从化学合成到生物合成——天然产物全合成新趋势

doi:10.12211/2096-8280.2021-039

合成生物学 ›› 2021, Vol. 2 ›› Issue (5): 674-696.DOI: 10.12211/2096-8280.2021-039

从化学合成到生物合成——天然产物全合成新趋势

张发光¹, 曲戈², 孙周通², 马军安¹

^1.天津大学理学院化学系，合成生物学前沿科学中心，天津 300072
^2.中国科学院天津工业生物技术研究所，天津 300308

收稿日期:2021-04-01 修回日期:2021-06-19 出版日期:2021-10-31 发布日期:2021-11-19
通讯作者: 孙周通,马军安
作者简介:张发光（1987—），男，博士，副教授。研究方向为有机氟化学、不对称合成、合成生物学。E-mail：zhangfg1987@tju.edu.cn
曲戈（1985—），男，博士，副研究员。研究方向为酶分子理性设计与生物催化。E-mail：qug@tib.cas.cn曲戈（1985—），男，博士，副研究员。研究方向为酶分子理性设计与生物催化。E-mail：qug@tib.cas.cn
孙周通（1982—），男，博士，研究员。研究方向为酶分子工程与工业生物催化。E-mail：sunzht@tib.cas.cn
马军安（1968—），男，博士，教授，合成生物学前沿科学中心PI。研究方向为有机合成与合成生物学。E-mail：majun_an68@tju.edu.cn
基金资助:
国家重点研发计划(2019YFA0905100);广东省重点领域研发计划(2020B0303070002)

From chemical synthesis to biosynthesis: trends toward total synthesis of natural products

ZHANG Faguang¹, QU Ge², SUN Zhoutong², MA Jun′an¹

^1.Department of Chemistry，School of Science，Frontiers Science Center for Synthetic Biology （Ministry of Education），Tianjin University，Tianjin 300072，China
^2.Tianjin Institute of Industrial Biotechnology，Chinese Academy of Sciences，Tianjin 300308，China

Received:2021-04-01 Revised:2021-06-19 Online:2021-10-31 Published:2021-11-19
Contact: SUN Zhoutong, MA Jun′an

摘要/Abstract

摘要：

结构复杂而多样的天然产物是药物发现和创制的重要宝库。为了克服有限的自然资源，来自学术界和工业界的科学家近两个世纪一直不断尝试人工合成天然产物。化学全合成已经取得了巨大成就，众多高度复杂的天然产物已经被有机化学家成功制备；但本领域仍存在诸多挑战性问题，例如化学反应中涉及昂贵的化学试剂、苛刻的反应条件、难控的立体选择性、冗长的合成路线以及较低的总收率等。随着合成生物学的发展，越来越多天然产物可通过生物细胞工厂实现人工制备，从而提供全新而互补的全合成策略。本文简要概括天然产物化学全合成，围绕几种药物活性天然产物的生物合成介绍其相关进展，以青霉素、红霉素、阿维菌素为例分析总结了天然产物同源途径的改造与优化；以维生素B₁₂、莨菪烷碱为例概括评述了天然产物的异源表达与生物制造；并以人源胰岛素、青蒿素、沙弗拉霉素、嗜氮酮、卡英酸、鬼臼毒素为例重点介绍了生物与化学交叉融合策略在天然产物全合成中的应用。尽管在类天然产物新分子、立体复杂天然产物等的全合成中仍面临诸多挑战，但生物全合成对这些天然产物分子的构建将发挥越来越显著的作用；通过化学合成与生物合成优势互补，并借助当今蓬勃发展的人工智能技术，实现生物全合成的智能化、自动化、高效化将是本领域发展的新趋势。

关键词: 天然产物, 全合成, 合成生物学, 生物催化, 化学-酶法合成

Abstract:

The complexity and diversity of natural products have made them a rich source for drug and agrochemical discovery. To overcome the supplying limitation of natural resources, tremendous effort has been made by the academic and industrial communities during the past two centuries for the total artificial synthesis of natural products. In this regard, total chemical synthesis has achieved significant progress, and numerous highly complex natural products have been synthesized through different chemical processes. Despite these great achievements in total chemical synthesis, there are still many challenges including expensive chemical reagents, harsh reaction conditions, difficult control on stereoselectivity, long synthetic route, and low product yield. Notably, the development of synthetic biology has allowed more and more natural products to be produced through biological cell factories, which provides a new and complementary strategy for the synthesis of natural products at a large scale. This review critically comments on the representative advances in total chemical synthesis of natural products (Section 1), and then highlight major progress and trends in the biosynthesis of pharmaceutically important natural products (Sections 2 and 3). In Section 2.1, we selected the production of penicillin, erythromycin, and avermectin as examples to analyze the modification and optimization of natural product biosynthetic pathways. The discovery and utilization of secondary metabolites from microorganisms has been a continuous driving force in the field of natural products. Notably, significant progress has been made in the total biosynthesis of natural products from secondary metabolism via the genetic manipulation of microbial cells. In Section 2.2, we selected Vitamin B₁₂ and Tropane alkaloids as examples to demonstrate the use of heterologous expression and biological production for natural product synthesis. In recent years, on the basis of analyzing the structure of natural products in animals, plants, and microorganisms, great advances have emerged in exploring their biochemical reaction mechanisms and synthetic routes. More importantly, expressing and regulating the relative genes in heterologous microbial cells have enabled the complete biosynthesis of many natural products. Furthermore, in Section 3, human insulin, artemisinin, saframycin, azaphilone, kainic acid, and podophyllotoxin were selected as examples to showcase the power of merging chemical and biological processes for the total synthesis of natural products. Although there are still many challenges in the total synthesis of new and complex natural products, biosynthesis will ultimately play a significant role in the construction of natural molecules and their relative analogues. By taking advantage of the merits with organic chemistry, synthetic biology, and artificial intelligence, the development of highly efficient and automatic biosynthesis could be a trend in this field.

Key words: natural products, total synthesis, synthetic biology, biocatalysis, chemoenzymatic synthesis

中图分类号:

张发光, 曲戈, 孙周通, 马军安. 从化学合成到生物合成——天然产物全合成新趋势[J]. 合成生物学, 2021, 2(5): 674-696.

ZHANG Faguang, QU Ge, SUN Zhoutong, MA Jun′an. From chemical synthesis to biosynthesis: trends toward total synthesis of natural products[J]. Synthetic Biology Journal, 2021, 2(5): 674-696.

图/表 15

图1 吗啡、水杨苷、水杨酸及乙酰水杨酸化学结构

Fig. 1 Chemical structures of morphine, salicin, salicylic acid, and acetylsalicylic acid

图2 天然产物中的部分明星药物分子结构

Fig. 2 Molecular structures of several star natural products as pharmaceuticals

图3 广谱抗癌活性天然产物紫杉醇Robert Holton全合成(a)及Pierre Potier半合成路线(b)

Fig. 3 Total synthesis of the anti-cancer natural product paclitaxel by Robert Holton (a) and its semi-synthesis by the Pierre Potier route (b)

图4 青霉素生物合成途径

Fig. 4 Biosynthetic pathway of penicillin

图5 红霉素A生物体内全合成路线

Fig. 5 Biosynthetic pathway of erythromycin A

图6 阿维菌素生物合成途径

Fig. 6 Biosynthetic pathway of avermectin

图7 维生素B12从头生物合成

Fig. 7 De novo biosynthesis of vitamin B12

图8 莨菪烷碱的生物合成机制解析

Fig. 8 Biosynthetic pathway of tropane alkaloids

图9 莨菪烷碱的酵母异源生物合成途径

Fig. 9 Heterologous biosynthesis of tropane alkaloids in yeast

图10 人源胰岛素分子A和B链的生物合成及化学连接

Fig. 10 Biosynthesis of human insulin A and B chains, as well as their chemical linkage

图11 青蒿素的生物-化学交叉全合成

Fig. 11 Total synthesis of artemisin via combining bio-synthesis and chemical synthesis

图12 沙弗拉霉素的化学-酶法全合成

Fig. 12 Syntheses of saframycins through the chemo-enzymatic catalysis

图13 嗜氮酮天然产物的化学-酶法立体多样性全合成

Fig. 13 Stereodivergent and chemoenzymatic synthesis of azaphilone natural products

