Catharanthus terpenoid indole alkaloids: biosynthesis and regulation

Abstract

Catharanthus roseus is still the only source for the powerful antitumour drugs vinblastine and vincristine. Some other pharmaceutical compounds from this plant, ajmalicine and serpentine are also of economical importance. Although C. roseus has been studied extensively and was subject of numerous publications, a full characterization of its alkaloid pathway is not yet achieved. Here we review some of the recent work done on this plant. Most of the work focussed on early steps of the pathway, particularly the discovery of the 2-C-methyl-D-erythritol 4-phosphate (MEP)-pathway leading to terpenoids. Both mevalonate and MEP pathways are utilized by plants with apparent cross-talk between them across different compartments. Many genes of the early steps in Catharanthus alkaloid pathway have been cloned and overexpressed to improve the biosynthesis. Research on the late steps in the pathway resulted in cloning of several genes. Enzymes and genes involved in indole alkaloid biosynthesis and various aspects of their localization and regulation are discussed. Much progress has been made at alkaloid regulatory level. Feeding precursors, growth regulators treatments and metabolic engineering are good tools to increase productivity of terpenoid indole alkaloids. But still our knowledge of the late steps in the Catharanthus alkaloid pathway and the genes involved is limited.

Cloning and Functional Analysis of Geraniol 10-Hydroxylase, a Cytochrome P450 fromSwertia mussotiiFranch

“…5,9,12) CYP76B1 of H. tuberosus was identified as 7-ethoxycoumarin O-deethylase, and is induced by xenobiotics. 23) CYP76B6 of C. roseus hydroxylates geraniol to 10-hydroxygeraniol both in vitro and in vivo.…”

“…1.14.14.1), a P450 in the CYP76B subfamily, hydroxylates geraniol at the C-10 position and is thought to be involved in the synthesis of indole alkaloids and iridoid monoterpenoid. [5][6][7][8][9][10][11][12] Similar G10H proteins have been extensively analyzed in several other species. [5][6][7][8][9] These studies have been focused on the importance of G10H in indole alkaloid synthesis, [8][9][10][11][12] but there is no longer a lack of research on iridoid monoterpenoid synthesis at the molecular level.…”

Microbial synthetic biology for human therapeutics

“…Vindoline, a toxoid, is the precursor of vincristine and vinblastine. It is formed as a product of several reactions combining the amino acid tryptophan and a metabolite of sterol synthesis, secologanin (Sayed and Verpoorte 2007;Ziegler and Facchini 2008). The enzymes involved in the synthesis of vindoline can be cloned and arranged as a cassette such that there is sequential and appropriate expression of all enzymes, followed by expression in a suitable bacterial system (Fig.…”

Engineering of gentiopicroside-producing yeast strain using low-energy ion implantation mediated synthetic biology

“…[12,13] Isomerization of IPP by IPP isomerase produces geranyl diphosphate, which is converted into geraniol via the enzyme geraniol synthase. [14] Geraniol is then converted into 10-hydroxygeraniol by the enzyme of geraniol 10-hydroxylase (G10H). Further, through a series of catalytic reactions involving the enzymes acyclic monoterpene primary alcohol dehydrogenase, monoterpene cyclase, secologanin synthase (SLS) and other undefined enzymes, 10-hydroxygeraniol is converted into secologanin.…”