Plant scientists have taken the crucial last steps in a 60-year quest to unravel the complex chemistry of Madagascar periwinkle in a breakthrough that opens up the potential for rapid synthesis of cancer-fighting compounds. The team in the laboratory of Professor Sarah O’Connor at the John Innes Centre have, after 15 years of research, located the last missing genes in the genome of the periwinkle that are devoted to building the chemical vinblastine.
This valuable natural product has been used as an anti-cancer drug since it was discovered in the 1950’s by a Canadian research team.
A potent inhibitor of cell division and used against lymphomas and testicular, breast, bladder and lung cancers, it is found in the leaves of Madagascar periwinkle (Catharanthus roseus).
Until now, the complex chemical mechanisms the periwinkle uses in the production of vinblastine have not been fully understood. Consequently, access to its life-extending chemistry has been laborious – it takes approximately 500 kg of dried leaves to produce 1g of vinblastine.
But the new study – lead author Dr Lorenzo Caputi – which appears in the peer-review journal Science, uses modern genome sequencing techniques to identify the final missing genes in the pathway. This research also identifies enzymes that build vinblastine precursor chemicals, which include catharanthine and tabersonine. These can be readily chemically coupled using synthetic biology techniques to give vinblastine.
“Vinblastine is one of the of the most structurally complex medicinally active natural products in plants – which is why so many people in the last 60 years have been trying to get where we have got to in this study. I cannot believe we are finally here,” said Professor O’Connor. “With this information we can now try to increase the amount of vinblastine produced either in the plant, or by placing synthetic genes into hosts such as yeast or plants.”
Its attractive white or pink flowers have made the Madagascar periwinkle a popular ornamental plant in homes across the world. But for decades it has been the focus of increasingly competitive research probing its natural chemistry and potential pharmacological activity.
The full findings can be found in the paper: Biosynthesis of the Vinblastine and Vincristine Precursors, Caranthine and Tabersonine, in the journal Science.
Photo. Madagascar periwinkle, 60 year search to unlock secrets. Andrew Davis