On the optimality of the enzyme-substrate relationship in bacteria.

Hugo Dourado,Matteo Mori,Martin J Lercher,Terence Hwa,Jason W Locasale

doi:10.1371/journal.pbio.3001416

Hugo Dourado, Matteo Mori + Show 3 more

Open Access

https://doi.org/10.1371/journal.pbio.3001416

Copy DOI

Abstract

Much recent progress has been made to understand the impact of proteome allocation on bacterial growth; much less is known about the relationship between the abundances of the enzymes and their substrates, which jointly determine metabolic fluxes. Here, we report a correlation between the concentrations of enzymes and their substrates in Escherichia coli. We suggest this relationship to be a consequence of optimal resource allocation, subject to an overall constraint on the biomass density: For a cellular reaction network composed of effectively irreversible reactions, maximal reaction flux is achieved when the dry mass allocated to each substrate is equal to the dry mass of the unsaturated (or “free”) enzymes waiting to consume it. Calculations based on this optimality principle successfully predict the quantitative relationship between the observed enzyme and metabolite abundances, parameterized only by molecular masses and enzyme–substrate dissociation constants (Km). The corresponding organizing principle provides a fundamental rationale for cellular investment into different types of molecules, which may aid in the design of more efficient synthetic cellular systems.

Highlights

Bacterial growth relies on the organized activity of thousands of chemical reactions
To assess the relevance of this trade-off, we looked at data from a recent quantitative metabolomics experiment for E. coli grown on glucose minimal media [12], which observed a total dry mass fraction of 3.1% for 43 assayed metabolites, mostly from central carbon metabolism
We have shown that the experimentally observed enzyme–substrate relationship is roughly consistent with an optimal allocation of cellular mass between catalysts and their substrates, where the cellular mass of a metabolite equals the combined mass of all free enzymes waiting to consume it

Summary

Introduction

Bacterial growth relies on the organized activity of thousands of chemical reactions. The optimal allocation of the protein part of this mass in schematic whole-cell models has provided qualitative explanations for several experimental observations in E. coli, such as the approximately linear scaling of the ribosomal protein fraction with growth rate [20,21,22,23,24,25], optimal and suboptimal regulatory strategies [24,25,26], and the emergence of overflow metabolism with increasing nutrient quality [20,27,28,29] While these studies considered only the protein part of the dry mass density, a given flux through an enzymatic reaction is determined by the concentrations of both the enzyme and the metabolites involved. This observation of near-constant enzyme concentrations across conditions indicates a limit to the optimal resource allocation quantified in Eqs (5) and (6): For most enzyme–substrate pairs with similar metabolic roles across multiple conditions, the cellular organization appears to approximate optimal metabolic efficiency at the highest flux condition (where cellular costs for this reaction are highest), but may not reduce enzyme concentrations in conditions that require lower fluxes

Conclusions

Findings

Materials and methods