基于诱导调控的多酶表达型全细胞催化剂及其在酚苷化合物结构修饰中的应用

随着人口老龄化加剧，阿兹海默症等痴呆型疾病在我国呈高发趋势，但至今仍缺乏有效的治疗药物。酚苷类化合物在治疗此类疾病时展示了作用靶点多、活性高且副作用低等优势，但却存在血脑屏障渗透性低、生物利用度差等问题。针对目前此类疾病新药研发的迫切需求和酚苷类化合物的应用局限性，本研究拟选育具有多脂肪酶表达活性的微生物全细胞，催化酚苷的酯化结构修饰；探讨不同结构诱导剂对细胞中多酶合成的诱导调控机制以及反应中多酶协同催化关系，揭示全细胞催化剂对酚苷底物的识别特性及相关影响规律；在此基础上，构建起可用于酚苷化合物多位点酯化修饰的绿色全细胞催化体系，并探讨修饰位点对产物血脑屏障透过性及生物活性的影响规律。本研究学科交叉特色鲜明，有利于促进全细胞生物催化技术的发展，提高生物催化技术的适用范围和过程经济性；并可为脑渗透性增强型天然产物药物研发提供新思路，为推动此类药物的临床应用及膳食营养预防奠定理论基础。

With the aggravation of the aging degree, Alzheimer's disease and other dementia diseases are rising in China. However, there are no effective drugs to reverse the development of these diseases. Phenolic glucosides compounds showed high activity and low side effects, but suffer from strong polarity and the low blood-brain-barrier permeability. To improve its brain permeability, basic researches on development of microbial whole-cells with multiple enzyme activities and their application for selective catalyzing the structural modification of phenolic glucosides will be explored. The regulatory mechanism of small molecule inducers will be explored for the biosynthesis and expression of multiple enzymes in cells and the synergistic catalytic mechanism of enzymes in the reaction. And the substrate recognition characteristics and influence rules of whole cell catalysts will be investigated. A whole cell catalytic system will be constructed for acyl modification of phenolic glucosides, and the relationship between the structures and the blood-brain barrier permeabilities and biological activities of phenolic glucoside derivatives will be discussed. This study will promote the development of whole-cell biocatalysis technology, and improve the application scope and process economy of biocatalysis technology. In addition, it provides new ideas for the research and development of natural products with enhanced brain permeability, and lays a theoretical foundation for promoting the clinical application of such drugs and dietary nutrition prevention strategies.