Synthetic Biology of Natural Products

Abstract

The diversity and natural modularity of their biosynthetic pathways has turned natural products into attractive, but challenging, targets for synthetic biology approaches. Here, we discuss the current state of the field, highlighting recent advances and remaining bottlenecks. Global genomic assessments of natural product biosynthetic capacities across large parts of microbial diversity provide a first survey of the available natural parts libraries and identify evolutionary design rules for further engineering. Methods for compound and pathway detection and characterization are developed increasingly on the basis of synthetic biology tools, contributing to an accelerated translation of genomic information into usable building blocks for pathway assembly. A wide range of methods is also becoming available for accessing ever larger parts of chemical space by rational diversification of natural products, guided by rapid progress in our understanding of the underlying biochemistry and enzymatic mechanisms. Enhanced genome assembly and editing tools, adapted to the needs of natural products research, facilitate the realization of ambitious engineering strategies, ranging from combinatorial library generation to high-throughput optimization of product titers. Together, these tools and concepts contribute to the emergence of a new generation of revitalized natural product research.

Unraveling Plant Natural Chemical Diversity for Drug Discovery Purposes

“…Then, basically, the strategy will consist in cloning the genes of the enzymes of the pathway that have been identified; constructing large plasmid (or family of plasmids) encoding for those enzymes; transfecting with the plasmid a microorganism that will be grown afterwards; and purifying the product . Several recent reviews detail how the technical advances in synthetic biology and multiplexed genome engineering allow for optimizing the design and synthesis of the pathways involved in NP production (Awan et al, 2016;Breitling and Takano, 2016;Carbonell et al, 2016;Smanski et al, 2016;Moses et al, 2017). Many such examples can be found such as for curcumin synthesis reconstitution in E. coli (Kang et al, 2018), polyunsaturated fatty acids production in the fungus Ashbya gossypii (Ledesma-Amaro et al, 2018), a-amyrin, lupulones ou ginsenosides synthesis in S. cerevisiae (Dai et al, 2014;Yu et al, 2018;Guo et al, 2019), or the diversification of the carotenoid biosynthetic pathways (Umeno et al, 2005).…”

Metabolic reprogramming during the Trypanosoma brucei life cycle

“…Fields such as immunometabolism emerged because of the development of highly sensitive metabolomic approaches, including untargeted metabolomic analysis, stable isotope labelling, mass spectrometry, and nuclear magnetic resonance 50 – 52 . Researchers discovered that during immune cell activation, the levels of many metabolites undergo alterations and these changes are directly linked to immune cell effector functions.…”

Chimeric Leader Peptides for the Generation of Non-Natural Hybrid RiPP Products

“…4−6 One popular approach has been to combine enzymes from different biosynthetic pathways to generate new products in a process known as combinatorial biosynthesis. 7,8 Most commonly, this procedure was applied to polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) pathways where different domains or modules were swapped or deleted.…”