BIOSYNTHETIC OPTIMIZATION OF BRYOSTATINS IN AQUACULTURE

该项目的商业目标是开发技术， 提高了有前景的抗癌药物苔藓抑素1的产量， 来自海洋苔藓虫Bugula neritina的水产养殖。苔藓抑素1， 该药物正在进行治疗多种癌症的II期临床试验， 不能经济地合成，必须从动物中获得。 目前，来自该系统的苔藓抑素1产量是次优的（7-8 μ g g/g vs. 15-16 μ g/g干重（来自自然界），部分原因是次优 在实验室定居的饮食中的生化前体的量 殖民地专有的水产养殖饲料将补充 苔藓抑素1合成的特定必需脂质和已知前体 以确定哪种组合诱导最大的生物量产量 和毒品苔藓抑素1的产量预计将增加两倍或更多。 确定哪种苔藓抑素是苔藓抑素1的前体将有助于 来设计最佳饮食。的代谢关系， 将使用放射性标记的苔藓抑素研究各种苔藓抑素 在整个动物和无细胞实验中。改进后的技术将 使CalBioMarine的水产养殖系统能够在经济上与 自然收集的Bugulu neritina种群， 年复一年地保持大规模收成。 拟定商业应用： 提供抗癌化合物的总产率的显著增加， 商业海洋生物的生物质输出中的化合物苔藓抑素L 应用知识改善饮食 的生物合成机制，并添加前体物质， 饮食配方。苔藓抑素产量-提高范围2-3 现在的产量被认为是可以达到的，因此大大减少了 生产成本，并使系统具有竞争力。

The commercial goal of this project is to develop technology for increasing the yield of the promising anticancer drug, bryostatin 1, from aquaculture of the marine bryozoan, Bugula neritina. Bryostatin 1, which is in Phase II clinical trials for treatment of several cancers, cannot be synthesized economically and must be obtained from the animal. Presently bryostatin 1 yields from the system are sub-optimal (7-8 mu g/g vs. 15-16 mu g/g dw from nature) due, in part, to sub-optimal amounts of biochemical precursors in the diet of laboratory-settled colonies. Proprietary aquaculture diets will be supplemented with specific essential lipids and known precursors of bryostatin 1 synthesis to determine which combinations induce the greatest yields of biomass and drug. Bryostatin 1 yields are expected to increase two-fold or more. Determining which bryostatin is the precursor to bryostatin 1 will help in designing the optimal diet. The metabolic relationships of the various bryostatins will be investigated using radiolabeled bryostatins in whole animal and cell-free experiments. The improved technology will allow CalBioMarine's aquaculture system to compete economically with natural collections of Bugulu neritina populations which could not sustain large-scale harvests on a year-to-year basis. PROPOSED COMMERCIAL APPLICATION: Provide for significant increases in overall yield of the anticancer compound bryostatin l in the biomass output from a commercial sea-based BuguLa neritina AquaPharm by improving diet through applying knowledge of the biosynthetic mechanisms, and addition of precursor substances to the diet formulation. Bryostatin yield-improvements in the range 2-3 times present yields are thought to be attainable, thus greatly reducing production costs, and allowing the system to be competitive.