Missing enzymes in the biosynthesis of the anticancer drug vinblastine in Madagascar periwinkle

被引：279

作者：

Caputi, Lorenzo ^{[1
]}

Franke, Jakob ^{[1
,4
]}

Farrow, Scott C. ^{[1
]}

Chung, Khoa ^{[1
]}

Payne, Richard M. E. ^{[1
,5
]}

Trinh-Don Nguyen ^{[1
]}

Dang, Thu-Thuy T. ^{[1
]}

Carqueijeiro, Ines Soares Teto ^{[2
]}

Koudounas, Konstantinos ^{[2
]}

de Bernonville, Thomas Duge ^{[2
]}

Ameyaw, Belinda ^{[1
,6
]}

Jones, D. Marc ^{[1
]}

Curcino Vieira, Ivo Jose ^{[3
]}

Courdavault, Vincent ^{[2
]}

O'Connor, Sarah E. ^{[1
]}

机构：

[1] John Innes Ctr, Dept Biol Chem, Norwich Res Pk, Norwich NR4 7UH, Norfolk, England

[2] Univ Tours, Biomol & Biotechnol Vegetales, EA2106, Parc Grandmont, F-37200 Tours, France

[3] Univ Estadual N Fluminen, Lab Ciencias Quim, BR-28013602 Campos dos Goytacazes, RJ, Brazil

[4] Leibniz Univ Hannover, Ctr Biomol Drug Res, Schneiderberg 38, D-30167 Hannover, Germany

[5] Univ Oxford, Dept Biochem, South Parks Rd, Oxford OX1 3QU, England

[6] Univ Lancaster, Dept Biol, Lancaster LA1 4YW, England

来源：

SCIENCE | 2018年 / 360卷 / 6394期

基金：

英国生物技术与生命科学研究理事会; 欧洲研究理事会;

关键词：

INDOLE ALKALOIDS; STEREOSPECIFIC MODELS; IBOGA-ALKALOIDS; ASPIDOSPERMA; PRECURSOR; LOCALIZATION; DIVERSITY; CHEMISTRY; BIOLOGY; PATHWAY;

D O I：

10.1126/science.aat4100

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Vinblastine, a potent anticancer drug, is produced by Catharanthus roseus (Madagascar periwinkle) in small quantities, and heterologous reconstitution of vinblastine biosynthesis could provide an additional source of this drug. However, the chemistry underlying vinblastine synthesis makes identification of the biosynthetic genes challenging. Here we identify the two missing enzymes necessary for vinblastine biosynthesis in this plant: an oxidase and a reductase that isomerize stemmadenine acetate into dihydroprecondylocarpine acetate, which is then deacetoxylated and cyclized to either catharanthine or tabersonine via two hydrolases characterized herein. The pathways show how plants create chemical diversity and also enable development of heterologous platforms for generation of stemmadenine-derived bioactive compounds.

引用

页码：1235 / 1238

页数：4

共 29 条

[1] TRUNCATED ASPIDOSPERMA ALKALOID-LIKE SCAFFOLDS: UNIQUE STRUCTURES FOR THE DISCOVERY OF NEW, BIOACTIVE COMPOUNDS [J].

Benson, Scott C. ;

Lee, Lily ;

Wei, Wanguo ;

Ni, Feng ;

Olmos, Julian David Janna ;

Strom, Kyle R. ;

Beeler, Aaron B. ;

Cheng, Ken Chih-Chien ;

Inglese, James ;

Kota, Smitha ;

Takahashi, Virginia ;

Strosberg, A. Donny ;

Connor, John H. ;

Bushkin, G. Guy ;

Snyder, John K. .

HETEROCYCLES, 2012, 84 (01) :135-155

[2] Immunocytological localization of two enzymes involved in berberine biosynthesis [J].

Bock, A ;

Wanner, G ;

Zenk, MH .

PLANTA, 2002, 216 (01) :57-63

[3] A Pressure Test to Make 10 Molecules in 90 Days: External Evaluation of Methods to Engineer Biology [J].

Casini, Arturo ;

Chang, Fang-Yuan ;

Eluere, Raissa ;

King, Andrew M. ;

Young, Eric M. ;

Dudley, Quentin M. ;

Karim, Ashty ;

Pratt, Katelin ;

Bristol, Cassandra ;

Forget, Anthony ;

Ghodasara, Amar ;

Warden-Rothman, Robert ;

Gan, Rui ;

Cristofaro, Alexander ;

Borujeni, Amin Espah ;

Ryu, Min-Hyung ;

Li, Jian ;

Kwon, Yong-Chan ;

Wang, He ;

Tatsis, Evangelos ;

Rodriguez-Lopez, Carlos ;

O'Connor, Sarah ;

Medema, Marnix H. ;

Fischbach, Michael A. ;

Jewett, Michael C. ;

Voigt, Christopher ;

Gordon, D. Benjamin .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2018, 140 (12) :4302-4316

[4]

Dadson B. A., 1969, J CHEM SOC CHEM COMM, V1969, p665b

[5]

Dang TTT, 2015, NAT CHEM BIOL, V11, P104, DOI [10.1038/nchembio.1717, 10.1038/NCHEMBIO.1717]

[6] Phytochemical genomics of the Madagascar periwinkle: Unravelling the last twists of the alkaloid engine [J].

de Bernonyille, Thomas Duge ;

Clastre, Marc ;

Besseau, Sebastien ;

Oudin, Audrey ;

Burlat, Vincent ;

Glevarec, Gaelle ;

Lanoue, Arnaud ;

Papon, Nicolas ;

Giglioli-Guivarc'h, Nathalie ;

St-Pierre, Benoit ;

Courdavault, Vincent .

PHYTOCHEMISTRY, 2015, 113 :9-23

[7] Alkaloid accumulation in Catharanthus roseus cell suspension cultures fed with stemmadenine [J].

El-Sayed, M ;

Choi, YH ;

Frédérich, M ;

Roytrakul, S ;

Verpoorte, R .

BIOTECHNOLOGY LETTERS, 2004, 26 (10) :793-798

[8] Total Synthesis of Vinblastine, Vincristine, Related Natural Products, and Key Structural Analogues [J].

Ishikawa, Hayato ;

Colby, David A. ;

Seto, Shigeki ;

Va, Porino ;

Tam, Annie ;

Kakei, Hiroyuki ;

Rayl, Thomas J. ;

Hwang, Inkyu ;

Boger, Dale L. .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2009, 131 (13) :4904-4916

[9] Progress in the Synthesis of Iboga-alkaloids and their Congeners [J].

Jana, Goutam Kumar ;

Paul, Sibasish ;

Sinha, Surajit .

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL, 2011, 43 (06) :541-573

[10] Genome-guided investigation of plant natural product biosynthesis [J].

Kellner, Franziska ;

Kim, Jeongwoon ;

Clavijo, Bernardo J. ;

Hamilton, John P. ;

Childs, Kevin L. ;

Vaillancourt, Brieanne ;

Cepela, Jason ;

Habermann, Marc ;

Steuernagel, Burkhard ;

Clissold, Leah ;

McLay, Kirsten ;

Buell, Carol Robin ;

O'Connor, Sarah E. .

PLANT JOURNAL, 2015, 82 (04) :680-692

← 1 2 3 →