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91.
Metabolic engineering of the omega-3 long chain polyunsaturated fatty acid biosynthetic pathway into transgenic plants 总被引:1,自引:0,他引:1
Omega-3 (ω-3) very long chain polyunsaturated fatty acids (VLC-PUFAs) such as eicosapentaenoic acid (EPA; 20:5 Δ5,8,11,14,17) and docosahexaenoic acid (DHA; 22:6 Δ4,7,10,13,16,19) have been shown to have significant roles in human health. Currently the primary dietary source of these fatty acids are marine fish; however, the increasing demand for fish and fish oil (in particular the expansion of the aquaculture industry) is placing enormous pressure on diminishing marine stocks. Such overfishing and concerns related to pollution in the marine environment have directed research towards the development of a viable alternative sustainable source of VLC-PUFAs. As a result, the last decade has seen many genes encoding the primary VLC-PUFA biosynthetic activities identified and characterized. This has allowed the reconstitution of the VLC-PUFA biosynthetic pathway in oilseed crops, producing transgenic plants engineered to accumulate ω-3 VLC-PUFAs at levels approaching those found in native marine organisms. Moreover, as a result of these engineering activities, knowledge of the fundamental processes surrounding acyl exchange and lipid remodelling has progressed. The application of new technologies, for example lipidomics and next-generation sequencing, is providing a better understanding of seed oil biosynthesis and opportunities for increasing the production of unusual fatty acids. Certainly, it is now possible to modify the composition of plant oils successfully, and, in this review, the most recent developments in this field and the challenges of producing VLC-PUFAs in the seed oil of higher plants will be described. 相似文献
92.
Noemi Ruiz-López Richard P. Haslam Mónica Venegas-Calerón Tianbi Li Joerg Bauer Johnathan A. Napier Olga Sayanova 《Transgenic research》2012,21(6):1233-1243
The synthesis and accumulation of long chain polyunsaturated fatty acids such as eicosapentaenoic acid has previously been demonstrated in the seeds of transgenic plants. However, the obtained levels are relatively low, indicating the need for further studies and the better definition of the interplay between endogenous lipid synthesis and the non-native transgene-encoded activities. In this study we have systematically compared three different transgenic configurations of the biosynthetic pathway for eicosapentaenoic acid, using lipidomic profiling to identify metabolic bottlenecks. We have also used genetic crossing to stack up to ten transgenes in Arabidopsis. These studies indicate several potential approaches to optimize the accumulation of target fatty acids in transgenic plants. Our data show the unexpected channeling of heterologous C20 polyunsaturated fatty acids into minor phospholipid species, and also the apparent negative metabolic regulation of phospholipid-dependent ??6-desaturases. Collectively, this study confirms the benefits of iterative approaches to metabolic engineering of plant lipid synthesis. 相似文献
93.
Although many potential pathways exist for the prebiotic condensation of amino acids to form simple peptides, minimal conditions for such a reaction in the dry state have yet to be defined. In this work, water was evaporated from a solution of alanine and copper chloride (CuCl2), creating a dry residue. Incubation of this residue at moderate temperatures over 25 days produced even greater amounts of di-alanine, as determined by high performance liquid chromatographic characterization of the re-dissolved residue. Copper(II) and chloride were required for the reaction and di-peptide yields were highest for 1:2 molar ratios of copper:alanine. These results define minimal conditions for a dry-state pathway that plausibly played a role in the prebiotic formation of simple peptides. 相似文献
94.
Paul S Gable K Beaudoin F Cahoon E Jaworski J Napier JA Dunn TM 《The Journal of biological chemistry》2006,281(14):9018-9029
Several 3-keto-synthases have been studied, including the soluble fatty acid synthases, those involved in polyketide synthesis, and the FAE1-like 3-ketoacyl-CoA synthases. All of these condensing enzymes have a common ancestor and an enzymatic mechanism that involves a catalytic triad consisting of Cys, His, and His/Asn. In contrast to the FAE1-like family of enzymes that mediate plant microsomal fatty acid elongation, the condensation step of elongation in animals and in fungi appears to be mediated by the Elop homologs. Curiously these proteins bear no resemblance to the well characterized 3-keto-synthases. There are three ELO genes in yeast that encode the homologous Elo1p, Elo2p, and Elo3p proteins. Elo2p and Elo3p are required for synthesis of the very long-chain fatty acids, and mutants lacking both Elo2p and Elo3p are inviable confirming that the very long-chain fatty acids are essential for cellular functions. In this study we show that heterologous expression of several Arabidopsis FAE1-like genes rescues the lethality of an elo2Deltaelo3Delta yeast mutant. We further demonstrate that FAE1 acts in conjunction with the 3-keto and trans-2,3-enoyl reductases of the elongase system. These studies indicate that even though the plant-specific FAE1 family of condensing enzymes evolved independently of the Elop family of condensing enzymes, they utilize the same reductases and presumably dehydratase that the Elop proteins rely upon. 相似文献
95.
Price DA Armour D de Groot M Leishman D Napier C Perros M Stammen BL Wood A 《Bioorganic & medicinal chemistry letters》2006,16(17):4633-4637
The discovery of maraviroc 17 is described with particular reference to the generation of high selectivity over affinity for the HERG potassium channel. This was achieved through the use of a high throughput binding assay for the HERG channel that is known to show an excellent correlation with functional effects. 相似文献
96.
