蛋白酶体因可调控细胞周期和细胞凋亡成为抗肿瘤药物筛选的重要靶标。微生物来源的syrbactins家族化合物是蛋白酶体抑制剂，结构新颖，具有抗肿瘤新药研发的巨大潜力；其生物合成的模块化组装方式为利用合成生物学技术进行抗肿瘤药物优化提供便利。本项目立足于理性设计和改造syrbactins的生物合成途径，实现化合物的构效优化：在进一步发掘syrbactins生物合成基因资源的基础上，利用本团队建立的Red/ET DNA重组工程合成生物学技术平台，对syrbactins生物合成基因元件进行优化、重排和组装，构建人工的syrbactins生物合成途径，在适配底盘细胞中高效表达，从而获得丰富的具有新型结构和活性的“非天然”化合物，筛选具有高效蛋白酶体抑制活性的抗肿瘤药物先导分子。本项目将会推进蛋白酶体抑制剂的新药研发，有助于我国新一代抗肿瘤药物的创新研制。

Cancer threat has been a global health issue. Proteasomes able to regulate cell cycle and cell apoptosis become essential targets for antitumor drug screening. Syrbactins isolated from microorganisms target the active site of proteasomes, therefore, becoming a potential class of leading compounds with antitumor activity. Moreover, modular assembly of genes and enzymes for syrbactin biosynthesis could promote us to engineer their biosynthetic pathways to generate improved leading compounds utilizing synthetic biological techniques. Based on the collection of syrbactin biosynthetic gene clusters from different bacterial resources and utilization of Red/ET DNA recombinieering, we intend to engineer the biosynthetic pathways of syrbactins via the gene mutation, replacement, rearrangement and assembly. We will create artificial biosynthetic pathways for production of unnatural biosynthesized syrbactin derivatives, which will be screened for proteasome inhibitors with improved antitumor activity. This project will broaden and strengthen the antitumor drug development in China as well yield more insights for strategies to bioengineer natural product pathways.