous expression in Saccharomyces cerevisiae and Brassica juncea.J. Biol. Chem. 2001; 276: 31561-31566Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar). of both and PUFAs was and used for engineering of DHA in an G. M. N. P. J. T. P. E. Qiu X. engineering to of very polyunsaturated fatty acids in Biotechnol. PubMed Scopus Google Scholar). In to these genes, front-end and desaturase genes in the aerobic pathway from the were these genes, of the were and used for with the total as the The of these desaturase genes were a and in The results showed that of desaturase genes an front-end desaturase a acid and acid and acid The fatty acid desaturation of desaturase genes, in showed Δ12 desaturase on acid to at the level of than of the total fatty as with the transformant with a Δ12 desaturase from a amount of two Δ12 desaturated and on two and was D. Qiu X. structure, and evolution of the fatty acid of Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar) desaturase gene desaturation fatty such as and their fatty such as and acid the desaturase in these indicate that for two ineffective and from to in the aerobic pathway in that the aerobic pathway by the two desaturation in the species, Thraustochytrium with fatty acid in the aerobic pathway to the desaturation and elongation in The results showed that Thraustochytrium both an desaturated fatty such as and a desaturated fatty such as with highly elongation on The elongation from to reached than The front-end and desaturation were also in the on the Δ9 desaturation on and Δ12 desaturation on were In Thraustochytrium, a very amount of of the total fatty was with a amount of from the Thraustochytrium with fatty from the These that the aerobic pathway was in sp. two desaturation and were either ineffective or from the vivo desaturation and elongation on fatty acids to Thraustochytrium sp. or was by are of in a was by are of the anaerobic pathway for the VLCPUFA biosynthesis in the and and of the that was highly to a PUFA synthase of (12Metz J.G. Roessler P. Facciotti D. Levering C. Dittrich F. Lassner M. Valentine R. Lardizabal K. Domergue F. Yamada A. et al.Production of polyunsaturated fatty acids by polyketide synthases in both prokaryotes and eukaryotes.Science. 2001; 293: 290-293Crossref PubMed Scopus (549) Google Scholar, A. J. B. D. S. J.G. Fatty acid production in of a polyunsaturated fatty acid synthase and a fatty acid PubMed Scopus Google Scholar) were in the were on the of active The of polyketide 2012; PubMed Scopus Google Scholar). synthase and two and and of two and and a gene for a to the A. J. B. D. S. J.G. Fatty acid production in of a polyunsaturated fatty acid synthase and a fatty acid PubMed Scopus Google Scholar) was also from the the PUFA the were E. coli a for for and for In addition, a from of a in sp. strain a in the of PubMed Scopus Google Scholar) was also in for the expression the were the expression was the was and was two to the for The final were by these to their a the anaerobic pathway were the E. coli strain The showed that the transformant produced two fatty DHA and with the strain with the amount of the two Δ4 desaturated VLCPUFAs produced was at only about of the total fatty acids in the transformant the that the PUFA synthase from Thraustochytrium was for the biosynthesis of VLCPUFAs. improve production of VLCPUFAs in E. to of of the PUFA synthase in an by the a with a of The total of the reached of the expression highly The was than and a was used to these a of showed that the transformant with the the production of DHA and was higher than the DHA produced in the E. coli was a to that in the Thraustochytrium. in a time course of the induced the amount of DHA and in the transformant was from day to day and reached the at day 6 at about 18% of the total fatty the amount of VLCPUFAs was in the strain was essential for to of a PUFA synthase to active function by E. coli an A. J. B. D. S. J.G. Fatty acid production in of a polyunsaturated fatty acid synthase and a fatty acid PubMed Scopus Google Scholar). on the structure, were and the the PUFA and of from prokaryotes for the PUFA synthase were such has been from the a from for a was used as a to of Thraustochytrium sp. and sp. a of Thraustochytrium. was from from the Thraustochytrium and from the that of and with acid with both to for PUFA synthases from Moritella and a of acid the and also two and is is a two were by the two than acids the two and