The Quest for Synthetic Methylotrophy

Microbial systems are attractive platforms for producing biofuels and commodity chemicals from natural gas (methane) and methanol. While organisms that naturally utilize methane and/or methanol have been known for years and have been explored for production of single-cell protein and few large molecules (PHB and carotenoids), no reports exist for the industrial production of small metabolites. Synthetic methylotrophy refers to the development of recombinant microbial strains that can utilize reduced one-carbon (C1) chemicals, and notably methane, methanol and formaldehyde as sole carbon and energy source and/or as co-substrates to sugars and other current substrates of microbial cultures.  The goal would be to use these C1 substrates to produce useful metabolites such as biofuels, commodity chemicals, chemical precursors and biopolymers. The impetus derives from two reasons. The first is that methane from natural gas constitutes an enormous in size resource for generating energy and producing chemicals. In the last few years, the availabilities of methane and its oxidation product methanol have been increasing at dramatic rates while their prices have been decreasing. The second reason is that methane and methanol are considerably more reduced than most sugar substrates and thus have to potential to enable the biological production of biofuels and chemicals with significantly increased yields. We will discuss the native biology of methylotrophy and how it can be engaged to develop superior methylotrophic strains using synthetic biology and metabolic engineering, with emphasis on the use of methanol and formaldehyde. Engineering platform organisms to utilize methanol for producing small metabolites is recently actively pursued, for now largely based on the patent literature. Metabolic engineering and synthetic biology of platform organisms, and notably E. coli, are key for technology advances to enable the conversion of the overabundant and inexpensive methane and methanol into useful chemicals and fuels.