title: Unravelling the architecture and dynamics of tropane alkaloid biosynthesis pathways using metabolite correlation networks.
abstract: The tropane alkaloid spectrum in Solanaceae is highly variable within and between species. Little is known about the topology and the coordination of the biosynthetic pathways leading to the variety of tropine and pseudotropine derived esters in the alkaloid spectrum, or about the metabolic dynamics induced by tropane alkaloid biosynthesis stimulating conditions. A good understanding of the metabolism, including all ramifications, is however necessary for the development of strategies to increase the abundance of pharmacologically interesting compounds such as hyoscyamine and scopolamine. The present study explores the tropane alkaloid metabolic pathways in an untargeted approach involving a correlation-based network analysis. Using GC-MS metabolite profiling, the variation and co-variation among tropane alkaloids and primary metabolites was monitored in 60 Datura innoxia Mill. individuals, of which half were exposed to tropane alkaloid biosynthesis stimulating conditions by co-culture with Agrobacterium rhizogenes. Considerable variation was evident in the relative proportions of the tropane alkaloids. Remodeling of the tropane alkaloid spectrum under co-culture with A. rhizogenes involved a specific and strong increase of hyoscyamine production and revealed that the accumulation of hyoscyamine, 3-tigloyloxy-6,7-epoxytropane, and 3-methylbutyryloxytropane was controlled independently of the majority of tropane alkaloids. Based on correlations between metabolites, we propose a biosynthetic origin of hygrine, the order of esterification of certain di-oxygenated tropanes, and that the rate of acetoxylation contributes to control of hyoscyamine production. Overall, this study shows that the biosynthesis of tropane alkaloids may be far more complex and finely controlled than previously expected.
authors.affiliation: EA3900 BioPI, University of Picardy Jules Verne, UFR Sciences, 33 rue Saint Leu, 80039 Amiens cedex, France. Electronic address: Nguyen.Thi.Kieu.Oanh0711@gmail.com.
authors.forename: Thi-Kieu-Oanh
authors.initials: TK
authors.lastname: Nguyen
authors.affiliation: EA3900 BioPI, University of Picardy Jules Verne, UFR Pharmacie, 1 rue des Louvels, 80039 Amiens cedex, France. Electronic address: arash.jamali@u-picardie.fr.
authors.forename: Arash
authors.initials: A
authors.lastname: Jamali
authors.affiliation: Laboratoire de biologie cellulaire et biochimie végétale, University of Tours, UFR de Sciences Pharmaceutiques, 31 Avenue Monge, 37200 Tours, France. Electronic address: arnaud.lanoue@univ-tours.fr.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Lanoue
authors.affiliation: EA3900 BioPI, University of Picardy Jules Verne, UFR Sciences, 33 rue Saint Leu, 80039 Amiens cedex, France. Electronic address: eric.gontier@u-picardie.fr.
authors.forename: Eric
authors.initials: E
authors.lastname: Gontier
authors.affiliation: EA3900 BioPI, University of Picardy Jules Verne, UFR Sciences, 33 rue Saint Leu, 80039 Amiens cedex, France. Electronic address: rebecca.dauwe@u-picardie.fr.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Dauwe
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000378:metabolism*; D053898:Biosynthetic Pathways; D032302:Datura / Q000737:chemistry* / Q000235:genetics; D008401:Gas Chromatography-Mass Spectrometry; D064692:Hyoscyamine / Q000032:analysis / Q000737:chemistry; D014326:Tropanes / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*
chemical_list: C000604272:3-methylbutyryloxytropane; C000604270:3-tigloyloxy-6,7-epoxytropane; D000470:Alkaloids; D014326:Tropanes; D064692:Hyoscyamine
keywords: Biosynthetic pathways; Correlation analysis; Datura innoxia; Hyoscyamine; Metabolite network; Metabolomics; Tropane alkaloids