图14 卡英酸的化学-酶法全合成

Fig. 14 Chemoenzymatic synthesis of kainic acid

图15 鬼臼毒素的两种化学-酶法合成途径

Fig. 15 Two chemoenzymatic synthesis pathways of podophyllotoxin

参考文献 130

1	BLAKEMORE P R, WHITE J D. Morphine, the proteus of organic molecules[J]. Chemical Communications, 2002, 38(11): 1159-1168.
2	BROOK K, BENNETT J, DESAI S P. The chemical history of Morphine: An 8000-year journey, from resin to de-novo synthesis[J]. Journal of Anesthesia History, 2017, 3(2): 50-55.
3	JACK D B. One hundred years of Aspirin[J]. Lancet, 1997, 350(9075): 437-439.
4	DESBOROUGH M J R, KEELING D M. The Aspirin story-from willow to wonder drug[J]. British Journal of Haematology, 2017, 177(5): 674-683.
5	徐任生. 天然产物化学[M]. 2版. 北京: 科学出版社, 2004;
	XU R S. Natural products chemistry[M]. 2nd Ed. Beijing: Science Press, 2004.
6	COOPER R. Natural products chemistry: sources, separations and structures[M]. NICOLA G, Eds. Florida: Boca Raton, 2016.
7	JACOB E J. Natural products-based drug discovery: some bottlenecks and considerations[J]. Current Science, 2009, 96(6): 753-754.
8	DAVID B, WOLFENDER J L, DIAS D A. The pharmaceutical industry and natural products: historical status and new trends[J]. Phytochemistry Reviews, 2015, 14(2): 299-315.
9	NEWMAN D J, CRAGG G M. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019[J]. Journal of Natural Products, 2020, 83(3): 770-803.
10	NICOLAOU K C, VOURLOUMIS D, WINSSINGER N, et al. The art and science of total synthesis at the dawn of the twenty-first century[J]. Angewandte Chemie International Edition, 2000, 39(1): 44-122.
11	NICOLAOU K C. Molecules that changed the world[M]. Weinheim: Wiley-VCH, 2008.
12	NICOLAOU K C. Classics in total synthesis: targets, strategies, methods[M]. Weinheim: VCH, 1996.
13	NICOLAOU K C. Classics in total synthesisⅡ: more targets, strategies, methods[M]. Weinheim: Wiley-VCH, 2003.
14	NICOLAOU K C. Classics in total synthesisⅢ: further targets, strategies, methods[M]. Weinheim: Wiley-VCH, 2011.
15	ROBINSON R. A synthesis of tropinone[J]. Journal of the Chemical Society, Transactions, 1917, 111: 762-768.
16	FISHER H, ZEILE K. Synthese des hämatoporphyrins, protoporphyrins und hämins[J]. Justus Liebigs Annalen der Chemie, 1929, 468(1): 98-116.
17	BACHMANN W E, COLE W, WILDS A L. The total synthesis of the sex hormone equilenin[J]. Journal of the American Chemical Society, 1939, 61(4): 974-975.
18	WOODWARD R B, DOERING W E. The total synthesis of quinine[J]. Journal of the American Chemical Society, 1944, 66(5): 849-850.
19	WOODWARD R B, SONDHEIMER F, TAUB D, et al. The total synthesis of steroids[J]. Journal of the American Chemical Society, 1952, 74(17): 4223-4251.
20	WOODWARD R B, SONDHEIMER F, TAUB D. The total synthesis of cortisone[J]. Journal of the American Chemical Society, 1951, 73(8): 4057.
21	WOODWARD R B, CAVA M P, OLLIS W D, et al. The total synthesis of strychnine[J]. Journal of the American Chemical Society, 1954, 76(18): 4749-4751.
22	WOODWARD R B, AYER W A, BEATON J M, et al. The total synthesis of Chlorophyll[J]. Journal of the American Chemical Society, 1960, 82(14): 3800-3802.
23	WOODWARD R B, HEUSLER K, GOSTELI J, et al. The total synthesis of cephalosporin C[J]. Journal of the American Chemical Society, 1966, 88(4): 852-853.
24	WOODWARD R B, AU-YEUNG B W, BALARAM P, et al. Asymmetric total synthesis of erythromycin. 2. Synthesis of an erythronolide A lactone system[J]. Journal of the American Chemical Society, 1981, 103(11): 3213-3215.
25	WOODWARD R B. Recent advances in the chemistry of natural products[J]. Pure and Applied Chemistry, 1968, 17(3): 519-547.
26	WOODWARD R B, HOFFMANN R. Structure of electrocyclic Reactions[J]. Journal of the American Chemical Society, 1966, 87(2): 395-397.
