De novo biosynthesis of a vinblastine precursor in Pichia pastoris

Plant metabolism and synthetic biology

“…Researchers are also investigating the potential of non-conventional microbial hosts as alternative chassis to produce plant metabolites, with the aim of finding hosts that possess unique properties and characteristics. In one commentary, Yu et al highlighted a recent synthetic biology effort in which Pichia pastoris , a methylotrophic yeast, was engineered to successfully produce catharanthine, a precursor to vinblastine, showcasing the potential of this non-model yeast as a chassis for the biosynthesis of complex plant natural products [ 10 ]. In addition to heterologous bioproduction, direct engineering of native plants can also be a valuable approach to enhance the accumulation of specific metabolites.…”

Advances in Metabolic Engineering of Plant Monoterpene Indole Alkaloids

“…The methods and tools, such as gene expression cassettes for the simultaneous integration of multiple genes in engineering P. pastoris, are more readily available [ 16 , 70 , 72 ]. Remarkably, the de novo biosynthesis of catharanthine in P. pastoris was recently described, allowing for improved production of catharanthine from simple carbon sources at a maximum titer of 2.57 mg/L in comparison to previously reported yield from S. cerevisiae [ 73 , 74 ]. This study highlights the significance of optimization strategies developed for reconstitution, such as the complex long MIA pathway in P. pastoris leading to catharanthine, by addressing various approaches.…”

“…This study highlights the significance of optimization strategies developed for reconstitution, such as the complex long MIA pathway in P. pastoris leading to catharanthine, by addressing various approaches. This includes the selection of suitable plant enzymes with enhanced functionality, facilitating the trafficking of substrates by expressing fusion protein, and the amplification of genes involved in rate-limiting steps [ 73 , 74 ]. The rapid development of tools in synthetic biology, including the application of CRISPR/Cas9, boosts the prospect of overcoming challenges in metabolic regulation to improve precursor supplies and ensures balanced microbial cell growth in the future industrial production of high-value natural products.…”