Protein allocation and enzymatic constraints explainEscherichia coliwildtype and mutant phenotypes

Abstract

Proteins have generally been recognized to constitute the key cellular component in shaping microbial phenotypes. Due to limited cellular resources and space, optimal allocation of proteins is crucial for microbes to facilitate maximum proliferation rates while allowing a flexible response to environmental changes. Regulatory patterns of protein allocation were utilized to account for the condition-dependent proteome in a genome-scale metabolic reconstruction of Escherichia coli by linearly linking mass concentrations of protein sectors and single metabolic enzymes to flux variables. The resulting protein allocation model (PAM) correctly approximates wildtype phenotypes and flux distributions for various substrates, even under data scarcity. Moreover, we showed the ability of the PAM to predict metabolic responses of single gene deletion mutants by additionally assuming growth-limiting, transcriptional restrictions. Thus, we promote the integration of protein allocation constraints into classical constraint-based models to foster their predictive capabilities and application for strain analysis and metabolic engineering purposes. K E Y W O R D S constraint-based modeling, enzyme kinetics, protein allocation, transcriptional control, Escherichia coli 1

Nutrition or nature: using elementary flux modes to disentangle the complex forces shaping prokaryote pan-genomes

“…Examples of missing features are the barriers and costs associated with accommodating foreign genes [ 4 ]. An objective function that considers total protein allocation [ 55 ] could simulate these costs with a similar framework as ours, but would also require high-quality protein-reaction maps, which are currently not available for most genomes. The use of a continuous distribution for the probability of sharing reactions would also likely increase the realism of our model.…”

Metabolic Modelling as a Framework for Metabolomics Data Integration and Analysis

“…To obtain more information about the variability of approaches of constraint-based methods, we refer the readers to the review by Lewis et al [29]. We also refer to other articles covering other powerful and widely used techniques such as the GECKO method [7], a method that enhances constraint-based methods to account for enzyme maximum capacity by incorporating kinetic constants, metabolism and expression models (ME models) [30] and protein allocation models [31][32][33][34].…”