27	COREY E J, SNIDER B B. Total synthesis of (+ -)-fumagillin[J]. Journal of the American Chemical Society, 1972, 94(7): 2549-2550.
28	COREY E J, TRYBULSKI E J, MELVIN L S, et al. Total synthesis of erythromycins. 3. Stereoselective routes to intermediates corresponding to C(1) to C(9) and C(10) to C(13) fragments of erythronolide B[J]. Journal of the American Chemical Society, 1978, 100(14): 4618-4620.
29	TAMELEN E E VAN, SPENCER J T A, ALLEN J D S, et al. The total synthesis of colchicine[J]. Journal of the American Chemical Society, 1959, 81(23): 6341-6342.
30	COREY E J, CROUSE D N, ANDERSON J E. Total synthesis of natural 20(S)-camptothecin[J]. The Journal of Organic Chemistry, 1975, 40(14): 2140-2141.
31	COREY E J, SCHAAF T K, HUBER W, et al. Total synthesis of Prostaglandins F2α and E2 as the naturally occuring forms[J]. Journal of the American Chemical Society, 1970, 92(2): 397-398.
32	FUKUYAMA T, YANG L H, AJECK K L, et al. Total synthesis of (.+ -.)-saframycin A[J]. Journal of the American Chemical Society, 1990, 112(9): 3712-3713.
33	COREY E J, HUA D H, PAN B C, et al. Total synthesis of aplasmomycin[J]. Journal of the American Chemical Society, 1982, 104(24): 6818-6820.
34	COREY E J, CHENG X M. The logic of chemical synthesis[M]. New York: Wiley, 1989.
35	KUNG Y T, DU Y C, HUANG W T, et al. Total synthesis of crystalline bovine insulin[J]. Scientia Sinica, 1965, 14(11): 1710-1716.
36	KUNG Y T, DU Y C, HUANG W D, et al. Total synthesis of crystalline insulin[J]. Scientia Sinica, 1966, 15(4): 544-561.
37	MCELHENY V K. Total synthesis of insulin in red China[J]. Science, 1966, 153(3733): 281-283.
38	中国科学院上海生物化学研究所, 等. 酵母丙氨酸转移核糖核酸的全合成[J]. 科学通报, 1982, 27(2): 106-109.
	Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, et al. The total synthesis of yeast alanine transfer RNA[J]. Chinese Science Bulletin, 1982, 27(2): 106-109.
39	王德宝, 郑可沁, 裘慕绥, 等. 酵母丙氨酸转移核糖核酸(酵母丙氨酸t-RNA)人工全合成[J]. 中国科学: B辑, 1983, 26(5): 385-398.
	WANG D B, ZHENG, K Q, QIU M S, et al. The man-total synthesis of yeast alanine transfer RNA[J]. Scientia Sinica: B, 1983, 26(5): 385-398.
40	许杏祥, 朱杰, 黄大中, 等. 青蒿素及其一类物结构和合成的研究X: 从青蒿酸立体控制合成青蒿素和脱氧青蒿素[J]. 化学学报, 1983, 41(6): 574-576.
	XU X X, ZHU J, HUANG D Z, et al. Studies on structure and syntheses of arteannuin and related compound XVII: The stereocontrolled synthesis of arteannuin and deoxyarteannuin from arteannuic acid[J]. Acta Chimica Sinica, 1983, 41(6): 574-576.
41	许杏祥, 朱杰, 黄大中, 等. 青蒿素及其一类物结构和合成的研究ⅩⅦ: 双氢青蒿酸甲酯的立体控制性全合成——青蒿素全合成[J]. 化学学报, 1984, 42(9): 940-942.
	XU X X, ZHU J, HUANG D Z, et al. Studies on structure and syntheses of arteannuin and related compound ⅩⅦ: The stereocontrolled total synthesis of methyl dihydroarteannuate─the total synthesis of arteannuin[J]. Acta Chimica Sinica, 1984, 42(9): 940-942.
42	NICOLAOU K C, YANG Z, LIU J J, et al. Total synthesis of taxol[J]. Nature, 1994, 367(6464): 630-634.
43	HOLTON R A, SOMOZA C, KIM H B, et al. First total synthesis of taxol: 1. Functionalization of the B ring[J]. Journal of the American Chemical Society, 1994, 116(4): 1597-1598.
44	HOLTON R A, KIM H B, SOMOZA C, et al. First total synthesis of taxol: 2. Completion of the C and D rings[J]. Journal of the American Chemical Society, 1994, 116(4): 1599-1600.
45	CHAUVIÉRE G, GUÉNARD D, PICOT F, et al. Structure and biochemistry of products isolated from Taxus baccata [J]. Seances de l'Academie des Sciences—SerieⅡ, 1981, 293(7): 501-503.
46	J-N DENIS, GREENE A E, GUENARD D, et al. Highly efficient, practical approach to natural taxol[J]. Journal of the American Chemical Society, 1988, 110(17): 5917-5919.
47	GUENARD D, GUERITTE-VOEGELEIN F, POTIER P. Taxol and taxotere: discovery, chemistry, and structure-activity relationships[J]. Accounts of Chemical Research, 1993, 26(4): 160-167.
