Design and analysis of metabolic pathways supporting formatotrophic growth for electricity-dependent cultivation of microbes

Electrosynthesis is a promising approach that enables the biological production of commodities, like fuels and fine chemicals, using renewably produced electricity. Several techniques have been proposed to mediate the transfer of electrons from the cathode to living cells. Of these, the electroproduction of formate as a mediator seems especially promising: formate is readily soluble, of low toxicity and can be produced at relatively high efficiency and at reasonable current density. While organisms that are capable of formatotrophic growth, i.e. growth on formate, exist naturally, they are generally less suitable for bulk cultivation and industrial needs. Hence, it may be helpful to engineer a model organism of industrial relevance, such as E. coli, for growth on formate. There are numerous metabolic pathways that can potentially support formatotrophic growth. Here we analyze these diverse pathways according to various criteria including biomass yield, thermodynamic favorability, chemical motive force, kinetics and the practical challenges posed by their expression. We find that the reductive glycine pathway, composed of the tetrahydrofolate system, the glycine cleavage system, serine hydroxymethyltransferase and serine deaminase, is a promising candidate to support electrosynthesis in E. coli. The approach presented here exemplifies how combining different computational approaches into a systematic analysis methodology provides assistance in redesigning metabolism. This article is part of a Special Issue entitled: Metals in Bioenergetics and Biomimetics Systems.