1. Academic Validation
  2. Discovery and engineering of colchicine alkaloid biosynthesis

Discovery and engineering of colchicine alkaloid biosynthesis

  • Nature. 2020 Aug;584(7819):148-153. doi: 10.1038/s41586-020-2546-8.
Ryan S Nett # 1 2 Warren Lau # 1 Elizabeth S Sattely 3 4
Affiliations

Affiliations

  • 1 Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
  • 2 Howard Hughes Medical Institute, Stanford, CA, USA.
  • 3 Department of Chemical Engineering, Stanford University, Stanford, CA, USA. sattely@stanford.edu.
  • 4 Howard Hughes Medical Institute, Stanford, CA, USA. sattely@stanford.edu.
  • # Contributed equally.
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.

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