合成生物学 ›› 2020, Vol. 1 ›› Issue (5): 583-592.DOI: 10.12211/2096-8280.2020-019
王清, 陈依军
收稿日期:
2020-03-08
修回日期:
2020-09-23
出版日期:
2020-10-31
发布日期:
2020-12-03
通讯作者:
陈依军
作者简介:
作者简介:王清(1994—),女,硕士研究生。研究方向:化学生物学。E-mail:基金资助:
Qing WANG, Yijun CHEN
Received:
2020-03-08
Revised:
2020-09-23
Online:
2020-10-31
Published:
2020-12-03
Contact:
Yijun CHEN
摘要:
微生物和植物来源的天然产物结构复杂多样,具有抗感染、抗肿瘤、免疫抑制等多种活性,是现代临床治疗药物的重要来源之一。然而,大部分天然产物存在水溶性差、活性不强、结构类似物多以及可及性受限等问题,难以通过简单的化学修饰和改造解决,极大限制了天然产物的成药性及其后续研发。综合基因工程、代谢工程、基因组学、系统生物学、合成化学和计算生物学等学科的合成生物学,为改善天然产物的成药性提供了新机遇。本文针对限制天然产物成药的主要因素,概述了近年来利用合成生物学方法与策略在提高天然产物成药性方面取得的研究进展。通过理性分析天然产物的构效关系、挖掘合成和调控元件、构建系列反应模块和人工合成体系、筛选并优化底盘生物等策略,实现了多种天然产物来源药物或前体在“细胞工厂”中的定向、高效合成。与此同时,合成生物学技术也衍生了结构多样和性质改良的生物活性分子和潜在新药。随着合成生物学、药学和信息科学等方面的发展,可以预见提高和改善天然产物成药性的研究将会进入一个崭新的时代。
中图分类号:
王清, 陈依军. 天然产物成药性的合成生物学改良[J]. 合成生物学, 2020, 1(5): 583-592.
Qing WANG, Yijun CHEN. Synthetic biology approaches to improve druggability of natural products[J]. Synthetic Biology Journal, 2020, 1(5): 583-592.
1 | DU Lin, ROBLES A J, KING J B, et al. Crowdsourcing natural products discovery to access uncharted dimensions of fungal metabolite diversity [J]. Angewandte Chemie International Edition, 2014, 53(3): 804-809. |
2 | BAUER A, BRÖNSTRUP M. Industrial natural product chemistry for drug discovery and development [J]. Natural Product Reports, 2014, 31(1): 35-60. |
3 | BROWN D G, LISTER T, MAY-DRACKA T L. New natural products as new leads for antibacterial drug discovery [J]. Bioorganic & Medicinal Chemistry Letters, 2014, 24(2): 413-418. |
4 | SCHEEPSTRA M, NIETO L, HIRSCH A K, et al. A natural-product switch for a dynamic protein interface [J]. Angewandte Chemie International Edition, 2014, 53(25): 6443-6448. |
5 | HARVEY A L, EDRADA-EBEL R A, QUINN R J. The re-emergence of natural products for drug discovery in the genomics era [J]. Nature Reviews Drug Discovery, 2015, 14(2): 111-129. |
6 | ZIMMERMANN T J, ROY S, MARTINEZ N E, et al. Biology-oriented synthesis of a tetrahydroisoquinoline-based compound collection targeting microtubule polymerization [J]. ChemBioChem, 2013, 14(3): 295-300. |
7 | LOWE D B. Drug discovery: combichem all over again [J]. Nature Chemistry, 2014, 6(10): 851-852. |
8 | NEWMAN D J, CRAGG G M. Natural products as sources of new drugs over the 30 years from 1981 to 2010 [J]. Journal of Natural Products, 2012, 75(3): 311-335. |
9 | RODRIGUES T, REKER D, SCHNEIDER P, et al. Counting on natural products for drug design [J]. Nature Chemistry, 2016, 8(6): 531-534. |
10 | DEITERS A, CROPP T A, SUMMERER D, et al. Site-specific PEGylation of proteins containing unnatural amino acids [J]. Bioorganic & Medicinal Chemistry Letters, 2004, 14(23): 5743-5745. |
11 | NEUMANN H, WANG Kaihang, DAVIS L, et al. Encoding multiple unnatural amino acids via evolution of a quadruplet-decoding ribosome [J]. Nature, 2010, 464(7287): 441-444. |
12 | BALTZ R H. Combinatorial biosynthesis of cyclic lipopeptide antibiotics: a model for synthetic biology to accelerate the evolution of secondary metabolite biosynthetic pathways [J]. ACS Synthetic Biology, 2014, 3(10): 748-758. |
13 | KHALIL A S, COLLINS J J. Synthetic biology: applications come of age [J]. Nature Reviews Genetics, 2010, 11(5): 367-379. |
14 | BREITLING R, TAKANO E. Synthetic biology advances for pharmaceutical production [J]. Current Opinion in Biotechnology, 2015, 35: 46-51. |