48	BALOGLU E, KINGSTON D G I. A new semisynthesis of paclitaxel from baccatinⅢ[J]. Journal of Natural Products, 1999, 62(7): 1068-1071.
49	NICOLAOU K C, MITCHELL H J, JAIN N F, et al. Total synthesis of vancomycin[J]. Angewandte Chemie International Edition, 1999, 38(1): 240-244.
50	EVANS D A, WOOD M R, TROTTER B W, et al. Total syntheses of vancomycin and eremomycin aglycons[J]. Angewandte Chemie International Edition, 1998, 37(19): 2700-2704.
51	BOGER D L, MIYAZAKI S, KIM S H, et al. Total synthesis of the vancomycin aglycon[J]. Journal of the American Chemical Society, 1999, 121(43): 10004-10011.
52	MADDESS M L, TACKETT M N, WATANABE H, et al. Total synthesis of rapamycin[J]. Angewandte Chemie International Edition, 2007, 46(4): 591-597.
53	SUH E M, KISHI Y. Synthesis of palytoxin from palytoxin carboxylic acid[J]. Journal of the American Chemical Society, 1994, 116(24): 11205-11206.
54	KISHI Y, ARATANI M, FUKAYAMA T, et al. Synthetic studies on tetrodotoxin and related compounds.Ⅲ. Stereospecific synthesis of an equivalent of acetylated tetrodamine[J]. Journal of the American Chemical Society, 1972, 94(26): 9217-9219.
55	AICHER T D, BUSZEK K R, FANG F G, et al. Total synthesis of halichondrin B and norhalichondrin B[J]. Journal of the American Chemical Society, 1992, 114(8): 3162-3164.
56	ZHENG W J, SELETSKY B M, PALME M H, et al. Macrocyclic ketone analogues of halichondrin B[J]. Bioorganic & Medicinal Chemistry Letter, 2004, 14(22): 5551-5554.
57	YU M J, ZHENG W J, SELETSKY B M, et al. Case history: discovery of eribulin (HALAVEN (TM)), a halichondrin B analogue that prolongs overall survival in patients with metastatic breast cancer[J]. Annual Reports in Medicinal Chemistry, 2011, 46: 227-241.
58	YU M J, ZHENG W J, SELETSKY M B. From micrograms to grams: scale-up synthesis of eribulin mesylate[J]. Natural Product Report, 2013, 30(9): 1158-1164.
59	卢志国, 汪建峰, 蒙海林, 等. 合成生物学与天然产物开发[J]. 生命科学, 2011, 23(9): 900-911.
	LU Z G, WANG J F, MENG H L, et al. Synthetic biology and natural products development[J]. Chinese Bulletin of Life Sciences, 2011, 23(9): 900-911.
60	潘海学, 袁华, 蹇晓红, 等. 天然产物生物合成与抗肿瘤药物合成生物学研究[J]. 中国科学:生命科学, 2015, 45(10): 1027-1039.
	PAN H X, YUAN H, JIAN X H, et al. Biosynthesis of natural products and synthetic biology of antitumor drugs[J]. Scientia Sinica Vitae, 2015, 45(10): 1027-1039.
61	SHELDON R A, WOODLEY J M. Role of biocatalysis in sustainable chemistry[J]. Chemical Reviews, 2018, 118(2): 801-838.
62	贺俊斌, 孟松, 潘海学, 等. 多酶催化串联策略在复杂天然产物合成中的应用[J]. 合成生物学, 2020, 1(2): 226-246.
	HE J B, MENG S, PAN H X, et al. Applications of the multienzyme-catalyzed tandem strategy in the synthesis of complex natural products[J]. Synthetic Biology Journal, 2020, 1(2): 226-246.
63	CURRIN A, SWAINSTON N, DAY P J, et al. Synthetic biology for the directed evolution of protein biocatalysts: navigating sequence space intelligently[J]. Chemical Society Reviews, 2015, 44(5): 1172-1239.
64	CRAVENS A, PAYNE J, SMOLKE C D. Synthetic biology strategies for microbial biosynthesis of plant natural products[J]. Nature Communications, 2019, 10(1): 2142.
65	饶聪, 云轩, 虞沂, 等. 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 C, YUN X, YU Y, et al. Recent progress of synthetic biology applications in microbial pharmaceuticals research[J]. Synthetic Biology Journal, 2020, 1(1): 92-102.
66	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.
67	HODGKIN D C. The X-ray analysis of the structure of penicillin[J]. Advancement of Science, 1949, 6(22): 85-89.
68	MARTÍN J F, DÍEZ B, ALVAREZ E, et al. Development of a transformation system in Penicillium chrysogenum: cloning of genes involved in penicillin biosynthesis[M]//ALACEVIC M, HRANUELI D, TOMAN Z. Genetics of industrial microorganism. Zagreb: Pliva, 1987: 297-308.
