Design principles of autocatalytic cycles constrain enzyme kinetics and force low substrate saturation at flux branch points.

Uri Barenholz,Ron Milo,Yinon Bar-On,Elad Noor,Ed Reznik,Niv Antonovsky,Dan Davidi

doi:10.7554/elife.20667

Uri Barenholz, Ron Milo + Show 5 more

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https://doi.org/10.7554/elife.20667

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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.

Highlights

An essential trait of living systems is their ability to reproduce
We define an autocatalytic cycle as a set of reactions and metabolites that form a cycle, and that, when the reactions are applied to the substrates at the given stoichiometric ratios, increase the amount of the intermediate metabolites
Our study into the dynamics and stability of autocatalytic cycles suggests design principles applicable to both systems biology, that aims to understand the function of natural networks, and in the context of synthetic biology, in the effort to express novel heterologous cycles

Summary

Introduction

An essential trait of living systems is their ability to reproduce This fundamental ability makes all living organisms autocatalytic by definition. Autocatalytic metabolism is considered to be one of the essential components of life (Ganti et al, 2003). We focus on autocatalytic cycles in chemical reaction systems, in the context of metabolic networks. The components we consider are the metabolites of the system, with autocatalytic cycles being formed using the reactions of the metabolic network. An illustrative example for a metabolic autocatalytic cycle is glycolysis. 2 ATP molecules are consumed in the priming phase, in order to produce 4 ATP molecules in the pay off phase. In order to produce ATP in glycolysis, ATP must already be present in the cell. Autocatalytic cycles have been shown to be optimal network topologies that minimize the number of reactions needed for the production of precursor molecules from different nutrient sources (Riehl et al, 2010)

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