15 | TANG Xiaolong, DAI Hong, ZHU Yongxiang, et al. Maytansine-loaded star-shaped folate-core PLA-TPGS nanoparticles enhancing anticancer activity [J]. American Journal of Translational Research, 2014, 6(5): 528-537. |
16 | JARAPRAKASH NG, SUROLIA A. Role of glycosylation in nucleating protein folding and stability [J]. Biochemical Journal, 2017, 474(14): 2333-2347. |
17 | JI Shuai, LIANG Wenfei, LI Ziwei, et al. Effcient and selective glucosylation of prenylated phenolic compounds by Mucor hiemalis [J]. RSC Advances, 2016, 6(25): 20791-20799. |
18 | LIU Xiaochen, ZHANG Liang. Biosynthesis of glycyrrhetinic acid-3-O-monoglucose using glycosyltransferase UGT73C11 from Barbarea vulgaris [J]. Industrial & Engineering Chemistry Research, 2017, 56(52): 14949-14958. |
19 | LIANG Wenfei, LI Ziwei, JI Shuai, et al. Microbial glycosylation of tanshinone IIA by Cunninghamella elegans AS 3.2028 [J]. RSC Advances, 2015, 5(78): 63753-63756. |
20 | HARMS J M, WILSON D N, SCHLUENZEN F, et al. Translational regulation via L11: molecular switches on the ribosome turned on and off by thiostrepton and micrococcin [J]. Molecular Cell, 2008, 30(1): 26-38. |
21 | ZHENG Qingfei, WANG Shoufeng, LIAO Rijing, et al. Precursor-directed mutational biosynthesis facilitates the functional assignment of two cytochromes P450 in thiostrepton biosynthesis [J]. ACS Chemical Biology, 2016, 11: 2673–2678. |
22 | WANG Shoufeng, ZHENG Qingfei, WANG Jianfeng, et al. Target-oriented design and biosynthesis of thiostrepton-derived thiopeptide antibiotics with improved pharmaceutical properties [J]. Organic Chemistry Frontiers, 2015, 2: 106-109. |
23 | EVANS B, CHEN Yunqiu, METCALF W, et al. Directed evolution of the nonribosomal peptide synthetase AdmK generates new Andrimid derivatives in vivo [J]. Chemistry & Biology, 2011, 18(5): 601-607. |
24 | MATSUDA Y, GOTFREDSEN C H, LARSEN T O. Genetic characterization of neosartorin biosynthesis provides insight into heterodimeric natural product generation [J]. Organic Letters, 2018, 20(22): 7197-7200. |
25 | JI Zhiqin, WEI Shaopeng, FAN Lixia, et al. Three novel cyclic hexapeptides from Streptomyces alboflavus 313 and their antibacterial activity [J]. European Journal of Medicinal Chemistry, 2012, 50: 296-303. |
26 | FAN Lixia, JI Zhiqin, GUO Zhengyan, et al. NW-G12, a novel nonchlorinated cyclohexapeptide from Streptomyces alboflavus313 [J]. Chemistry of Natural Compounds, 2013, 49(5): 910-913. |
27 | GUO Zhengyan, LI Pengwei, CHEN Guozhu, et al. Design and biosynthesis of dimeric alboflavusins with biaryl linkages via regiospecific C—C bond coupling [J]. Journal of the American Chemical Society, 2018, 140(51): 18009-18015. |
28 | HINDRA, YANG Dong, TENG Qihui, et al. Genome mining of Streptomyces mobaraensis DSM40847 as a bleomycin producer providing a biotechnology platform to engineer designer bleomycin analogues [J]. Organic Letters, 2017, 19(6): 1386-1389. |
29 | BUTLER M S, ROBERTSON A A B, COOPER M A. Natural product and natural product derived drugs in clinical trials [J]. Natural Product Reports, 2014, 31(11): 1612-1661. |
30 | CHEN Yun, DENG Wei, WU Jiequn, et al. Genetic modulation of the overexpression of tailoring genes eryK and eryG leading to the improvement of erythromycin A purity and production in Saccharopolyspora erythraea fermentation [J]. Applied and Environmental Microbiology, 2008, 74(6): 1820-1828. |
