Unlocking the Diversity of Alkaloids in Catharanthus roseus: Nuclear Localization Suggests Metabolic Channeling in Secondary Metabolism

摘要

class="head no_bottom_margin" id="sec1title">IntroductionThe monoterpene indole alkaloids (MIAs) are a highly diverse family of natural products that are produced in a wide variety of medicinal plants. Over 3000 members of this natural product class, which includes compounds such as quinine, vinblastine, reserpine, and yohimbine, are derived from a common biosynthetic intermediate, strictosidine aglycone (). How plants transform strictosidine aglycone into divergent structural classes has remained unresolved.The recent availability of transcriptome and genome data has dramatically accelerated the rate at which new plant biosynthetic genes are discovered. All genes that lead to strictosidine aglycone have been recently cloned from the well-characterized medicinal plant Catharanthus roseus, which produces over 100 MIAs (). However, gene products that act on strictosidine aglycone have not been identified in any plant, despite decades of effort. Attempts have been hampered in part by the reactivity and instability of strictosidine aglycone. In C. roseus, there are at least two major pathway branches derived from strictosidine aglycone (). One pathway is hypothesized to lead to the aspidosperma and the iboga classes to yield the precursors of vinblastine, while the other is expected to lead to alkaloids of the heteroyohimbine type (A). These alkaloids have diverse biological activities: vinblastine is used as an anticancer agent () and the heteroyohimbines have a range of pharmacological uses (). While it is unknown how many C. roseus enzymes use strictosidine aglycone as a substrate, there is clearly more than one enzyme that acts at this crucial branchpoint.The Monoterpene Indole Alkaloids(A) Representative monoterpene indole alkaloids derived from strictosidine and strictosidine aglycone found in Catharanthus roseus.(B) Heteroyohimbine biosynthesis.