Principles for circadian orchestration of metabolic pathways

Significance Circadian (24-h) rhythms influence the behavior and physiology of many organisms. These rhythms are generated at the gene expression level, causing the waxing and waning of protein abundances. Metabolic enzymes are affected, but the principles for the propagation of enzyme rhythmicity to cellular metabolism as quantified by fluxes through metabolic pathways and metabolite concentrations are not understood. We used the mathematics of chemical kinetics to systematically investigate how rhythms in enzyme activity are propagated to pathway fluxes and concentrations. It turned out that rhythms are often optimally propagated when several enzyme activities are rhythmic but with different timing. We performed measurements of circadian enzyme activities in mouse muscle that confirmed such timing differences.