Design principles of autocatalytic cycles constrain enzyme kinetics and force low substrate saturation at flux branch points
- The Weizmann Institute of Science, Israel
- The Weizmann Institute for Science, Israel
- Memorial Sloan Kettering Cancer Center, United States
- ETH Zurich, Switzerland
Abstract
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 of E.coli. This work demonstrates that the topology of a metabolic network can shape kinetic parameters of enzymes and lead to seemingly wasteful enzyme usage.
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Author details
Funding
Israel Science Foundation (740/16)
- Uri Barenholz
- Dan Davidi
- Yinon Bar-On
- Niv Antonovsky
- Ron Milo
European Research Council (NOVCARBFIX 646827)
- Uri Barenholz
- Dan Davidi
- Yinon Bar-On
- Niv Antonovsky
- Ron Milo
Beck-Canadian Center for Alternative Energy Research
- Uri Barenholz
- Dan Davidi
- Yinon Bar-On
- Niv Antonovsky
- Ron Milo
Dana and Yossie Hollander
- Uri Barenholz
- Dan Davidi
- Yinon Bar-On
- Niv Antonovsky
- Ron Milo
Helmsley Charitable Foundation
- Uri Barenholz
- Dan Davidi
- Yinon Bar-On
- Niv Antonovsky
- Ron Milo
The Larson Charitable Foundation
- Uri Barenholz
- Dan Davidi
- Yinon Bar-On
- Niv Antonovsky
- Ron Milo
Wolfson Family Charitable Trust
- Uri Barenholz
- Dan Davidi
- Yinon Bar-On
- Niv Antonovsky
- Ron Milo
Charles Rothchild
- Uri Barenholz
- Dan Davidi
- Yinon Bar-On
- Niv Antonovsky
- Ron Milo
Selmo Nussenbaum
- Uri Barenholz
- Dan Davidi
- Yinon Bar-On
- Niv Antonovsky
- Ron Milo
Alternative sustainable Energy Research Initiative (Graduate Student Fellowship)
- Uri Barenholz
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2017, Barenholz et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Design principles of autocatalytic cycles constrain enzyme kinetics and force low substrate saturation at flux branch points
eLife 6:e20667.
https://doi.org/10.7554/eLife.20667
