Design principles of autocatalytic cycles constrain enzyme kinetics and force low substrate saturation at flux branch points.
A set of chemical reactions that require a metabolite to synthesize more of that metabolite is an autocatalytic cycle. Here, we show that most of the reactions in the core of central carbon metabolism are part of compact autocatalytic cycles. Such metabolic designs must meet specific conditions to support stable fluxes, hence avoiding depletion of intermediate metabolites. As such, they are subjected to constraints that may seem counter-intuitive: the enzymes of branch reactions out of the cycle must be overexpressed and the affinity of these enzymes to their substrates must be relatively weak. We use recent quantitative proteomics and fluxomics measurements to show that the above conditions hold for functioning cycles in central carbon metabolism ofE. coli. This work demonstrates that the topology of a metabolic network can shape kinetic parameters of enzymes and lead to seemingly wasteful enzyme usage.
Department of Plant and Environmental Sciences, The Weizmann Institute of Science, Rehovot, Israel.
Uri
0000-0002-3097-9681
U
Barenholz
Department of Plant and Environmental Sciences, The Weizmann Institute of Science, Rehovot, Israel.
Dan
D
Davidi
Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.|Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, United States.
Ed
0000-0002-6511-5947
E
Reznik
Department of Plant and Environmental Sciences, The Weizmann Institute of Science, Rehovot, Israel.
Yinon
Y
Bar-On
Department of Plant and Environmental Sciences, The Weizmann Institute of Science, Rehovot, Israel.
Niv
N
Antonovsky
Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
Elad
E
Noor
Department of Plant and Environmental Sciences, The Weizmann Institute of Science, Rehovot, Israel.
Ron
0000-0003-1641-2299
R
Milo
D002244:Carbon / Q000378:metabolism*; D004926:Escherichia coli / Q000201:enzymology*; D015964:Gene Expression Regulation, Bacterial; D015971:Gene Expression Regulation, Enzymologic; D007700:Kinetics; D064688:Metabolic Flux Analysis; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D040901:Proteomics
D002244:Carbon
E. coli; computational biology; dynamic analysis; enzyme kinetics; metabolism; systems biology