Neil Moss Younggi Choi Derek Cogan Adam Flegg Andreas Kahrs Pui Loke Orietta Meyn Raj Nagaraja Spencer Napier Ashley Parker J. Thomas Peterson Philip Ramsden Christopher Sarko Donna Skow Josh Tomlinson Heather Tye Mark Whitaker 《Bioorganic & medicinal chemistry letters》2009,19(8):2206-2210
We have been exploring the potential of 5-HT2B antagonists as a therapy for chronic heart failure. To assess the potential of this therapeutic approach, we sought compounds possessing the following attributes: (a) potent and selective antagonism of the 5-HT2B receptor, (b) low impact of serum proteins on potency, and (c) desirable pharmacokinetic properties. This Letter describes our investigation of a biphenyl benzimidazole class of compounds that resulted in 5-HT2B antagonists possessing the above attributes. Improving potency in a human serum albumin shift assay proved to be the most significant SAR discovery. 相似文献
97.
98.
Although plant plastidial ω3-desaturases are closely related to microsomal desaturases, heterologous expression in yeast of the Helianthus annuus FAD7 ω3-desaturase showed low activity in contrast to similar expression of microsomal FAD3 ω3-desaturases. However, the removal of the plastidial transit peptide and the incorporation of a KKNL motif to the C-terminus of HaFAD7 increased the activity by 10-fold compared to the native protein. N-terminal fusion of transmembrane-domains from either the yeast microsomal ELO3, (a type III signal anchor domain), or FAE1, an endoplasmic reticulum membrane anchoring domain, resulted in moderate increases in enzyme activity (5- and 7-fold, respectively), suggesting that the first, most hydrophobic transmembrane domain of HaFAD7 is sufficient to direct targeting to, and insertion into, the endoplasmic reticulum membrane. Furthermore, fusing a hemagglutinin (HA) epitope tag upstream of an endogenous C-terminal KEK motif resulted in a significant loss of activity compared to the un-tagged construct, indicating that the endogenous KEK C-terminal di-lysine motif is capable of directing in yeast the ER-retention of this normally plastidial-located protein. Western blotting analysis of constructs with internal HA epitope revealed that in whole cell extracts, with the exception of the one bound to C-terminal, it did not display a reduced level of protein accumulation. Whilst ferredoxin was shown to be required for HaFAD7 activity in yeast, it appears not necessary for protein stability and accumulation of this plastidial desaturase in the endoplasmic reticulum. 相似文献
99.
Nichole Cerutti Barry V. Mendelow Grant B. Napier Maria A. Papathanasopoulos Mark Killick Makobetsa Khati Wendy Stevens Alexio Capovilla 《The Journal of biological chemistry》2010,285(33):25743-25752
HIV-1 enters cells via interaction between the trimeric envelope (Env) glycoprotein gp120/gp41 and the host cell surface receptor molecule CD4. The requirement of CD4 for viral entry has rationalized the development of recombinant CD4-based proteins as competitive viral attachment inhibitors and immunotherapeutic agents. In this study, we describe a novel recombinant CD4 protein designed to bind gp120 through a targeted disulfide-exchange mechanism. According to structural models of the gp120-CD4 receptor complex, substitution of Ser60 on the CD4 domain 1 α-helix with Cys positions a thiol in proximity of the gp120 V1/V2 loop disulfide (Cys126–Cys196), satisfying the stereochemical and geometric conditions for redox exchange between CD4 Cys60 and gp120 Cys126, and the consequent formation of an interchain disulfide bond. In this study, we provide experimental evidence for this effect by describing the expression, purification, refolding, receptor binding and antiviral activity analysis of a recombinant two-domain CD4 variant containing the S60C mutation (2dCD4-S60C). We show that 2dCD4-S60C binds HIV-1 gp120 with a significantly higher affinity than wild-type protein under conditions that facilitate disulfide exchange and that this translates into a corresponding increase in the efficacy of CD4-mediated viral entry inhibition. We propose that targeted redox exchange between conserved gp120 disulfides and nucleophilic moieties positioned strategically on CD4 (or CD4-like scaffolds) conceptualizes a new strategy in the development of high affinity HIV-1 Env ligands, with important implications for therapy and vaccine development. More generally, this chalcogen substitution approach provides a general means of stabilizing receptor-ligand complexes where the structural and biophysical conditions for disulfide exchange are satisfied. 相似文献
100.
Shagina NB Tolstykh EI Zalyapin VI Degteva MO Kozheurov VP Tokareva EE Anspaugh LR Napier BA 《Radiation research》2003,159(2):239-246
The Mayak Production Association released large amounts of 90Sr into the Techa River with peak amounts in 1950-1951. Residents near the Techa River ingested an average of approximately 3,000 kBq of 90Sr. The affected people have been followed by scientists at the Urals Research Center for Radiation Medicine. The whole-body content of 90Sr of approximately 15,000 individuals has been measured over a period of 24 years (1974-1997) using a special whole-body counter. This report evaluates the gender and age dependences of individual rates of strontium elimination. Data on persons who had been measured 12 or more times were selected for study. There were 108 men and 81 women older than 30 years who met this criterion. Individual measurement results were fitted to an exponential function and grouped mean averages of the rate of strontium elimination as a function of age for each sex were derived. For men, a significant increase (from 2.8% year(-1) to 3.2% year(-1)) in the rate of strontium elimination after age 55 years is seen. For women, the increase in the rate of elimination was significant at age 45 and reached 5.8% year(-1) after the age of 60. The results may be used to develop a gender- and age-dependent model of strontium metabolism. 相似文献