Computational Design of Novel Enzymes and Metabolic Pathways for Industrial Biotechnology

Our ability to design cell factories to produce valuable chemicals requires the “recombination” not only of existing but also designer enzymes into novel metabolic pathways to achieve entirely new metabolic function. This poses two distinct challenges that need to be solved in an integrated way if we ambition to fully deliver on the promise of synthetic biology. The first challenge deals with the design, at scale, of novel enzymes with high level of activities for reactions not known to be catalyzed in nature. To this end, Arzeda has developed and scaled high-throughput computational methodologies to exploit natural enzyme latent catalytic promiscuity and rapidly design new biocatalysts. A successful industrial application of this technology will be presented.

The second challenge is that of finding optimal ways to arrange natural and designed enzymes to biosynthetize a small-molecule of interest. To illustrate our progress towards solving this challenge, we will discuss a novel computational tool that Arzeda has developed for the automated design of novel biosynthetic pathways. Inspired by retrosynthetic methods in organic chemistry, our software draws on databases of known natural enzymatic reactions as well as reactions that can be catalyzed by designed enzymes to exhaustively enumerate biosynthetic routes from a set of desired metabolites down to any small molecule of interest. Pathways are ranked based on thermodynamic feasibility and other metrics. We will discuss applications of industrial relevance in the field of fine and bulk chemicals.