31 | 张万祥, 汪焰胜, 吴杭, 等. 前体代谢工程提高红霉素产量的研究进展[J]. 生物技术通讯, 2019, 30(1): 140-145. |
ZHANG Wanxiang, WANG Yansheng, WU Hang, et al. Advances in metabolic engineering of precursors for improving Erythromycin production [J]. Letters in Biotechnology, 2019, 30(1): 140-145. | |
32 | WU Jiequn, ZHANG Qinglin, DENG Wei, et al. Toward improvement of erythromycin A production in an industrial Saccharopolyspora erythraea strain via facilitation of genetic manipulation with an artificial attB site for specific recombination [J]. Applied and Environmental Microbiology, 2011, 77(21): 7508-7516. |
33 | LIAN Jiazhang, SI Tong, NAIR N U, et al. Design and construction of acetyl-CoA overproducing Saccharomyces cerevisiae strains [J]. Metabolic Engineering, 2014, 24: 139-149. |
34 | KRIVORUCHKO A, ZHANG Yiming, SIEWERS V, et al. Microbial acetyl-CoA metabolism and metabolic engineering [J]. Metabolic Engineering, 2015, 28: 28-42. |
35 | LIU Yiqi, BAI Chenxiao, LIU Qi, et al. Engineered ethanol-driven biosynthetic system for improving production of acetyl-CoA derived drugs in Crabtree-negative yeast [J]. Metabolic Engineering, 2019, 54: 275-284. |
36 | 朱灵英, 郭娟, 张爱丽, 等. 参与植物三萜生物合成的细胞色素P450酶研究进展[J]. 中草药, 2019, 50(22): 5597-5610. |
ZHU Lingying, GUO Juan, ZHANG Aili, et al. Research progress on CYP450 involved in medicinal plant triterpenoid biosynthesis [J]. Chinese Traditional and Herbal Drugs, 2019, 50(22): 5597-5610. | |
37 | 漆丽华, 张媚, 潘海学, 等. 基于生物合成途径改造的一个三欣卡辛类似物的发现[J]. 生命有机化学, 2014, 34(7): 1376-1381. |
XI Lihua, ZHANG Mei, PAN Haixue, et al. Production of a trioxacarcin analogue by engineering of its biosynthetic pathway [J]. Chinese Journal of Organic Chemistry, 2014, 34(7): 1376-1381. | |
38 | MARTIN V J J, PITERA D J, WITHERS S T, et al. Engineering a mevalonate pathway in Escherichia coli for production of terpenoids [J]. Nature Biotechnology, 2003, 21(7): 796-802. |
39 | 范楚珧, 刘龙英, 沈玥, 等. 吗啡的合成生物学研究和工业化生产[J]. 科学通报, 2016, 61: 1436-1444. |
FAN Chuyao, LIU Longying, SHEN Yue, et al. Progress of biosynthesis of morphine and its industrial manufacture [J]. Chinese Science Bulletin, 2016, 61: 1436-1444. | |
40 | NAKAGAWA A, MINAMI H, KIM Ju-Sung, et al. A bacterial platform for fermentative production of plant alkaloids [J]. Nature Communications, 2011, 2(1): 1-9. |
41 | NEUMANN H, NEUMANN-STAUBITZ P. Synthetic biology approaches in drug discovery and pharmaceutical biotechnology [J]. Applied Microbiology and Biotechnology, 2010, 87(1): 75-86. |
42 | ENGELS B, DAHM P, JENNEWEIN S. Metabolic engineering of taxadiene biosynthesis in yeast as a first step towards Taxol (Paclitaxel) production [J]. Metabolic Engineering, 2008, 10(3/4): 201-206. |
43 | KIRBY J, KEASLING J D. Metabolic engineering of microorganisms for isoprenoid production [J]. Natural Product Reports, 2008, 25(4): 656-661. |
44 | WALTHER T, CALVAYRAC F, MALBERT Y, et al. Construction of a synthetic metabolic pathway for the production of 2,4-dihydroxybutyric acid from homoserine [J]. Metabolic Engineering, 2018, 45: 237-245. |
45 | WEI Liang, WANG Qian, XU Ning, et al. Combining protein and metabolic engineering strategies for high level production of O-acetylhomoserine in Escherichia coli [J]. ACS Synthetic Biology, 2019, 8: 1153-1167. |
