Discovery and engineering of colchicine alkaloid biosynthesis

Nature. 2020 Aug;584(7819):148-153. doi: 10.1038/s41586-020-2546-8. Epub 2020 Jul 22.

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 establishes a metabolic route to tropolone-containing colchicine alkaloids and provides insights into the unique chemistry that plants use to generate complex, bioactive metabolites from simple amino acids.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biosynthetic Pathways* / genetics
  • Colchicaceae / enzymology
  • Colchicaceae / genetics
  • Colchicaceae / metabolism
  • Colchicine / biosynthesis*
  • Colchicine / chemistry
  • Colchicine / metabolism
  • Cytochrome P-450 Enzyme System / metabolism
  • Gene Expression Regulation, Plant
  • Metabolic Engineering*
  • Metabolomics
  • Phenylalanine / metabolism
  • Tobacco / genetics
  • Tobacco / metabolism
  • Transcriptome
  • Tyrosine / metabolism

Substances

  • Tyrosine
  • Phenylalanine
  • Cytochrome P-450 Enzyme System
  • Colchicine