gene was along with Thraustochytrium PUFA synthase in E. The showed that the VLCPUFAs, and the also produced only a amount of and DHA in the E. coli showed that these two either or very in E. at the in was that both and the with the from the at the both and were for the E. coli expression. the of and the in E. coli for the production of the two VLCPUFAs. the the two eukaryotic were active as with the for VLCPUFAs in E. The of the two VLCPUFAs produced with a from were and higher than with from Thraustochytrium and the relationship the expression level of the genes in the two pathways and of VLCPUFAs in the Thraustochytrium, Δ4 desaturase the final step of DHA biosynthesis in the aerobic pathway and the of of the PUFA synthase in the anaerobic pathway were for The showed that production of DHA was highly correlated with the expression level of the PUFA synthase gene, with that of the Δ4 desaturase gene in the the time the amount of DHA produced in Thraustochytrium for about of total fatty and the amount of fatty acids was about at the time of the the amount of DHA reached to of the total fatty acids in the cell and the amount of fatty acids to In other the amount of DHA produced at was by about from that at the expression level of the PUFA synthase gene at was about that of the Δ4 desaturase gene in the while at the expression level of the PUFA synthase gene was about that of the Δ4 desaturase gene in the cell the level of the gene at both time was the expression level of the Δ4 desaturase gene at was only of that at while the expression level of the PUFA synthase gene at was two and than that at These results that the PUFA synthase pathway was responsible for the VLCPUFA biosynthesis in Thraustochytrium sp. acids of sp. at the and were from the of are the of with in a were from the of are the of with Thraustochytrium sp. a level of VLCPUFAs, mainly DHA and in the and The Δ4 desaturase in the biosynthesis of VLCPUFAs is from the species, that DHA can by the aerobic pathway (17Qiu X. Hong H. MacKenzie S.L. Identification of a Delta 4 fatty acid desaturase from Thraustochytrium sp. involved in the biosynthesis of docosahexanoic acid by heterologous expression in Saccharomyces cerevisiae and Brassica juncea.J. Biol. Chem. 2001; 276: 31561-31566Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar). recent on VLCPUFA that an anaerobic pathway a PUFA synthase can also used to synthesize VLCPUFAs (12Metz J.G. Roessler P. Facciotti D. Levering C. Dittrich F. Lassner M. Valentine R. Lardizabal K. Domergue F. Yamada A. et al.Production of polyunsaturated fatty acids by polyketide synthases in both prokaryotes and eukaryotes.Science. 2001; 293: 290-293Crossref PubMed Scopus (549) Google Scholar, A. J. B. D. S. J.G. Fatty acid production in of a polyunsaturated fatty acid synthase and a fatty acid PubMed Scopus Google Scholar, J.G. J. B. Roessler P. R. of polyunsaturated fatty acid synthesis in of the as fatty 2009; 47: PubMed Scopus Google Scholar, K. of eicosapentaenoic acid from marine PubMed Google Scholar). These results to a pathway also in Thraustochytrium, and pathway is for the biosynthesis of VLCPUFAs in the these a genomic of genes involved in the biosynthesis of VLCPUFAs in the the in both pathways, for the Δ9 desaturase gene in the aerobic pathway, in the biosynthesis of VLCPUFAs were pathway was and in to in a gene in the two pathways through by the to were to in both pathways by in the to the of in vivo feeding and of the genes in both pathways in heterologous of the results to the that the anaerobic pathway is responsible for the VLCPUFA biosynthesis in Thraustochytrium. the genomic that the Δ9 desaturase gene was in the Heterologous expression of the Δ12 desaturase candidate in showed Δ12 desaturase indicates that two in the aerobic pathway are ineffective for the biosynthesis of VLCPUFAs. the fatty acid feeding that Δ9 and Δ12 desaturation was on the with and heterologous expression of of the PUFA synthase along with from Thraustochytrium that the anaerobic pathway was highly active for the biosynthesis of VLCPUFAs in E. of the genes in the two pathways showed that the expression level of the PUFA synthase genes was much higher than that of the Δ4 desaturase gene, in the cells at the the the expression level of the PUFA synthase gene was about than that of the Δ4 desaturase the expression was highly correlated with the amount of DHA produced in the cells at the two time