Back to the future: Why we need enzymology to build a synthetic metabolism of the future

Abstract

Biology is turning from an analytical into a synthetic discipline. This is especially apparent in the field of metabolic engineering, where the concept of synthetic metabolism has been recently developed. Compared to classical metabolic engineering efforts, synthetic metabolism aims at creating novel metabolic networks in a rational fashion from bottom-up. However, while the theoretical design of synthetic metabolic networks has made tremendous progress, the actual realization of such synthetic pathways is still lacking behind. This is mostly because of our limitations in enzyme discovery and engineering to provide the parts required to build synthetic metabolism. Here I discuss the current challenges and limitations in synthetic metabolic engineering and elucidate how modern day enzymology can help to build a synthetic metabolism of the future.

Keywords: enzymes; in vitro biochemistry; metabolic engineering; synthetic biology.

Figure 1

The five levels of metabolic engineering and their definitions according to [11]. The enzyme solution space describes the number of available enzyme reactions. 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 enzyme reactions, level 4 and 5 metabolic engineering efforts are built on new enzyme reactions, which expands the number of pathway solutions.

Figure 2

Two level 4 pathways that were recently realized in vitro. (a) The CETCH cycle for CO₂ fixation [13] and (b) the formolase pathway for formate assimilation [17]. Important enzymes that were engineered to establish these cycles and are mentioned in the text are highlighted in purple.