PECASE: Bioengineering of Secondary Metabolic Pathways

四环素类药物已作为广谱抗生素被开出处方，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。将追求四个具体目标：(1)重组和理解酰胺化四环素骨架的组装；(2)重组土霉素(OXY)途径中的第一个四环中间体，并利用代谢工程产生新的C8羟化中间体；(3)重建OXY途径中的剪裁步骤，构建一系列能够产生有价值的代谢中间体的菌株；(4)通过异源次生代谢途径的改组，工程合成新型糖基化四环素类似物。研究和教育工作将通过下列机制结合起来：1)将丰富最近开发的两门核心生物技术课程，以增加学生的批判性思维和积极学习；2)将强调社区外联，邀请大洛杉矶大都市区的贫困少数族裔学生在夏季几个月学习研究，以及参加大学-社区活动，以促进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.