PECASE: Bioengineering of Secondary Metabolic Pathways

四环素类药物作为广谱抗生素被开处方，最近被用于抗癌治疗。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)重组和了解修饰四环素骨架的组装；(2)重组土霉素（oxy）途径中的第一个四环中间体，并利用代谢工程技术生产一种新的c8 -羟基化中间体；(3)重构氧途径的裁剪步骤，构建一系列能产生有价值代谢中间体的菌株；(4)通过重组异源次生代谢途径，工程生物合成新型四环素糖基化类似物。研究和教育工作将通过以下机制整合：1)将丰富最近开发的两门核心生物技术课程，以提高学生的批判性思维和主动学习能力；2)将强调社区外展，邀请洛杉矶大都市区贫困的少数民族学生在夏季学习研究，并参加大学社区活动，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.