合成生物学 ›› 2020, Vol. 1 ›› Issue (1): 92-102.DOI: 10.12211/2096-8280.2020-036
饶聪1, 云轩1, 虞沂1, 邓子新1,2
收稿日期:
2020-03-26
修回日期:
2020-04-19
出版日期:
2020-02-29
发布日期:
2020-07-07
通讯作者:
虞沂,邓子新
作者简介:
饶聪(1996-),男,硕士研究生。基金资助:
RAO Cong1, YUN Xuan1, YU Yi1, DENG Zixin1,2
Received:
2020-03-26
Revised:
2020-04-19
Online:
2020-02-29
Published:
2020-07-07
Contact:
YU Yi, DENG Zixin
摘要:
微生物天然产物一直都是新型生物药物创新的主要源泉,是目前开发临床抗菌、抗肿瘤、免疫抑制剂等药物的重要资源。随着临床耐药菌的日益增多,新型病原菌和病毒的不断出现,以及新骨架天然产物挖掘难度的增加,新型微生物药物的开发正面临着巨大挑战。作为21世纪生命医学领域催动原创突破和学科交叉融合的前沿学科,合成生物学的崛起为解决药物研发困境提供了新的思路和方法,它可以突破天然药物发现的瓶颈,设计新的生物合成途径,产生更多天然药物及类似物。本文综述了近五年来合成生物学在微生物药物研究领域的技术革新,及其在氨基糖苷类抗生素、核苷类抗生素、核糖体肽、萜类以及聚酮类化合物等5大类微生物天然药物的发掘、生物合成以及新结构创制等方面的应用。
中图分类号:
饶聪, 云轩, 虞沂, 邓子新. 微生物药物的合成生物学研究进展[J]. 合成生物学, 2020, 1(1): 92-102.
RAO Cong, YUN Xuan, YU Yi, DENG Zixin. Recent progress of synthetic biology applications in microbial pharmaceuticals research[J]. Synthetic Biology Journal, 2020, 1(1): 92-102.
图1 Valienamine天然多步合成途径及改造后的简化合成途径
Fig. 1 The natural multistep biosynthetic pathway of valienamine, and the simplified biosynthetic pathway after modification
图3 喹啉酸及其类似物喂养工程菌SL3052产生siomycin及其类似物
Fig. 3 The engineered strain SL3052 fed with quinolinic acid and its analogues, leading to the production of siomycin and its analogues
1 | NEWMAN David J, CRAGG Gordon M. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019[J]. Journal of Natural Product, 2020, 83 (3): 770-803. |
2 | BERDY J. Thoughts and facts about antibiotics: where we are now and where we are heading[J]. Journal of Antibiotics, 2012, 65(8): 385-395. |
3 | KELWICK R, MACDONALD J T, WEBB A J, et al. Developments in the tools and methodologies of synthetic biology[J]. Frontiers in Bioengineering and Biotechnology, 2014, 2: 60. |
4 | MUKHERJEE S, STAMATIS D, BERTSCH J, et al. Genomes OnLine database (GOLD) v.7: updates and new features[J]. Nucleic Acids Research, 2019, 47 (D1): 649-659. |
5 | SMANSKI M J, ZHOU H, CLAESEN J, et al. Synthetic biology to access and expand nature’s chemical diversity[J]. Nature Reviews Microbiology, 2016,14 (3):135-149. |
6 | BLIN Kai, PASCAL ANDREU Victòria, DE LOS SANTOS Emmanuel L C, et al. The antiSMASH database version 2: a comprehensive resource on secondary metabolite biosynthetic gene clusters[J]. Nucleic Acids Research, 2018, 47 (D1): 625-630. |
7 | NAVARRO MU OZ Jorge C, SELEM MOJICA Nelly, MULLOWNEY Michael W, et al. A computational framework for systematic exploration of biosynthetic diversity from large-scale genomic data[J]. bioRxiv., 2018: 445270.DOI: 10.110/445270 |
8 | Gökcen ERASLAN, Žiga AVSEC, GAGNEUR Julien, et al. Deep learning: new computational modelling techniques for genomics[J]. Nature Reviews Genetics, 2019, 20 (7): 389-403. |
9 | TIETZ Jonathan I, SCHWALEN Christopher J, PATEL Parth S, et al. A new genome-mining tool redefines the lasso peptide biosynthetic landscape[J]. Nature Chemical Biology, 2017, 13 (5): 470-478. |
10 | HU Qiannan, DENG Zhe, HU Huanan, et al. RxnFinder: biochemical reaction search engines using molecular structures, molecular fragments and reaction similarity[J]. Bioinformatics, 2011, 27 (17): 2465-2467. |
11 | CHENG Xingxiang, SUN Dandan, ZHANG Dachuan, et al. RxnBLAST: molecular scaffold and reactive chemical environment feature extractor for biochemical reactions[J]. Bioinformatics, 2020,36(9): 2946-2947. |
12 | ZHANG Tong, TIAN Yu, YUAN Le, et al. Bio2Rxn: sequence-based enzymatic reaction predictions by a consensus strategy[J]. Bioinformatics, 2020. DOI: 10.1093/bio in formatics/baa135 . |
13 | TU Weizhong, ZHANG Haoran, LIU Juan, et al. BioSynther: a customized biosynthetic potential explorer[J]. Bioinformatics, 2015, 32 (3): 472-473. |
14 | DING Shaozhen, LIAO Xiaoping, TU Weizhong, et al. EcoSynther: a customized platform to explore biosynthetic potential in E. coli [J]. ACS Chemical Biology, 2017, 12 (11), 2823-2829. |