69	ALVAREZ E, CANTORAL J M, BARREDO J L, et al. Purification to homogeneity and characterization of acyl coenzyme A: 6-aminopenicillanic acid acyltransferase of Penicillium chrysogenum [J]. Antimicrob Agents Chemother, 1987, 31(11): 1675-1682.
70	MCGUIRE J M, BUNCH R L, ANDERSON R C, et al. Ilotycin, a new antibiotic[J]. Antibiotics and Chemotherapy, 1952, 2(6): 281-283.
71	CHEN L, SUN S F, SONG G W. Biosynthesis and combinatorial biosynthesis of erythromycin[J]. Chinese Journal of Organic Chemistry, 2012, 32(7): 1232-1240.
72	陈单丹, 吴杰群, 刘文. 以生物合成为基础的红霉素A的产量提高和结构改造[J]. 生物工程学报, 2015, 31(6): 939-954.
	CHEN D D, WU J Q, LIU W. Biosynthesis-based production improvement and structure modification of erythromycin A[J]. Chinese Journal of Biotechnology, 2015, 31(6): 939-954.
73	CHEN Y, DENG W, WU J Q, 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 Environmental Microbiology, 2008, 74(6): 1820-1828.
74	CAMPBELL W C. History of avermectin and ivermectin, with notes on the history of other macrocyclic lactone antiparasitic agents[J]. Current Pharmaceutical Biotechnology 2012, 13(6): 853-865.
75	IKEDA H, NONOMIYA T, USAMI M, et al. Organization of the biosynthetic gene cluster for the polyketide anthelmintic macrolide avermectin in Streptomyces avermitilis [J]. Proceedings of the National Academy of Sciences of the United States of America, 1999, 96(17): 9509-9514.
76	OMURA S, IKEDA H, ISHIKAWA J, et al. Genome sequence of an industrial microorganism Streptomyces avermitilis: deducing the ability of producing secondary metabolites[J]. Proceedings of the National Academy of Sciences of the United States of America, 2001, 98(21): 12215-12220.
77	YOON Y J, KIM E S, HWANG Y S, et al. Avermectin: biochemical and molecular basis of its biosynthesis and regulation[J]. Applied Microbiology and Biotechnology, 2004, 63(6): 626-634.
78	ZHUO Y, ZHANG W Q, CHEN D F, et al. Reverse biological engineering of hrdB to enhance the production of avermectins in an industrial strain of Streptomyces avermitilis [J]. Proceedings of the National Academy of Sciences of the United States of America, 2010, 107(25): 11250-11254.
79	LIU W S, STEWART C N. Plant synthetic biology[J]. Trends in Plant Science, 2015, 20(5): 309-317.
80	POUVREAU B, VANHERCKE T, SINGH S. From plant metabolic engineering to plant synthetic biology: the evolution of the design/build/test/learn cycle[J]. Plant Science, 2018, 273: 3-12.
81	张博, 马永硕, 尚轶, 等. 植物合成生物学研究进展[J]. 合成生物学, 2020, 1(2): 121-140.
	ZHANG B, MA Y S, SHANG Y, et al. Recent advances in plant synthetic biology[J]. Synthetic Biology Journal, 2020, 1(2): 121-140.
82	WOODWARD R B. The total synthesis of vitamin B₁₂ [J]. Pure and Applied Chemistry, 1973, 33(1): 145-178.
83	ESCHENMOSER A, WINTNER C. Natural product synthesis and vitamin B12[J]. Science, 1977, 196(4297): 1410-1420.
84	FANG H, LI D, KANG J, et al. Metabolic engineering of Escherichia coli for de novo biosynthesis of vitamin B₁₂ [J]. Nature Communications, 2018, 9(1): 4917.
85	HUANG J P, WANG Y J, TIAN T,et al. Tropane alkaloid biosynthesis: a centennial review[J]. Natural Product Reports, 2021, 38(9): 1634-1658
86	QIU F, YANG C X, YUAN L N, et al. A phenylpyruvic acid reductase is required for biosynthesis of tropane alkaloids[J]. Organic Letters, 2018, 20(24): 7807-7810.
87	QIU F, ZENG J L, WANG J, et al. Functional genomics analysis reveals two novel genes required for littorine biosynthesis[J]. The New Phytologist, 2020, 225(5): 1906-1914.
88	ZHAO T, LI S, WANG J, et al. Engineering tropane alkaloid production based on metabolic characterization of ornithine decarboxylase in Atropa belladonna [J]. ACS Synthetic Biology, 2020, 9(2): 437-448.
