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A Novel Alternate Pathway For Long Chain Polyunsaturated Fatty Acid Biosynthesis And Alternative Transcripts Of Fatty Acid Desaturase Genes
Long chain polyunsaturated fatty acids (LCPUFA), especially arachidonic acid (ARA, 20:4n-6), eicosapentaenoic acid (EPA, 20:5n-3), and docosahexaenoic acid (DHA, 22:6n-3) are essential for human health and cognitive development, are the major structural components of the cell membranes, are precursors for cellular signaling molecules and are also known to regulate transcription of genes. It is widely believed that the biosynthesis of LCPUFA from linoleic acid (18:2n-6) and linolenic acid (18:3n-3) takes place by alternating series of position-specific desaturases, chain-elongation reactions and a peroxisomal beta-oxidation for DHA synthesis. The existence of an alternative biosynthetic pathway was first observed in a protozoan (Euglena gracilis), in which 18:2n-6 and 18:3n-3 are first elongated to 20:2n-6 and 20:3n-3, followed by ∆8- and ∆5-desaturation, respectively to yield 20:4n-6 and 20:5n-3. We hypothesized that the primate FADS2 gene product would have ∆8-desaturase activity and cloned baboon FADS2 into Saccharomyces cerevisiae, to test for gain of ∆8-desaturation activity. The novel data that we have published (park et al, 2009, JLR) show evidence that the FADS2 protein product is a ∆8-desaturase (as well as a ∆6-desaturase). FADS1, FADS2, and FADS3 are localized within a 100 kb region on human chromosome 11q12-13.1. FADS1 and FADS2 genes encode for enzymes catalyzing ∆5- and ∆6- & ∆8-desaturation, respectively and only a single transcript has been identified for both genes. Function(s) of FADS3 showing high homology to FADS1 and FADS2 are unknown. We reported the results for the existence of alternative transcripts (AT) for FADS2 and FADS3 genes. Investigating the role of FADS genes, we performed RT-PCR analysis using baboon cDNA and detected an AT for FADS2 and multiple AT for FADS3 generated by alternative splicing (Park et al, 2009, Mol Biol Reports; Park et al, 2009, Gene). We also found that these AT are well conserved across several vertebrate species. The FADS2 AT and FADS3 AT are expressed in many neonate baboon tissues. FADS3 AT also showed changes in abundance in response to human neuronal cell differentiation. Determining the functions of these AT, conserved among species, provides a putative mechanism for understanding of LCPUFA biosynthetic regulation, and how it differs among individuals.
dissertation or thesis