both aerobic and anaerobic pathways for DHA biosynthesis in Thraustochytrium, the in the aerobic pathway is to two ineffective and the PUFA synthase is solely responsible for the biosynthesis of VLCPUFAs in The that both aerobic and anaerobic pathways in a has been in other the of VLCPUFAs in is very In Thraustochytrium of the of Thraustochytrium, both pathways are involved in the biosynthesis of VLCPUFAs T. K. R. T. E. Y. M. D. Y. S. et of acid desaturase function that two distinct pathways are active for the synthesis of PUFAs in T. Lipid Res. 2012; 53: Full Text Full Text PDF PubMed Scopus Google Scholar). In a of the the aerobic pathway is with different components J.G. of both polyunsaturated fatty acid pathways in 2009; PubMed Scopus Google Scholar). In Thraustochytrium sp. both Δ9 desaturation and Δ12 desaturation are to to synthesize both and in the aerobic pathway in the These results that the aerobic pathway in the as the anaerobic pathway is different components in the aerobic pathway or in different has the anaerobic pathway in E. coli with a PUFA synthase from Thraustochytrium along with a results in the production of a level of two VLCPUFAs, DHA and in the strain of the total fatty the the of DHA and is about the strain a higher level of than DHA (22:6n-3). The for is E. coli utilizes a with for fatty acid is that of these to with the Thraustochytrium PUFA synthase to the in the in the VLCPUFA is essential for a to the of a PUFA synthase synthase to active for a PUFA synthase from were and such has been from two from Thraustochytrium and for the synthase by to the as function by the of E. of the Thraustochytrium along with the Thraustochytrium PUFA VLCPUFAs at a level that is to that of the along with the PUFA synthase in E. The for to the used for the expression of these from the as the PUFA are eukaryotic The from have to in E. in in the expression with a eukaryotic PUFA PUFA synthase has been in a of and for the biosynthesis of VLCPUFAs (12Metz J.G. Roessler P. Facciotti D. Levering C. Dittrich F. Lassner M. Valentine R. Lardizabal K. Domergue F. Yamada A. et al.Production of polyunsaturated fatty acids by polyketide synthases in both prokaryotes and eukaryotes.Science. 2001; 293: 290-293Crossref PubMed Scopus (549) Google Scholar, 13Okuyama H. Orikasa Y. Nishida T. Watanabe K. Morita N. Bacterial genes responsible for the biosynthesis of eicosapentaenoic and docosahexaenoic acids and their heterologous expression.Appl. Environ. Microbiol. 2007; 73: 665-670Crossref PubMed Scopus (108) Google Scholar, 14Morita N. Tanaka M. Okuyama H. Biosynthesis of fatty acids in the docosahexaenoic acid-producing bacterium Moritella marina strain MP-1.Biochem. Soc. Trans. 2000; 28: 943-945Crossref PubMed Scopus (34) Google Scholar, and of the omega-3 polyunsaturated fatty acid synthase genes from the bacterium strain PubMed Scopus Google Scholar, of lipid biosynthesis in 2011; PubMed Scopus Google Scholar). The of the to synthesize VLCPUFAs the pathway is the production of VLCPUFAs by the very H. Chen Q. Yin F.Q. Regulation of the biosynthesis of 22:5n-6 and 22:6n-3: a complex intracellular process.Lipids. 1999; 34: S153-S156Crossref PubMed Google Scholar). to and the PUFA synthase can with The fatty acid synthesis as a and as the for the chain with also of an with a to a to to to a from in an and of to a fatty acid the synthesis of VLCPUFAs by a PUFA synthase the step of a a to in the chain (1Bazinet R.P. Laye S. Polyunsaturated fatty acids and their metabolites in brain function and disease.Nat. Rev. Neurosci. 2014; 15: 771-785Crossref PubMed Scopus (818) Google Scholar, 7Khozin-Goldberg I. Iskandarov U. Cohen Z. LC-PUFA from photosynthetic microalgae: occurrence, biosynthesis, and prospects in biotechnology.Appl. Microbiol. Biotechnol. 2011; 91: 905-915Crossref PubMed Scopus (160) Google Scholar). is about a PUFA synthase in VLCPUFAs. of the Thraustochytrium PUFA synthase only to of the the biosynthesis of VLCPUFAs in the species, also in metabolic engineering of VLCPUFAs in heterologous in N. S. Napier J.A. R.P. the lipid and of engineering the production of Microbiol. Biotechnol. 2015; PubMed Scopus Google Scholar). The to Chen for for fatty acid for and for of the with α-linolenic acid arachidonic acid acid fatty acid acid synthase acid polyketide synthase phosphopantetheinyl transferase stearic acid very long chain PUFA

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