#Principles for circadian orchestration of metabolic pathways [Applied Mathematics]

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Principles for circadian orchestration of metabolic pathways [Applied Mathematics]

Principles for circadian orchestration of metabolic pathways

Kevin Thurleya,b,c,

Christopher Herbstb,1,

Felix Wesenera,1,

Barbara Kollerb,

Thomas Wallachb,

Bert Maierb,

Achim Kramerb, and

Pål O Westermarka,2,3

aInstitute for Theoretical Biology, Charité–Universitätsmedizin Berlin, 10115 Berlin, Germany;

bLaboratory of Chronobiology, Institute for Medical Immunology, Charité–Universitätsmedizin Berlin, 10117 Berlin, Germany;

cDepartment of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158-2330

Edited by Joseph S. Takahashi, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, and approved December 23, 2016 (received for review August 10, 2016)

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.

Abstract

Circadian rhythms govern multiple aspects of animal metabolism. Transcriptome-, proteome- and metabolome-wide measurements have revealed widespread circadian rhythms in metabolism governed by a cellular genetic oscillator, the circadian core clock. However, it remains unclear if and under which conditions transcriptional rhythms cause rhythms in particular metabolites and metabolic fluxes. Here, we analyzed the circadian orchestration of metabolic pathways by direct measurement of enzyme activities, analysis of transcriptome data, and developing a theoretical method called circadian response analysis. Contrary to a common assumption, we found that pronounced rhythms in metabolic pathways are often favored by separation rather than alignment in the times of peak activity of key enzymes. This property holds true for a set of metabolic pathway motifs (e.g., linear chains and branching points) and also under the conditions of fast kinetics typical for metabolic reactions. By circadian response analysis of pathway motifs, we determined exact timing separation constraints on rhythmic enzyme activities that allow for substantial rhythms in pathway flux and metabolite concentrations. Direct measurements of circadian enzyme activities in mouse skeletal muscle confirmed that such timing separation occurs in vivo.

Footnotes

Author contributions: K.T., A.K., and P.O.W. designed research; K.T., C.H., F.W., B.K., and P.O.W. performed research; K.T., T.W., B.M., A.K., and P.O.W. contributed new reagents/analytic tools; K.T. and P.O.W. analyzed data; and K.T. and P.O.W. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1613103114/-/DCSupplemental.

— PNAS AOP