Integrative genome-scale metabolic modeling reveals versatile metabolic strategies for methane utilization in Methylomicrobium album BG8

Methylomicrobium album BG8 is an aerobic methanotrophic bacterium that can mitigate environmental methane emission, and is a promising microbial cell factory for the conversion of methane to value-added chemicals. However, the lack of a genome-scale metabolic model (GEM) of M. album BG8 has hindered the development of systems biology and metabolic engineering of this methanotroph. To fill this gap, a high-quality GEM was constructed to facilitate a system-level understanding on the biochemistry of M. album BG8. Next, experimental time-series growth and exometabolomics data were integrated into the model to generate context-specific GEMs. Flux balance analysis (FBA) constrained with experimental data derived from varying levels of methane, oxygen, and biomass were used to model the metabolism of M. album BG8 and investigate the metabolic states that promote the production of biomass and the excretion of carbon dioxide, formate, and acetate. The experimental and modeling results indicated that the system-level metabolic functions of M. album BG8 require a ratio > 1:1 between the oxygen and methane specific uptake rates for optimal growth. Integrative modeling revealed that at a high ratio of oxygen-to-methane uptake flux, carbon dioxide and formate were the preferred excreted compounds; at lower ratios, however, acetate accounted for a larger fraction of the total excreted flux. The results of this study reveal a trade-off between biomass production and organic compound excretion and provide evidence that this trade-off is linked to the ratio between the oxygen and methane specific uptake rates.