46 | WILLIAMS T L, YIN Yuhui W, CARTER C W. Selective inhibition of bacterial tryptophanyl-tRNA synthetases by indolmycin is mechanism-based [J]. Journal of Biological Chemistry, 2016, 291(1): 255-265. |
47 | DU Yiling, HIGGINS M A, ZHAO Guiyun, et al. Convergent biosynthetic transformations to a bacterial specialized metabolite [J]. Nature Chemical Biology, 2019, 15(11): 1043-1048. |
48 | DANGEL V, WESTRICH L, SMITH M C M, et al. Use of an inducible promoter for antibiotic production in a heterologous host [J]. Applied Microbiology and Biotechnology, 2010, 87(1): 261-269. |
49 | YAN Fu, BURGARD C, POPOFF A, et al. Synthetic biology approaches and combinatorial biosynthesis towards heterologous lipopeptide production [J]. Chemical Science, 2018, 9(38): 7510-7519. |
50 | KOMATSU M, KOMATSU K, KOIWAI H, et al. Engineered Streptomyces avermitilis host for heterologous expression of biosynthetic gene cluster for secondary metabolites [J]. ACS Synthetic Biology, 2013, 2(7): 384-396. |
51 | LUO Yunzi, HUANG Hua, LIANG Jing, et al. Activation and characterization of a cryptic polycyclic tetramate macrolactam biosynthetic gene cluster [J]. Nature Communications, 2013, 4: 94-105. |
52 | TAN Gaoyi, DENG Kunhua, LIU Xinhua, et al. Heterologous biosynthesis of spinosad: an omics-guided large polyketide synthase gene cluster reconstitution in Streptomyces [J]. ACS Synthetic Biology, 2017, 6(6): 995-1005. |
53 | D'ISCHIA M, WAKAMATSU K, CICOIRA F, et al. Melanins and melanogenesis: from pigment cells to human health and technological applications [J]. Pigment Cell & Melanoma Research, 2015, 28(5): 520-544. |
54 | KIM Young Jo, KHETAN A, WU Wei, et al. Evidence of porphyrin-like structures in natural melanin pigments using electrochemical fingerprinting [J]. Advanced Materials, 2016, 28(16): 3173-3180. |
55 | WANG Zheng, TSCHIRHART T, SCHULTZHAUS Z, et al. Characterization and application of melanin produced by the fast-growing marine bacterium Vibrio natriegens through heterologous biosynthesis [J]. Applied and Environmental Microbiology, 2020, 86(5): e02749-19. |
[1] | 刁志钿, 王喜先, 孙晴, 徐健, 马波. 单细胞拉曼光谱测试分选装备研制及应用进展[J]. 合成生物学, 2023, 4(5): 1020-1035. |
[2] | 卢挥, 张芳丽, 黄磊. 合成生物学自动化装置iBioFoundry的构建与应用[J]. 合成生物学, 2023, 4(5): 877-891. |
[3] | 白仲虎, 任和, 聂简琪, 孙杨. 高通量平行发酵技术的发展与应用[J]. 合成生物学, 2023, 4(5): 904-915. |
[4] | 吴玉洁, 刘欣欣, 刘健慧, 杨开广, 随志刚, 张丽华, 张玉奎. 基于高通量液相色谱质谱技术的菌株筛选与关键分子定量分析研究进展[J]. 合成生物学, 2023, 4(5): 1000-1019. |
[5] | 胡哲辉, 徐娟, 卞光凯. 自动化高通量技术在天然产物生物合成中的应用[J]. 合成生物学, 2023, 4(5): 932-946. |
[6] | 刘欢, 崔球. 原位电离质谱技术在微生物菌株筛选中的应用进展[J]. 合成生物学, 2023, 4(5): 980-999. |
[7] | 王雁南, 孙宇辉. 碱基编辑技术及其在微生物合成生物学中的应用[J]. 合成生物学, 2023, 4(4): 720-737. |
[8] | 刘晚秋, 季向阳, 许慧玲, 卢屹聪, 李健. 限制性内切酶的无细胞快速制备研究[J]. 合成生物学, 2023, 4(4): 840-851. |
[9] | 孙美莉, 王凯峰, 陆然, 纪晓俊. 解脂耶氏酵母底盘细胞的工程改造及应用[J]. 合成生物学, 2023, 4(4): 779-807. |
[10] | 张凡忠, 相长君, 张骊駻. 进化与大数据导向生物信息学在天然产物研究中的发展及应用[J]. 合成生物学, 2023, 4(4): 629-650. |
[11] | 曾涛, 巫瑞波. 数据驱动的酶反应预测与设计[J]. 合成生物学, 2023, 4(3): 535-550. |
[12] | 孙智, 杨宁, 娄春波, 汤超, 杨晓静. 功能拓扑的理性设计及其在合成生物学中的应用[J]. 合成生物学, 2023, 4(3): 444-463. |
[13] | 赖奇龙, 姚帅, 查毓国, 白虹, 宁康. 微生物组生物合成基因簇发掘方法及应用前景[J]. 合成生物学, 2023, 4(3): 611-627. |
[14] | 孟巧珍, 郭菲. “可折叠性”在酶智能设计改造中的应用研究——以AlphaFold2为例[J]. 合成生物学, 2023, 4(3): 571-589. |
[15] | 王晟, 王泽琛, 陈威华, 陈珂, 彭向达, 欧发芬, 郑良振, 孙瑨原, 沈涛, 赵国屏. 基于人工智能和计算生物学的合成生物学元件设计[J]. 合成生物学, 2023, 4(3): 422-443. |
阅读次数 | ||||||
全文 |
|
|||||
摘要 |
|
|||||