89	HUANG J P, FANG C, MA X, et al. Tropane alkaloids biosynthesis involves an unusual typeⅢ polyketide synthase and non-enzymatic condensation[J]. Nature Communications, 2019, 10: 4036.
90	QIU F, YAN Y J, ZENG J L, et al. Biochemical and metabolic insights into hyoscyamine dehydrogenase[J]. ACS Catalysis, 2021, 11(5): 2912-2924.
91	SRINIVASAN P, SMOLKE C D. Biosynthesis of medicinal tropane alkaloids in yeast[J]. Nature, 2020, 585(7826): 614-619.
92	LI J, AMATUNI A, RENATA H. Recent advances in the chemoenzymatic synthesis of bioactive natural products[J]. Current Opinion in Chemical Biology, 2020, 55: 111-118.
93	李晓军, 张万斌, 高栓虎. 复杂天然产物全合成: 化学合成与生物合成结合的策略[J]. 有机化学, 2018, 38: 2185-2198.
	LI X J, ZHANG W B, GAO S H. Total synthesis of complex natural products: combination of chemical synthesis and biosynthesis strategies[J]. Chinese Journal of Organic Chemistry, 2018, 38: 2185-2198.
94	ITAKURA K, HIROSE T, CREA R, et al. Expression in Escherichia coli of a chemically synthesized gene for the hormone somatostatin[J]. Science, 1977, 198(4321): 1056-1063.
95	CREA R, KRASZEWSKI A, HIROSE T, et al. Chemical synthesis of genes for human insulin[J]. Proceedings of the National Academy of Sciences of the United States of America, 1978, 75(12): 5765-5769.
96	GOEDEEL D V, KLEID D G, BOLIVAR F, et al. Expression in Escherichia coli of chemically synthesized genes for human insulin[J]. Proceedings of the National Academy of Sciences of the United States of America, 1979, 76(1): 106-110.
97	RIGGS A D. Making, cloning, and the expression of human insulin genes in bacteria: the path to humulin[J]. Endocrine Reviews, 2021, 42(3): 374-380.
98	屠呦呦. 青蒿及青蒿素类药物[M]. 北京: 化学工业出版社, 2015.
	TU Y Y. Relative drugs of qinghao and qinghaosu[M]. Beijing: Chemical Industrial Press, 2015.
99	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.
100	TURCONI J, GRIOLET F, GUEVEL R, et al. Semisynthetic artemisinin, the chemical path to industrial production[J]. Organic Process Research & Development, 2014, 18(3): 417-422.
101	AMARA Z, BELLAMY J F B, HORVATH R, et al. Applying green chemistry to the photochemical route to artemisinin[J]. Nature Chemistry, 2015, 7(6): 489-495.
102	SCOTT J D, WILLIAMS R M, Chemistry and biology of the tetrahydroisoquinoline antitumor antibiotics[J]. Chemical Reviews, 2002, 102:1669-1730.
103	CHRZANOWSKA M, GRAJEWSKA A, ROZWADOWSKA M D. Asymmetric synthesis of isoquinoline alkaloids: 2004-2015[J]. Chemical Reviews, 2016, 116(19): 12369-12465.
104	GLENN W S, RUNGUPHAN W, O'CONNO S E. Recent progress in the metabolic engineering of alkaloids in plant systems [J]. Current Opinion in Chemical Biology, 2013, 24:354-365.
105	TANIFUJI R, KOKETSU K, TAKAKURA M, et al. Chemo-enzymatic total syntheses of jorunnamycin A, saframycin A, and N‑Fmoc saframycin Y3[J]. Journal of the American Chemical Society, 2018, 140:10705-10709.
106	PYSER J B, DOCKREY S A B, BENITEZ A R, et al. Stereodivergent, chemoenzymatic synthesis of azaphilone natural products[J]. Journal of the American Chemical Society, 2019, 141(46): 18551-18559.
107	CHAKRABARTY S, ROMERO E O, PYSER J B, et al. Chemoenzymatic total synthesis of natural products[J]. Accounts of Chemical Research, 2021, 54(6): 1374-1384.
108	WERNER P, VOIGT M, KEINÄNEN K, et al. Cloning of a putative high-affinity kainate receptor expressed predominantly in hippocampal CA3 cells[J]. Nature, 1991, 351: 742-744.
109	STATHAKIS C I, YIOTI E G, GALLOS J K, Total Syntheses of (-)‐α‐kainic acid[J]. European Journal of Organic Chemistry, 2012: 4661-4673.
110	CHEKAN J R, MCKINNIE S M K, MOORE M L, et al. Scalable biosynthesis of the seaweed neurochemical, kainic acid[J]. Angewandte Chemie International Edition, 2019, 58: 8454-8457.
