Synthetic metabolism: metabolic engineering meets enzyme design

Abstract

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.

Graphical abstract

Figure 1. The five different levels of metabolic engineering as defined in this review.

The enzyme solution space describes the number of possible enzymes reactions available for a given strategy while the pathway solution space corresponds to the number of possible pathways that can be constructed. While level 1, 2 and 3 metabolic engineering efforts do not differ in enzyme solution space, because they all rely on known enzymes, level 4 and 5 metabolic engineering efforts provide new enzymes created through enzyme engineering or de novo-design.