Discovery and engineering of colchicine alkaloid biosynthesis.

Nature
Ryan S NettElizabeth S Sattely

Abstract

Few complete pathways have been established for the biosynthesis of medicinal compounds from plants. Accordingly, many plant-derived therapeutics are isolated directly from medicinal plants or plant cell culture1. A lead example is colchicine, a US Food and Drug Administration (FDA)-approved treatment for inflammatory disorders that is sourced from Colchicum and Gloriosa species2-5. Here we use a combination of transcriptomics, metabolic logic and pathway reconstitution to elucidate a near-complete biosynthetic pathway to colchicine without prior knowledge of biosynthetic genes, a sequenced genome or genetic tools in the native host. We uncovered eight genes from Gloriosa superba for the biosynthesis of N-formyldemecolcine, a colchicine precursor that contains the characteristic tropolone ring and pharmacophore of colchicine6. Notably, we identified a non-canonical cytochrome P450 that catalyses the remarkable ring expansion reaction that is required to produce the distinct carbon scaffold of colchicine. We further used the newly identified genes to engineer a biosynthetic pathway (comprising 16 enzymes in total) to N-formyldemecolcine in Nicotiana benthamiana starting from the amino acids phenylalanine and tyrosine. This study...Continue Reading

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Citations

Nov 10, 2020·ChemMedChem·Emily A StanderVincent Courdavault
Dec 18, 2020·Frontiers in Bioengineering and Biotechnology·Ruobing GuanYongjun Wei
Jan 30, 2021·Frontiers in Plant Science·Riccardo Delli-PontiMarek Mutwil
Feb 4, 2021·Journal of Natural Products·Sharna-Kay Daley, Geoffrey A Cordell
Nov 27, 2020·Frontiers in Chemistry·Kaouthar Eljounaidi, Benjamin R Lichman
Mar 19, 2021·Organic Letters·Xiao LiangYu-Rong Yang
Apr 29, 2021·Chemical Society Reviews·Cooper S JamiesonJohn M Billingsley
Apr 19, 2021·Current Opinion in Biotechnology·Shaoqun Zhou, Georg Jander
Jun 12, 2021·Proceedings of the National Academy of Sciences of the United States of America·Ryan S NettElizabeth S Sattely
Jun 19, 2021·Proceedings of the National Academy of Sciences of the United States of America·Prashanth Srinivasan, Christina D Smolke
Jun 19, 2021·Chemical Society Reviews·Dong YiUwe T Bornscheuer
Jul 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Sweta BhambhaniAshok P Giri
Jul 4, 2021·Molecular Plant·Cecilie Cetti HansenDaniele Werck-Reichhart
Aug 10, 2021·Frontiers in Plant Science·Trinh-Don Nguyen, Thu-Thuy T Dang
Nov 16, 2021·Journal of the American Chemical Society·Ryan S Nett, Elizabeth S Sattely

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Datasets Mentioned

BETA
AB267399.2
KM592961.1

Methods Mentioned

BETA
RNA-seq
chip
PCR
Protein Assay
NMR

Software Mentioned

GraphPad Prism
edgeR
CAP3
JMP Pro
HIT
Excel
TreeView
MSConvert
MassHunter Qualitative Analysis
CD

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