15 | HAMEDIRAD Mohammad, CHAO Ran, WEISBERG Scott, et al. Towards a fully automated algorithm driven platform for biosystems design[J]. Nature Communications, 2019, 10 (1): 5150. |
16 | HERRMANN S, SIEGL T, LUZHETSKA M, et al. Site-specific recombination strategies for engineering actinomycete genomes[J]. Applied and Environmental Microbiology, 2012, 78 (6): 1804-1812. |
17 | JIANG W, BIKARD D, COX D, et al. RNA-guided editing of bacterial genomes using CRISPR-Cas systems[J]. Nature Biotechnology, 2013, 31 (3): 233-239. |
18 | JINEK M, CHYLINSKI K, FONFARA I, et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity[J]. Science, 2012, 337 (6096): 816-821. |
19 | COBB Ryan E, WANG Yajie, ZHAO Huimin. High-efficiency multiplex genome editing of streptomyces species using an engineered CRISPR/Cas system[J]. ACS Synthetic Biology, 2015, 4 (6): 723-728. |
20 | ZHANG M M, WONG F T, WANG Y, et al. CRISPR-Cas9 strategy for activation of silent Streptomyces biosynthetic gene clusters[J]. Nature Chemical Biology, 2017, 13: 607-609. |
21 | WANG Hailong, LI Zhen, JIA Ruonan, et al. RecET direct cloning and Redαβ recombineering of biosynthetic gene clusters, large operons or single genes for heterologous expression[J]. Nature Protocols, 2016, 11 (7): 1175-1190. |
22 | BU Qingting, YU Pin, WANG Jue, et al. Rational construction of genome-reduced and high-efficient industrial Streptomyces chassis based on multiple comparative genomic approaches[J]. Microbial Cell Factories, 2019, 18 (1): 16. |
23 | KALLIFIDAS Dimitris, JIANG Guangde, DING Yousong, et al. Rational engineering of Streptomyces albus J1074 for the overexpression of secondary metabolite gene clusters[J]. Microbial Cell Factories, 2018, 17 (1): 25. |
24 | LUO X, REITER M A, D'ESPAUX L,et al. Complete biosynthesis of cannabinoids and their unnatural analogues in yeast[J]. Nature, 2019, 567 (7746): 123-126. |
25 | JUNG W S, LEE S K, HONG J S, et al. Heterologous expression of tylosin polyketide synthase and production of a hybrid bioactive macrolide in Streptomyces venezuelae [J]. Applied Microbiology and Biotechnology, 2006, 72 (4): 763-769. |
26 | PADDON C J, WESTFALL P J, PITERA D J, et al. High-level semi-synthetic production of the potent antimalarial artemisinin[J]. Nature, 2013, 496 (7446): 528-532. |
27 | LI Sicong, GUO Junhong, REVA Anna, et al. Methyltransferases of gentamicin biosynthesis[J]. PNAS, 2018, 115 (6): 1340. |
28 | BURY Priscila dos Santos, HUANG Fanglu, LI Sicong, et al. Structural basis of the selectivity of GenN, an aminoglycoside N-methyltransferase involved in gentamicin biosynthesis[J]. ACS Chemical Biology, 2017, 12 (11): 2779-2787. |
29 | TAO Weixin, CHEN Li, ZHAO Chunhua, et al. In vitro packaging mediated one-step targeted cloning of natural product pathway[J]. ACS Synthetic Biology, 2019, 8 (9): 1991-1997. |
30 | CUI Li, ZHU Ying, GUAN Xiaoqing, et al. De novo biosynthesis of β-valienamine in engineered Streptomyces hygroscopicus 5008[J]. ACS Synthetic Biology, 2016, 5 (1): 15-20. |
31 | CUI Li, WEI Xiaodong, WANG Xinran, et al. A validamycin shunt pathway for valienamine synthesis in engineered Streptomyces hygroscopicus 5008[J]. ACS Synthetic Biology, 2020, 9(2), 294-303. |
32 | ZHAO Q, LUO Y, ZHANG X, et al. A severe leakage of intermediates to shunt products in acarbose biosynthesis[J]. Nature Communications, 2020, 11 (1): 1468. |
33 | CHEN Wenqing, QI Jianzhao, WU Pan, et al. Natural and engineered biosynthesis of nucleoside antibiotics in Actinomycetes[J]. Journal of Industrial Microbiology & Biotechnology, 2016, 43 (2): 401-417. |
34 | QI Jianzhao, WAN Dan, MA Hongmin, et al. Deciphering carbamoylpolyoxamic acid biosynthesis reveals unusual acetylation cycle associated with tandem reduction and sequential hydroxylation[J]. Cell Chemical Biology, 2016, 23 (8): 935-944. |
