The Integration of Metabolomics and Next-Generation Sequencing Data to Elucidate the Pathways of Natural Product Metabolism in Medicinal Plants

Abstract

Plants have always been used as medicines since ancient times to treat diseases. The knowledge around the active components of herbal preparations has remained nevertheless fragmentary: the biosynthetic pathways of many secondary metabolites of pharmacological importance have been clarified only in a few species, while the chemodiversity present in many medicinal plants has remained largely unexplored. Despite the advancements of synthetic biology for production of medicinal compounds in heterologous hosts, the native plant species are often the most reliable and economic source for their production. It thus becomes fundamental to investigate the metabolic composition of medicinal plants to characterize their natural metabolic diversity and to define the biosynthetic routes of important compounds to develop strategies to further increase their content. We present here a number of case studies for selected classes of secondary metabolites and we review their health benefits and the historical developments in their structural elucidation and characterization of biosynthetic genes. We cover the cases of benzoisoquinoline and monoterpenoid indole alkaloids, cannabinoids, caffeine, ginsenosides, withanolides, artemisinin, and taxol; we show how the "early" biochemical or the more recent integrative approaches-based on omics-analyses-have helped to elucidate their metabolic pathways and cellular compartmentation. We also summarize how the knowledge generated about their biosynthesis has been used to develop metabolic engineering strategies in heterologous and native hosts. We conclude that following the advent of novel, high-throughput and cost-effective analytical technologies, the secondary metabolism of medicinal plants can now be examined under the lens of systems biology.

Metabolomics in the Context of Plant Natural Products Research: From Sample Preparation to Metabolite Analysis

“…Given that this subject has been extensively reviewed [3], we will keep this section short, suffice to say that the chemistry of many medicinal plants has remained largely unexplored. Despite the advances of synthetic biology for the production of medicinal compounds in heterologous hosts (described in the section below), the native plant species often remain the most reliable and economic source for their production.…”

“…In recent years, the Food and Drug Administration (FDA) has approved an impressive number of modern drugs that are also natural products or directly derived therefrom [2]. These mostly constitute compounds belonging to secondary metabolic pathways with prominent examples including taxol from Taxus brevifolia, vinblastine from Catharanthus roseus, doxorubicin from Streptomyces peucetius, and cyclosporine from Tolypocladium inflatum [3,4]. The first step in the discovery of lead compounds from natural sources is the release of bioactive metabolites from their biomass through various extraction techniques viz., supercritical fluid extraction [5,6], microwave-assisted and ultrasonic-assisted extraction [7], molecular distillation methods [8], and membrane separation technology [9].…”

Unraveling Plant Natural Chemical Diversity for Drug Discovery Purposes

“…Indeed, the use of the recent integrative approaches based on "Omic" analyses (metabolomics, proteomics, transcriptomic, and genomics) can be of great value. Indeed, knowing the precursors and intermediates through the biochemical status of a tissue, identifying the key enzymes and the limiting steps of the pathways, monitoring indirectly the function of the genes involved in these pathways and their regulation will contribute to decipher the biosynthetic routes in planta (Cheallaigh et al, 2018;Scossa et al, 2018). The relative ease at which one can now obtain large-scale data has facilitated the analyses at the level of the whole metabolic network (Paddon and Keasling, 2014;Ikram and Simonsen, 2017).…”

“…Furthermore, the discovery that genes linked to biosynthetic pathways are organized in clusters has opened new opportunities by adapting methodologies developed initially for microorganisms to plants like systematic cluster mining algorithms (Owen et al, 2017). Scossa et al (2018) reviewed recently the progresses made in the understanding of plant biosynthetic pathways with the integration of metabolomics and next-generation sequencing based on various families of compounds: for example, benzoisoquinoline and monoterpenoid indole alkaloids, cannabinoids, ginsenosides, or withanolides. They also emphasized the new insight that this area can bring in the field of synthesis of NP.…”

“…They also emphasized the new insight that this area can bring in the field of synthesis of NP. They mention for example, the intriguing case of caffeine biosynthesis that evolved independently in several orders of eudicots: at least three metabolic pathways evolved separately coopting genes from different gene families illustrating how biosynthetic pathways can evolve with land plant diversification (Scossa et al, 2018).…”