Gene Discovery in Gelsemium Highlights Conserved Gene Clusters in Monoterpene Indole Alkaloid Biosynthesis

Abstract

Genome mining is a routine technique in microbes for discovering biosynthetic pathways. In plants, however, genomic information is not commonly used to identify novel biosynthesis genes. Here, we present the genome of the medicinal plant and oxindole monoterpene indole alkaloid (MIA) producer Gelsemium sempervirens (Gelsemiaceae). A gene cluster from Catharanthus roseus, which is utilized at least six enzymatic steps downstream from the last common intermediate shared between the two plant alkaloid types, is found in G. sempervirens, although the corresponding enzymes act on entirely different substrates. This study provides insights into the common genomic context of MIA pathways and is an important milestone in the further elucidation of the Gelsemium oxindole alkaloid pathway.

Harnessing the Chemistry of the Indole Heterocycle to Drive Discoveries in Biology and Medicine

“…Indole alkaloids are produced by plants using a series of unique biosynthetic pathways, leading to an impressive diversity of complex natural products . Many indole alkaloids are endowed with significant biological activities important to human health and the treatment of disease (Scheme ) . The indole alkaloids vincristine ( 88 ) and vinblastine ( 70 ) were discovered in Catharanthus roseus (Madagascar periwinkle) and have had a remarkable impact on cancer therapies over the past several decades .…”

“…With the significant therapeutic value of indole alkaloids and derived natural products (e.g., quinine 100 , camptothecin 102 ; quinoline‐derived alkaloids from strictosidine; Scheme ), extensive investigations regarding the biosynthetic pathways of these alkaloids has been an area of intense interest . Many details regarding the enzymes and chemical transformations involved in the biosynthesis of monoterpene indole alkaloids have been elucidated; however, additional information is needed to fully elucidate these pathways.…”

“…Many details regarding the enzymes and chemical transformations involved in the biosynthesis of monoterpene indole alkaloids have been elucidated; however, additional information is needed to fully elucidate these pathways. O'Connor and co‐workers have made significant contributions towards our understanding of monoterpenoid indole alkaloid biosynthesis . Currently, efforts are aimed at employing synthetic biology strategies to produce therapeutically valuable indole alkaloids (e.g., vincristine, ibogaine) to support therapeutic applications in human medicine.…”

“…Monoterpene indole alkaloids are biosynthesized from tryptophan and isopentenyl diphosphate (IPP, 92 ; precursor to all terpenoids) . Tryptophan ( 91 ) is decarboxylated by the pyridoxal dependent enzyme tryptophan decarboxylase (TD, Scheme ) to form tryptamine ( 49 ), while IPP undergoes an extensive series of biosynthetic transformations to the aldehyde‐containing intermediate secologanin ( 93 ) .…”

“…quinoline-derived alkaloidsf rom strictosidine;S cheme 9), extensivei nvestigations regarding the biosynthetic pathways of these alkaloids has been an area of intensei nterest. [4,6,[69][70][71][72][73]99] Many detailsr egarding the enzymes andc hemical transformations involved in the biosynthesis of monoterpene indole alkaloids have been elucidated;h owever,a dditional information is neededt of ully elucidate these pathways. O'Connor and coworkers have made significant contributions towards our understanding of monoterpenoid indole alkaloid biosynthe-sis.…”