35 | CHEN Wenqing, LI Yan, LI Jie, et al. An unusual UMP C-5 methylase in nucleoside antibiotic polyoxin biosynthesis[J]. Protein & Cell, 2016, 7 (9): 673-683. |
36 | WU Pan, WAN Dan, XU Gudan, et al. An unusual Protector-Protégé strategy for the biosynthesis of purine nucleoside antibiotics[J]. Cell Chemical Biology, 2017, 24 (2): 171-181. |
37 | ZHANG Meng, ZHANG Peichao, XU Gudan, et al. Comparative investigation into formycin A and pyrazofurin A biosynthesis reveals branch pathways for the construction of C-nucleoside scaffolds[J]. Applied and Environmental Microbiology, 2019. DOI:10.1128/AEM.01971-19 . |
38 | LIU Yan, GONG Rong, LIU Xiaoqin, et al. Discovery and characterization of the tubercidin biosynthetic pathway from Streptomyces tubercidicus NBRC 13090[J]. Microbial Cell Factories, 2018, 17 (1): 131. |
39 | XU Gudan, KONG Liyuan, GONG Rong, et al. Coordinated biosynthesis of the purine nucleoside antibiotics aristeromycin and coformycin in actinomycetes[J]. Applied and Environmental Microbiology, 2018, 84 (22).DOI: 10.1128/AEM.01860-18 . |
40 | ZHANG Yi, CHEN Manyun, BRUNER Steven D, et al. Heterologous production of microbial ribosomally synthesized and post-translationally modified peptides[J]. Frontiers in Microbiology, 2018, 9: 1801. |
41 | ZHENG Qingfei, FANG Hui, LIU Wen. Post-translational modifications involved in the biosynthesis of thiopeptide antibiotics[J]. Organic & Biomolecular Chemistry, 2017, 15 (16): 3376-3390. |
42 | QIU Yanping, DU Yanan, WANG Shoufeng, et al. Radical S-adenosylmethionine protein NosN forms the side ring system of nosiheptide by functionalizing the polythiazolyl peptide S-conjugated indolic moiety[J]. Organic Letters, 2019, 21 (5): 1502-1505. |
43 | LIU Jingyu, LIN Zhi, CHEN Hua, et al. Biosynthesis of the central piperidine nitrogen heterocycle in series a thiopeptides[J]. Chinese Journal of Chemistry, 2019, 37 (1): 35-41. |
44 | WANG Jian, LIN Zhi, BAI Xuebing, et al. Optimal design of thiostrepton-derived thiopeptide antibiotics and their potential application against oral pathogens[J]. Organic Chemistry Frontiers, 2019, 6 (8): 1194-1199. |
45 | MO Tianlu, LIU Wanqiu, JI Wenjuan, et al. Biosynthetic insights into Linaridin natural products from genome mining and Precursor peptide mutagenesis[J]. ACS Chemical Biology, 2017, 12 (6): 1484-1488. |
46 | BIAN Guangkai, HAN Yichao, HOU Anwei, et al. Releasing the potential power of terpene synthases by a robust precursor supply platform[J]. Metabolic Engineering, 2017, 42: 1-8. |
47 | BIAN Guangkai, HOU Anwei, YUAN Yujie, et al. Metabolic engineering-based rapid characterization of a sesquiterpene cyclase and the skeletons of Fusariumdiene and Fusagramineol from Fusarium graminearum [J]. Organic Letters, 2018, 20 (6): 1626-1629. |
48 | CHENG S, LIU X, JIANG G, et al. Orthogonal engineering of biosynthetic pathway for efficient production of Limonene in Saccharomyces cerevisiae [J]. ACS Synthetic Biology, 2019, 8 (5): 968-975. |
49 | KANG Wei, MA Tian, LIU Min, et al. Modular enzyme assembly for enhanced cascade biocatalysis and metabolic flux[J]. Nature Communications, 2019, 10 (1): 1-11. |
50 | WANG Weishan, LI Shanshan, LI Zilong, et al. Harnessing the intracellular triacylglycerols for titer improvement of polyketides in Streptomyces [J]. Nature Biotechnology, 2020, 38 (1): 76-83. |
51 | YOU Di, WANG Miaomiao, YIN Bincheng, et al. Precursor supply for Erythromycin biosynthesis: Engineering of propionate assimilation pathway based on propionylation modification[J]. ACS Synthetic Biology, 2019, 8 (2): 371-380. |
52 | PALAZZOTTO E, TONG Y, LEE S Y, et al. Synthetic biology and metabolic engineering of actinomycetes for natural product discovery[J]. Biotechnology Advances, 2019, 37 (6): 107366. |
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