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 rapid design of novel enzymes with high level of activities for reactions not known to be catalyzed in nature. To this end, Arzeda is developing high-throughput computational methodologies to exploit natural enzyme latent catalytic promiscuity to rapidly design new catalysts. 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 tool that Arzeda has been developing 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 computationally 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 designability of each enzymatic step. We will discuss applications of industrial relevance in the field of fine and bulk chemicals.