PECASE: Bioengineering of Secondary Metabolic Pathways

四环素类药物已被处方为广谱抗生素，最近已用于抗癌治疗。 本研究的目的是了解四环素生物合成的代谢途径，分子组装和组合潜力。 本论文的主要目标是：（1）重构并理解酰胺化四环素骨架的组装;（2）重构土霉素（oxytetracycline，oxy）途径中的第一个四环中间体，并利用代谢工程技术生产新的四环中间体的C8-羟基化类似物;（3）重构oxytetracycline途径中的剪裁步骤，构建一系列能产生有价值的代谢中间体的菌株;（4）通过异源次级代谢途径的改组工程化生物合成新型糖基化四环素类似物。 将通过以下机制将研究和教育工作结合起来：1）将充实两门最近开发的核心生物技术课程，以提高学生的批判性思维和主动学习能力; 2）社区外展将通过邀请大洛杉矶都市区的贫困少数民族学生在夏季学习研究来强调，以及参与大学与社区合办的活动，以推广科学教育和终身学习。

Tang0545860Tetracyclines have been prescribed as broad-spectrum antibiotics and have recently been used in anticancer therapies. The objective of this research is to understand the metabolic pathway, the molecular assembly, and the combinatorial potential of tetracycline biosynthesis. Four specific aims will be pursued: (1) Reconstitute and understand the assembly of the amidated tetracycline backbone; (2) Reconstitute the first tetracyclic intermediate in oxytetracycline (oxy) pathway and use metabolic engineering to produce a novel C8-hydroxylated analog of the intermediate; (3) Reconstitute the tailoring steps in oxy pathway and construct a series of strains that can produce valuable metabolic intermediates; (4) Engineered biosynthesis of novel glycosylated analogs of tetracycline through shuffling of heterologous secondary metabolic pathways. The research and education efforts will be integrated through the following mechanisms: 1) Two recently developed, core biotechnology courses will be enriched to increase critical thinking and active learning by the students; 2) Community outreach will be emphasized by inviting underprivileged minority students in the greater Los Angeles metropolitan area to learn research during the summer months, as well as participating in university-community events to promote science education and life-long learning.