111	SHAH Z, GOHAR U F, JAMSHED I, et al. Podophyllotoxin: history, recent advances and future prospects[J]. Biomolecules, 2021, 11: 603-629.
112	CHANG W C, YANG Z J, TU Y H, et al. Reaction mechanism of a nonheme iron enzyme catalyzed oxidative cyclization via C-C bond formation[J]. Organic Letters, 2019, 21(1): 228-232.
113	LAZZAROTTO M, HAMMERER L, HETMANN M, et al. Chemoenzymatic total synthesis of deoxy-, epi-, and podophyllotoxin and a biocatalytic kinetic resolution of dibenzylbutyrolactones[J]. Angewandte Chemie International Edition, 2019, 58: 8226-8230.
114	LI J, ZHANG X, RENATA H. Asymmetric chemoenzymatic synthesis of ((-))-podophyllotoxin and related aryltetralin lignans[J]. Angewandte Chemie International Edition, 2019, 58(34): 11657-11660.
115	DAI Z B, WANG B B, LIU Y, et al. Producing aglycons of ginsenosides in bakers' yeast[J]. Scientific Reports, 2014, 4: 3698.
116	王高丽, 金雪芮, 罗云孜. 合成生物学在含氟化合物生产中的应用[J]. 合成生物学, 2020, 1(3): 358-371.
	WANG G L, JIN X R, LUO Y Z. Applications of synthetic biology in the production of fluorinated compounds[J]. Synthetic Biology Journal, 2020, 1(3): 358-371.
117	O' HAGAN D, SCHAFFRATH C, COBB S L, et al. Biochemistry: biosynthesis of an organofluorine molecule[J]. Nature, 2002, 416(6878): 279.
118	THURONYI B W, CHANG M C Y. Synthetic biology approaches to fluorinated polyketides[J]. Accounts of Chemical Research, 2015, 48(3): 584-592.
119	NIE J, GUO H C, CAHARD D, et al. Asymmetric construction of stereogenic carbon centers featuring a trifluoromethyl group from prochiral trifluoromethylated substrates[J]. Chemical Reviews, 2011, 111(2): 455-529.
120	MA J A, CAHARD D. Update 1 of: asymmetric fluorination, trifluoromethylation, and perfluoroalkylation reactions[J]. Chemical Reviews, 2008, 108(9): PR1-PR43.
121	HUANG Q L, ROESSNER C A, CROTEAU R, et al. Engineering Escherichia coli for the synthesis of taxadiene, a key intermediate in the biosynthesis of taxol[J]. Bioorganic & Medicinal Chemistry, 2001, 9(9): 2237-2242.
122	LI J H, DAI J G, CHEN X G, et al. Microbial transformation of cephalomannine by Luteibacter sp[J]. Journal of Natural Products, 2007, 70(12): 1846-1849.
123	AJIKUMAR P K, XIAO W H, TYO K E J, et al. Isoprenoid pathway optimization for taxol precursor overproduction in Escherichia coli [J]. Science, 2010, 330(6000): 70-74.
124	MALIK S, CUSIDO R M, MIRJALILI M H, et al. Production of the anticancer drug taxol in Taxus Baccata suspension cultures: a review[J]. Process Biochemistry, 2011, 46(1): 23-34.
125	HOWAT S, PARK B, OH I S, et al. Paclitaxel: biosynthesis, production and future prospects[J]. New Biotechnology, 2014, 31(3): 242-245.
126	MUCHIRI R, WALKER K D. Paclitaxel biosynthesis: adenylation and thiolation domains of an NRPS TycA PheAT module produce various arylisoserine CoA thioesters[J]. Biochemistry, 2017, 56(10): 1415-1425.
127	FARHADI S, MOIENI A, SAFAIE N, et al. Fungal cell wall and methyl-β-cyclodextrin synergistically enhance paclitaxel biosynthesis and secretion in Corylus avellana cell suspension culture[J]. Scientific Reports, 2020, 10: 5427.
128	蒋迎迎, 曲戈, 孙周通. 机器学习助力酶定向进化[J]. 生物学杂志, 2020, 37(4): 1-11.
	JIANG Y Y, QU G, SUN Z T. Machine learning-assisted enzyme directed evolution[J]. Journal of Biology, 2020, 37(4): 1-11.
129	LI G Y, DONG Y J, REETZ M T. Can machine learning revolutionize directed evolution of selective enzymes?[J]. Advanced Synthesis & Catalysis, 2019, 361(11): 2377-2386.
130	BASTANLARY, OZUYSAL M. Introduction to machine learning[M]. Methods in Molecular Biology, 2014: 105-128.

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从化学合成到生物合成——天然产物全合成新趋势

From chemical synthesis to biosynthesis: trends toward total synthesis of natural products

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