Enzyme levels broadly influence flux throughout the metabolic network

Metabolic reaction flux is regulated in response to nutritional, environmental or pathological conditions by changes in either metabolite or metabolic enzyme levels. Previous studies proposed that flux is predominately regulated by metabolite, rather than enzyme, levels. However, the extent to which changes in enzyme levels affect flux throughout the metabolic network remains unclear. Here, we combine available yeast enzyme level, flux data, and metabolic network modeling to demonstrate three paradigms by which enzyme levels are broadly associated with flux: cognate reaction, pathway-level coordination, and flux coupling. We find that the architecture of the metabolic network enables the reach of influence for most enzymes. We implemented enzyme reach as a novel parameter in an enhanced flux potential analysis algorithm, which predicts relative flux levels under different conditions from variations in enzyme expression. This algorithm was tested in yeast and humans. Our study suggests that metabolic network architecture facilitates a broad physiological impact of changes in enzyme levels and may form a foundation for using enzyme expression data for a variety of systems, and eventually, individual cells.