The Large Scale Structure of Human Metabolism Reveals Resilience via Extensive Signaling Crosstalk.

Laura Gómez-Romero,Karina López-Reyes,Enrique Hernández-Lemus

doi:10.3389/fphys.2020.588012

Laura Gómez-Romero, Karina López-Reyes + Show 1 more

Open Access

https://doi.org/10.3389/fphys.2020.588012

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Abstract

Metabolism is loosely defined as the set of physical and chemical interactions associated with the processes responsible for sustaining life. Two evident features arise whenever one looks at metabolism: first, metabolism is conformed as a very complex and intertwined construct of the many associated biomolecular processes. Second, metabolism is characterized by a high degree of stability reflected by the organisms resilience to either environmental changes or pathogenic conditions. Here we will investigate the relationship between these two features. By having access to the full set of human metabolic interactions as reported in the highly curated KEGG database, we built an integrated human metabolic network comprising metabolic, transcriptional regulation, and protein-protein interaction networks. We hypothesized that a metabolic process may exhibit resilience if it can recover from perturbations at the pathway level; in other words, metabolic resilience could be due to pathway crosstalk which may implicate that a metabolic process could proceed even when a perturbation has occurred. By analyzing the topological structure of the integrated network, as well as the hierarchical structure of its main modules or subnetworks, we observed that behind biological resilience lies an intricate communication structure at the topological and functional level with pathway crosstalk as the main component. The present findings, alongside the advent of large biomolecular databases, such as KEGG may allow the study of the consequences of this redundancy and resilience for the study of healthy and pathological phenotypes with many potential applications in biomedical science.

Highlights

Metabolism is defined as the sum of physical and biochemical processes in living organisms that either produce or consume energy
In a protein-protein interaction network (PPN), these interactions are represented by undirected connections between the genes that codify for such proteins
Metabolism is composed of a series of highly intertwined processes in which different types of biomolecules interact and react with each other

Summary

Introduction

Metabolism is defined as the sum of physical and biochemical processes in living organisms that either produce or consume energy. Metabolic alterations often lead to cellular dysfunction, which is usually translated into disease (DeBerardinis and Thompson, 2012). Metabolism and disease are so tightly linked that diseases associated with adjacent metabolic reactions present higher comorbidity than diseases that have no metabolic links between them (Lee et al, 2008). Driver reactions, defined as the smallest set of reactions that must be controlled to control the activity of all reactions of the metabolic network, have been proposed as potential therapeutic targets in cancer cells (Basler et al, 2016). Understanding how the metabolism works, is one of the foundations to understand human disease.

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