The chemical synthesis of natural molecules is often complex. Undesirable by-products are frequently generated and, in many cases, reaction mechanisms are unclear, rendering a host of natural compounds virtually unattainable by synthetic means. Plants, on the other hand, can naturally produce a wealth of valuable compounds but at typically low concentrations, causing extraction to be costly and resulting in expensive products when placed on the market. Furthermore, the extraction of functional compounds from biomass often depends on feedstock availability, which can lead to price fluctuations and environmental impacts associated with land-use change. In contrast, natural molecules may instead be generated by microbial production, as is already the case for many industrial compounds, where microbial hosts are able to naturally manufacture desired products, acting as “cell factories” with fully characterized bio-synthetic pathways.
The ShikiFactory100 project aims to exploit the microbial production of more than 100 high value compounds derived from the shikimate pathway, a hub in cell metabolism. This will be achieved through the development of optimized shikimate chassis (based in 3 sub-hubs: Phe, Trp and Tyr), and the characterization and implementation of novel bio-synthetic routes for the production of existing and newly designed compounds.
The shikimate pathway links the metabolism of carbohydrates to the biosynthesis of aromatic compounds. In a sequence of steps, intermediate compounds are converted by hosts into aromatic amino acids (AAAs) and many other aromatic secondary metabolites, which act as branch points for other metabolic pathways. The shikimate pathway is commercially very significant, with many compounds derived from this pathway associated with multi-million dollar global markets.
This project will proceed via 3 main focus vectors, which will be innovatively and synergistically integrated:
- Discovery: collection of natural and non-natural reactions and compounds, as well as the discovery and ranking of novel pathways for the production of the target compounds.
- Design & Implementation: in silico and in vivo design, rapid prototyping for pathways selected in vector 1, and optimization efforts toward chassis and advancing production strains.
- Validation: application and initial upscaling for a subset of select compounds, in addition to an appraisal of compound sustainability.