Advanced Strategies for Production of Natural Products in Yeast

Abstract

Natural products account for more than 50% of all small-molecule pharmaceutical agents currently in clinical use. However, low availability often becomes problematic when a bioactive natural product is promising to become a pharmaceutical or leading compound. Advances in synthetic biology and metabolic engineering provide a feasible solution for sustainable supply of these compounds. In this review, we have summarized current progress in engineering yeast cell factories for production of natural products, including terpenoids, alkaloids, and phenylpropanoids. We then discuss advanced strategies in metabolic engineering at three different dimensions, including point, line, and plane (corresponding to the individual enzymes and cofactors, metabolic pathways, and the global cellular network). In particular, we comprehensively discuss how to engineer cofactor biosynthesis for enhancing the biosynthesis efficiency, other than the enzyme activity. Finally, current challenges and perspective are also discussed for future engineering direction. Production of Natural Products in YeastWith the recent advances of functional genomics, metabolic engineering, systems and synthetic biology, a plenty of natural products or their precursors have been heterologously synthesized in microbes especially My lab website: www.synbc. dicp.ac.cn Dedicated to the 70th anniversary of Dalian Institute of Chemical Physics, Chinese Academy of Sciences

Activation and enhancement of Caerulomycin A biosynthesis in marine-derived Actinoalloteichus sp. AHMU CJ021 by combinatorial genome mining strategies

“…Engineering the riboflavin biosynthesis by increasing the supplement of the precursor to the flavin coenzyme formation is an efficient pathway that could indirectly activate the secondary metabolite biosynthesis [37][38][39][40]. This cofactor engineering type method has been well utilized in another marine actinomycete [43].…”

“…Further enhancement of CRM A bioproduction by optimizing intracellular riboflavin supplement Enhancing the cofactor level by engineering its biosynthetic process could drive metabolic flux to improve the biosynthesis of target metabolites [37]. This new metabolic engineering strategy named as cofactor engineering has been well applied to microbial second metabolites development [38][39][40].…”

Activation and enhancement of Caerulomycin A biosynthesis in marine-derived Actinoalloteichus sp. AHMU CJ021 by combinatorial genome mining strategies

“…Traditional UV mutagenesis is a mature technique that induces a high mutation rate into the receptor strains. Engineering the ribo avin biosynthesis by increasing the supplement of the precursor to the avin coenzyme formation is an e cient pathway that could indirectly activate the secondary metabolite biosynthesis [38][39][40][41]. This cofactor engineering type method has been well utilized in another marine actinomycete [44].…”

“…Further enhancement of CRM A production by optimizing intracellular ribo avin supplement Enhancing the cofactor level by engineering its biosynthetic process could drive metabolic ux to improve the biosynthesis of target metabolites [38]. This new metabolic engineering strategy named as cofactor engineering has been well applied to microbial second metabolites development [39][40][41]. Previous study had revealed that the biosynthesis of CRM A required several essential avoenzymes, including CamD, which completed the formation of the picolinic acid precursor; CamH, which catalyzed the formation of the oxime group, and CamK, which maintained the substrate recycling process [23,28,29].…”

Deploying Microbial Synthesis for Halogenating and Diversifying Medicinal Alkaloid Scaffolds

“…This includes the production of methylxanthines from the S-adenosyl methionine (SAM) de novo purine synthesis pathways, and adenine nucleotide pools (McKeague et al, 2016), as well as phenylpropanoids resveratrol and breviscapin produced from the shikimate pathway (Becker et al, 2003;Liu et al, 2018). Together with an elaborate review of yeast metabolism for the production of broader classes of plant natural products, this has recently been excellently covered by Chen et al (2020).…”