基于亲缘关系和次生代谢相似性发掘药用重楼新资源

The genus Daiswa, bearing the Chinese name “Chonglou”, is an economically importance plant group with medicinal significance. Daiswa polyphylla var. chinensis and D. polyphylla var. yunnanensis are the two botanical origins of the medicinal “Chonglou”, whose dried rhizomes are used as the main crude material for more than 40 commercial drugs in China. Due to long-term of over-harvesting, their natural populations have been severely decreased in recent years, resulting in critical shortage of crew material supply for many pharmaceutical companies. The habitats suitable for the cultivation of medicinal “Chonglou” are narrow and limited, hence, the cultivation of D. polyphylla var. chinensis and D. polyphylla var. yunnanensis cannot produce enough raw materials for pharmaceutical industry. In this project, we aim to explore new resources with similarly medicinal properties from those species closely related to medicinal “Chonglou”, by following the correlation between phylogeny and plant secondary metabolite. We firstly reconstruct the high-resolution and well-supported infra-generic phylogeny in Daiswa with genomic data. Under the framework of phylogeny, we then investigate the similarity of the biosynthesis pathway to steroidal saponins (diosgenin glycosides and pennogenin glycosides) and their content among medicinal “Chonglou” and their close relatives, by using comparative transcriptome analysis and MS molecular networking. On the basis of the results of interspecific relationships, the similarity of secondary metabolite and chemical contents, we aim to suggest 3-5 Daiswa species with high-content of diosgenin glycosides or pennogenin glycosides, which might be used as new resource of medicinal “Chonglou”. These results can make it feasible to expand the scale of medicinal “Chonglou” cultivation to resolve the raw material shortage for relevant pharmaceutical companies. Our finding may offer theoretical direction to introduction, domestication, and discovery of bioactive compounds and new drugs from Daiswa species.

重楼属是一个具有较高经济价值的药用植物类群。药用重楼以云南重楼和七叶一枝花为基源植物，其根状茎是“云南白药”、“宫血宁胶囊”等40多种药品的主要原料。近年来，因过度利用、野生重楼资源的枯竭导致相关医药企业出现了严重的原料危机。由于适宜种植区域相对狭窄，云南重楼和七叶一枝花的人工种植至今难以扩大规模，无法满足医药工业的原料需求。本项目以植物系统发育—次生代谢相关性原理为指导，通过系统发育基因组学分析，重建重楼属高分辨、高支持的系统发育关系。在系统发育的框架下，采用比较转录组学和质谱分子网络等方法，对药用重楼与近缘种的生物活性成分（薯蓣皂苷和偏诺皂甙）的生物合成途径及其含量情况进行整合分析，从中发掘出3-5种富含薯蓣皂苷或偏诺皂苷的药用重楼新资源。研究结果可为扩大药用重楼种植规模，保障相关医药企业的原料供给奠定基础，还可为重楼属植物的引种驯化、活性天然产物发现和新药开发等相关研究提供理论指导。

重楼属是一个具有较高经济价值的药用植物类群，近年来，因过度利用、野生重楼资源的枯竭导致相关医药企业出现了严重的原料危机。本项目以植物系统发育/次生代谢相关性原理为指导，在系统发育的框架下，对药用重楼与近缘种的生物活性成分的生物合成途径及其含量进行整合分析；以此为指导，定向发掘富含薯蓣皂苷或偏诺皂苷的药用重楼新资源。本项目通过对重楼属的系统发育基因组学研究，提出了一个新的属下分类系统；基于形态和分子证据，对重楼属进行了全面的分类修订，澄清了该属长期以来的分类混乱。在此基础上，通过比较转录组分析，对重楼属甾体皂苷生物合成的基因通路进行解析。系统发育、生物地理学、植物化学方面的整合证据表明重楼属蚤休组和五指莲组植物偏诺甾体皂苷/薯蓣甾体皂苷的相对含量与亲缘关系、地理分布密切相关。分布于华东-华中-华南-中南半岛的种类，其偏诺甾体皂苷含量高于薯蓣甾体皂苷含量，可从中发掘作为止血药原料的新资源植物；分布于横断山¬-喜马拉雅地区的种类则薯蓣甾体皂苷含量显著高于偏诺甾体皂苷含量，可从中发掘作为抗肿瘤药物的新资源植物。基于重楼属种系分化的时空格局及其与化学表型变异的相关性，从七叶一枝花的近缘种中定向发掘到球药隔重楼（P. fargesii）和啟良重楼（P. qiliangiana）两种富含偏诺皂苷、适宜于作为止血药原料的药用重楼新资源。这两种新资源植物的发现，为妇科止血药“宫血宁胶囊”的原料供给提供了新的解决思路。研究结果可为扩大药用重楼种植规模，保障相关医药企业的原料供给奠定基础，还可为重楼属植物的引种驯化、活性天然产物发现和新药开发等相关研究提供理论指导。