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Six enzymes from mayapple that complete the biosynthetic pathway to the etoposide aglycone

Science  11 Sep 2015:
Vol. 349, Issue 6253, pp. 1224-1228
DOI: 10.1126/science.aac7202

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Transplanting the wisdom of the mayapple

Etoposide, a topoisomerase inhibitor, is used to treat various cancers. However, etoposide isn't that easy to get. Its precursor comes from the very slow-growing mayapple plant. Lau and Sattely used bioinformatics, heterologous enzyme expression, and kinetic characterization, to work out the pathway that makes the precursor in mayapple (see the Perspective by O'Connor). They then successfully transplanted the full biosynthetic pathway into tobacco plants.

Science, this issue p. 1224; see also p. 1167

Abstract

Podophyllotoxin is the natural product precursor of the chemotherapeutic etoposide, yet only part of its biosynthetic pathway is known. We used transcriptome mining in Podophyllum hexandrum (mayapple) to identify biosynthetic genes in the podophyllotoxin pathway. We selected 29 candidate genes to combinatorially express in Nicotiana benthamiana (tobacco) and identified six pathway enzymes, including an oxoglutarate-dependent dioxygenase that closes the core cyclohexane ring of the aryltetralin scaffold. By coexpressing 10 genes in tobacco—these 6 plus 4 previously discovered—we reconstitute the pathway to (–)-4′-desmethylepipodophyllotoxin (the etoposide aglycone), a naturally occurring lignan that is the immediate precursor of etoposide and, unlike podophyllotoxin, a potent topoisomerase inhibitor. Our results enable production of the etoposide aglycone in tobacco and circumvent the need for cultivation of mayapple and semisynthetic epimerization and demethylation of podophyllotoxin.

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