鬼臼毒素的生物合成及药理活性研究进展

Research progress on biosynthesis, and pharmacological activity of podophyllotoxin

关键词:  鬼臼毒素  鬼臼属植物  生物合成  抗肿瘤

Key words:  podophyllotoxin  podophyll plant  biosynthesis  antitumor

摘要:

鬼臼毒素是来源于鬼臼属植物的芳基萘类木脂素化合物,是鬼臼属植物的次级代谢产物,同时也是植物来源的药用天然产物,具有广谱抗肿瘤活性,目前对鬼臼毒素的相关研究较少。中国是鬼臼属植物的多样性中心和分布中心,为保护其现有资源,鬼臼毒素的生物合成特别是合成生物学逐渐成为当今研究的新方向。鬼臼毒素及其类似物具有强烈细胞毒性,对多种肿瘤细胞、病毒、细菌的增殖均有良好的抑制效果,广泛应用于各类肿瘤的临床治疗。本文对鬼臼属植物在我国的植物分布进行归纳总结,对鬼臼毒素的生物合成步骤、应用及生物学研究进行综述,同时概述了鬼臼毒素的药理活性,以期为鬼臼资源的应用、鬼臼毒素的合成、鬼臼类药物的开发提供参考,对恶性疾病治疗具有深远意义。

Abstract:

Podophyllotoxin is an aryl naphthalene lignan-like secondary metabolite, which is widely existed in plants of the podophyllum. It exhibits a broad spectrum of antitumor activity and holds significant clinical value as a medicinal natural product of plant origin. This review discusses podophyllotoxin from three aspects: plant distribution, biosynthesis and pharmacological effects. Distribution of podophyllotoxin in nature: Podophyllotoxin and its analogues are mainly found in 12 genera of three families, which are Berberidaceae, Linaceae and Cupressaceae, respectively. They are mostly distributed in East Asia and North America, especially in China, which is not only the diversity center of the podophyllum, but also the distribution center. Among all these plants, the genera Dysosma and Sinopodophyllum are the focus of the relevant research. Biosynthesis of podophyllotoxin: In order to take the alleviation of the pressure of podophyllotoxin that is in short supply of natural resources, and to protect its existing resources, the biosynthesis of podophyllotoxin, especially synthetic biology, has gradually become a new direction of current research. Compared with chemical synthesis which has the shortcoming of low synthesis efficiency, high production cost and cumbersome steps, biosynthesis has a variety of advantages. It’s not limited by resources, easy to cultivate on a large scale and has fast production speed, low production cost and simple genetic manipulation, so there is a broader prospect for the exact purpose of biosynthetic development. The biosynthesis of podophyllotoxin is divided into four steps in general, including the synthesis of coniferyl alcohol, the synthesis of matairesinol, the synthesis of deoxypodophyllotoxin and the synthesis of podophyllotoxin. It requires various enzymes catalyzed during the synthesis process, such as pinoresinol-lariciresinol reductase (PLR), secoisolariciresinol dehydrogenase (SDH) and others. At present, by means of synthetic biology, heterologous production of natural drugs in microbial cell factories, the synthesis of the intermediate coniferyl alcohol has been achieved in Escherichia coli with an increased yield of 124.9±5.1 mg·L-1, and the concentration of (-)-pluviatolide was elevated to 137 mg·L-1. In addition, p-coumaric acid in Saccharomyces cerevisiae was obtained to 71.71 mg·L-1, and in a tobacco plant production chassis, highly purified (-)-deoxypodophyllotoxin was increased to 0.71 mg·g-1 (dry weight) after chromatographic separation. Overall, the utilization of biosynthesis can significantly increase the yield of podophyllotoxin and improve the research and production efficiency of anti-tumor drugs greatly, which brings a more effective strategy for the treatment of related diseases. The pharmacological activity of podophyllotoxin: Podophyllotoxin and its analogues have strong cytotoxicity and they exert good inhibitory effects on the proliferation of multifarious tumor cells, viruses and bacteria. So they are widely applied to the clinical treatment of various types of tumors, such as colorectal cancer, lung cancer, cervical cancer, hemangioma, breast cancer, esophageal cancer, etc. The molecular mechanism of its cancer treatment is mainly in the G1, G2/M to block the cell cycle to make drugs work. Meanwhile, podophyllotoxin has relatively significant toxic side effects and drawbacks that can’t be ignored as a drug with superior therapeutic effect on specific diseases, which tends to increase the risk of bone marrow suppression, chromosomal aberrations and so forth. In conclusion, this literature sums up the distribution of podophyll plants in China, making review of the biosynthetic steps, applications, and biological research of podophyllotoxin, and outlines the pharmacological activity of podophyllotoxin. It aims to set the foundation for the reasonable application of podophyllotoxin resources, the efficient synthesis of podophyllotoxin, and the development of podophylloid drugs which are highly effective and low toxic. At the same time, this paper gives full play to the clinical medicinal value of podophyllotoxin, which has important influence and far-reaching significance in the treatment of malignant diseases, and promotes the modernization of traditional Chinese medicine.