Enzyme levels broadly influence flux throughout the metabolic network

Abstract

Metabolic reaction flux is regulated in response to nutritional, environmental or pathological conditions by changes in either metabolite or metabolic enzyme levels1. Recent studies have proposed that flux is predominately regulated by metabolite, rather than enzyme, levels based on kinetics of selected reactions2–5. However, the extent to which enzyme levels affect flux throughout the metabolic networkin vivoremains unclear6. Here, we combine available yeast enzyme level, flux data, and metabolic network modeling to discover three paradigms by which enzyme levels are broadly associated with, and likely influence, 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. This enzyme reach is implemented as a novel parameter in an enhanced flux potential analysis algorithm to predict flux from enzyme levels 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 understanding metabolic states using enzyme expression data for a variety of systems, and eventually, individual cells.