Manipulating indole alkaloid production by Catharanthus roseus cell cultures in bioreactors: from biochemical processing to metabolic engineering

Abstract

Catharanthus roseus plants produce many pharmaceutically important indole alkaloids, of which the bisindole alkaloids vinblastine and vincristine are antineoplastic medicines and the monoindole alkaloids ajmalicine and serpentine are antihypertension drugs. C. roseus cell cultures have been studied for producing these medicines or precursors catharanthine and vindoline for almost four decades but so far without a commercially successful process due to biological and technological limitations. The research thus focused on the one hand on engineering the bioreactor process on the other engineering the cell factory itself. This review mainly summarizes the progress made on biochemical engineering aspects of C. roseus cell cultures in bioreactors in the past decades and metabolic engineering of indole alkaloid production in recent years. The paper also attempts to highlight new strategies and technologies to improve alkaloid production and bioreactor performance. Perspectives of metabolic engineering to create new cell lines for large-scale production of indole alkaloids in bioreactors and effective combination of these up-and downstream processing are presented.

Metabolic alterations and distribution of five-carbon precursors in jasmonic acid-elicited Catharanthus roseus cell suspension cultures

“…Nevertheless, semisynthesis of bisindole alkaloids is possible by coupling catharanthine and vindoline, thus optimizing cell or organ cultures to produce the individual precursors is an interesting target. Although ajmalicine and serpentine accumulate in C. roseus cell cultures, the productivity is too low compared to the intact plants for a cost-competitive mass production (Zhao and Verpoorte 2007).…”

“…Elicitation strategies using exogenous jasmonic acid (JA) or its volatile methyl ester, i.e., methyl jasmonic (MeJA), often result in elevated levels of certain secondary metabolites. In the elicitation process, jasmonates play an important role as regulatory signals to induce de novo transcription and translation leading to the induction of secondary metabolite biosynthesis in plant cell cultures Zhao and Verpoorte 2007). Exogenous application of jasmonates to C. roseus cell cultures (El-Sayed and Verpoorte 2002; Lee-Parsons and Royce 2006;Vázquez-Flota et al 2009), hairy roots (Rijhwani and Shanks 1998;Vázquez-Flota et al 2009), shoot cultures (Vázquez-Flota et al 2009) and seedlings (ElSayed and Verpoorte 2004) increased the production of TIA caused by an elevated expression of a set of biosynthesis related genes .…”

Enhancement of Vindoline Production in Suspension Culture of the Catharanthus roseus Cell Line C20hi by Light and Methyl Jasmonate Elicitation

“…1 However, the yields of TIAs are commonly very limited, and the production of vinblastine and vincristine have failed in cell and hairy root cultures, though various biochemical and bioengineering protocols have been applied to manipulate indole alkaloid production. [2][3][4][5] Vinblastine and vincristine are dimeric alkaloids formed by the peroxidase-catalyzed condensation of vindoline and catharanthine.…”

Opium poppy and Madagascar periwinkle: model non‐model systems to investigate alkaloid biosynthesis in plants

“…Several reviews have also been published on the analysis (Hisiger and Jolicoeur, 2007), chemistry (O'Connor and Maresh, 2006), biosynthesis (El-Sayed and Verpoorte, 2007;Hedhili et al, 2007;LoyolaVargas et al, 2007;Oudin et al, 2007a), regulation (Memelink and Gantet, 2007), intra-cellular, inter-cellular and organ-specific compartmentation (Mahroug et al, 2007), plant cell culture-based production (Zhao and Verpoorte, 2007), biotechnological production (Zá rate and , functional genomics (Goossens and Rischer, 2007) and transport (Roytrakul and Verpoorte, 2007) of MIAs in C. roseus. Together, these reviews reflect the profusion of scientific achievements that highlight opium poppy and C. roseus as two of the most thoroughly investigated medicinal plants.…”