Genome-scale metabolic modelling common cofactors metabolism in microorganisms

- The consensus genome-scale cofactor metabolic model for industrial microbes was reconstructed.
- Production, consumption, and interaction of common cofactors in microbes was enumerated.
- Supply and efficient utilization of ATP, NAD, NADPH, acetyl-CoA could increase cell growth.
- Cofactors act on carbon flux distribution and the accumulation of metabolites by four common modes.
- A link between four kinds of stress responses and the form and concentration of prominent cofactors were elucidated.

The common cofactors ATP/ADP, NAD(P)(H), and acetyl-CoA/CoA are indispensable participants in biochemical reactions in industrial microbes. To systematically explore the effects of these cofactors on cell growth and metabolic phenotypes, the first genome-scale cofactor metabolic model, icmNX6434, including 6434 genes, 1782 metabolites, and 6877 reactions, was constructed from 14 genome-scale metabolic models of 14 industrial strains. The origin, consumption, and interactions of these common cofactors in microbial cells were elucidated by the icmNX6434 model, and they played important roles in cell growth. The essential cofactor modules contained 2480 genes and 2948 reactions; therefore, improving cofactor biosynthesis, directing these cofactors into essential metabolic pathways, as well as avoiding cofactor utilization during byproduct biosynthesis and futile cycles, are three ways to increase cell growth. The effects of these common cofactors on the distribution and rate of the carbon flux in four universal modes, as well as an optimized metabolic flux, could be obtained by manipulating cofactor availability and balance. Significant changes in the ATP, NAD(H), NADP(H), or acetyl-CoA concentrations triggered relevant metabolic responses to acidic, oxidative, heat, and osmotic stress. Globally, the model icmNX6434 provides a comprehensive platform to elucidate the physiological effects of these cofactors on cell growth, metabolic flux, and industrial robustness. Moreover, the results of this study are a further example of using a consensus genome-scale metabolic model to increase our understanding of key biological processes.