Synthetic metabolism: metabolic engineering meets enzyme design

Highlights

• Multiple levels of metabolic engineering can be defined, from ‘copy and paste’ to various forms of ‘synthetic metabolism’.•
• The biochemical solution space for ‘synthetic metabolism’ can be increased by designing and evolving new enzyme reactions and chemistries.
• Implementation of synthetic pathways is challenged by interference with endogenous metabolism, side-reactions and dead-end metabolites.
• Integration of ‘hermeting strategies’ into synthetic pathway design may help to overcome these challenges.
• Global challenges could be addressed if we harness synthetic metabolism to its fullest extent.

Metabolic engineering aims at modifying the endogenous metabolic network of an organism to harness it for a useful biotechnological task, for example, production of a value-added compound. Several levels of metabolic engineering can be defined and are the topic of this review. Basic ‘copy, paste and fine-tuning’ approaches are limited to the structure of naturally existing pathways. ‘Mix and match’ approaches freely recombine the repertoire of existing enzymes to create synthetic metabolic networks that are able to outcompete naturally evolved pathways or redirect flux toward non-natural products. The space of possible metabolic solution can be further increased through approaches including ‘new enzyme reactions’, which are engineered on the basis of known enzyme mechanisms. Finally, by considering completely ‘novel enzyme chemistries’ with de novo enzyme design, the limits of nature can be breached to derive the most advanced form of synthetic pathways. We discuss the challenges and promises associated with these different metabolic engineering approaches and illuminate how enzyme engineering is expected to take a prime role in synthetic metabolic engineering for biotechnology, chemical industry and agriculture of the future.