Discovery and engineering of colchicine alkaloid biosynthesis

Article

关键词: RING-EXPANSION;    O-METHYLANDROCYMBINE;    YEAST EXPRESSION;    NATURAL-PRODUCTS;    INTERMEDIATE;    ALIGNMENT;    PROTEINS;    PATHWAY;    PLANTS;   

DOI  :  10.1038/s41586-020-2546-8

来源: SCIE

【 摘 要 】

Discovery of a near-complete colchicine biosynthetic pathway enables the engineered production of the tropolone-containing alkaloidN-formyldemecolcine from amino acid precursors inNicotiana benthamiana. 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 culture(1). A lead example is colchicine, a US Food and Drug Administration (FDA)-approved treatment for inflammatory disorders that is sourced fromColchicumandGloriosaspecies(2-5). 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 fromGloriosa superbafor the biosynthesis ofN-formyldemecolcine, a colchicine precursor that contains the characteristic tropolone ring and pharmacophore of colchicine(6). 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) toN-formyldemecolcine inNicotiana benthamianastarting 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.

【 授权许可】

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