Zhang Guojian, Li Yi, Fang Lei, Pfeifer Blaine A
Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Buffalo, NY 14260-4200, USA.
Sci Adv. 2015 May 29;1(4):e1500077. doi: 10.1126/sciadv.1500077. eCollection 2015 May.
Type I modular polyketide synthases are responsible for potent therapeutic compounds that include avermectin (antihelinthic), rapamycin (immunosuppressant), pikromycin (antibiotic), and erythromycin (antibiotic). However, compound access and biosynthetic manipulation are often complicated by properties of native production organisms, prompting an approach (termed heterologous biosynthesis) illustrated in this study through the reconstitution of the erythromycin pathway through Escherichia coli. Using this heterologous system, 16 tailoring pathways were introduced, systematically producing eight chiral pairs of deoxysugar substrates. Successful analog formation for each new pathway emphasizes the remarkable flexibility of downstream enzymes to accommodate molecular variation. Furthermore, analogs resulting from three of the pathways demonstrated bioactivity against an erythromycin-resistant Bacillus subtilis strain. The approach and results support a platform for continued molecular diversification of the tailoring components of this and other complex natural product pathways in a manner that mirrors the modular nature of the upstream megasynthases responsible for aglycone polyketide formation.
I型模块化聚酮合酶负责合成多种强效治疗性化合物，包括阿维菌素（抗蠕虫药）、雷帕霉素（免疫抑制剂）、苦霉素（抗生素）和红霉素（抗生素）。然而，由于天然生产菌株的特性，化合物的获取和生物合成操作往往很复杂，这促使了一种方法（称为异源生物合成），本研究通过在大肠杆菌中重建红霉素途径对此进行了说明。利用这个异源系统，引入了16条修饰途径，系统地产生了8对手性脱氧糖底物。每个新途径成功形成类似物，强调了下游酶适应分子变异的显著灵活性。此外，其中三条途径产生的类似物对耐红霉素的枯草芽孢杆菌菌株具有生物活性。该方法和结果支持了一个平台，以一种反映负责糖苷配基聚酮形成的上游巨型合酶的模块化性质的方式，继续对该复杂天然产物途径及其他复杂天然产物途径的修饰成分进行分子多样化。
