Abstract:

Traditional Chinese medicine (TCM) is a treasure of Chinese civilization and an important driving force for drug development in China. Many TCM materials come from scarce species. The difficulty in large-scale preparation of TCM pharmaceutical substances results in a bottleneck that substantially impedes TCM-based drug development. The emergence and rapid development of synthetic biology have provided a new way to overcome this bottleneck. At present, significant progress has been made in bio-production of single TCM molecules. Nevertheless, the efficacy of TCM mainly stems from the synergistic or superimposed effects of multiple ingredients. Pharmaceutical ingredient groups are therefore the main forms of TCM pharmaceutical substances, but there are few reports on construction of bio-production platforms of pharmaceutical ingredient groups. The key to establishing bio-production approaches of TCM pharmaceutical ingredient groups is to precisely regulate the proportion of constituent molecules, thereby producing high-quality pharmaceutical ingredient groups. Herein, we summarize the progress on the biogenetic mechanism of TCM pharmaceutical ingredient groups of important types, such as volatile oils, saponins, flavonoids, lignans and alkaloids. For some pharmaceutical ingredient groups (e.g. ginsenosides), their member molecules are synthesized by multiple branching pathways; for the others (e.g. sandalwood oil), they are entirely from single pathways. The formers can be prepared by combining single member molecules which may be produced by biotechnology approaches. To bio-produce the latter type of pharmaceutical ingredient groups, their key biosynthetic enzymes must be engineered to optimize the ratio of their member molecules. We introduce the strategy of combining enzyme engineering and metabolic engineering to achieve dual optimization of molecular ratio and yield of pharmaceutical ingredient groups. Finally, we outline the prospects for synthetic biology research of pharmaceutical ingredient groups, including: (1) complete clarification of the biogenetic mechanism of more complex pharmaceutical ingredient groups, (2) development of innovative metabolic engineering approaches for breaking through methodology homogenization on the basis of revealing unknown metabolic regulation mechanisms in host cells, (3) optimization of catalytic characteristics of key biosynthetic enzymes (e.g. product ratio and catalytic efficiency) by combining rational design and directed evolution.

Key words: traditional Chinese medicine, pharmaceutical ingredient groups, synthetic biology, pathway elucidation, volatile oil, saponins, flavonoids, lignans, alkaloids

摘要：

中药是中华民族的文化瑰宝，也是我国在新药创制领域的重要驱动力。许多中药材来源于稀缺物种，其药效物质的规模化获取困难，是制约中药新药创制研究的重要瓶颈。合成生物学的出现和快速发展为解决这一瓶颈问题提供了新的途径。目前，中药药效物质的合成生物学研究在单个药效分子的生物制备方法上取得了重要进展。中药的药效主要源于多成分作用的叠加和协同，所以药效成分群是中药药效物质的主要形式，然而针对药效成分群的合成生物学研究鲜有报道。建立中药药效成分群合成生物技术的关键是精确调控组成分子的比例，从而产出优质药效成分群。本文首先总结了挥发油、总皂苷、总黄酮、总木脂素、总生物碱等重要类型中药药效成分群形成机制的研究进展。然后，重点以檀香挥发油为例，介绍如何通过酶工程和代谢工程的联合运用实现药效成分群成分比例和产量的双重优化。最后，对中药药效成分群合成生物学领域的未来研究重点进行了展望，包括：（1）加强中药药效成分群生物合成途径解析方面的研究，重点深入阐明复杂药效成分群的形成机制；（2）加强代谢优化手段方面的创新研究，重点揭示未知代谢调控机制并基于此发展创新调控策略；（3）加强酶工程方法学的创新研究，重点发展新型理性设计和定向进化的联用技术以及人工智能辅助的酶工程技术。

关键词: 中药, 药效成分群, 合成生物学, 途径解析, 挥发油, 皂苷, 黄酮, 木脂素, 生物碱