The topology of genome-scale metabolic reconstructions unravels independent modules and high network flexibility

Abstract

The topology of metabolic networks is recognisably modular with modules weakly connected apart from sharing a pool of currency metabolites. Here, we defined modules as sets of reversible reactions isolated from the rest of metabolism by irreversible reactions except for the exchange of currency metabolites. Our approach identifies topologically independent modules under specific conditions associated with different metabolic functions. As case studies, the E.coli iJO1366 and Human Recon 2.2 genome-scale metabolic models were split in 103 and 321 modules respectively, displaying significant correlation patterns in expression data. Finally, we addressed a fundamental question about the metabolic flexibility conferred by reversible reactions: “Of all Directed Topologies (DTs) defined by fixing directions to all reversible reactions, how many are capable of carrying flux through all reactions?”. Enumeration of the DTs for iJO1366 model was performed using an efficient depth-first search algorithm, rejecting infeasible DTs based on mass-imbalanced and loopy flux patterns. We found the direction of 79% of reversible reactions must be defined before all directions in the network can be fixed, granting a high degree of flexibility.

A Lifelike guided journey through the pathophysiology of pulmonary hypertension—from measured metabolites to the mechanism of action of drugs

“…To allow for improved graph traversal, selected relationships were reversed or added. Because currency metabolites, e.g., ATP, NAD(P)H and , can artificially connect metabolic reactions and pathways in network analyses ( 43 , 44 ) we labeled such compounds plus the regulatory protein ubiquitin accordingly ( Currency nodes ) and thereby excluded them from all analyses. Finally, the database was transformed into an ArangoDB graph database consisting of 1,703,054 nodes and 3,368,926 edges, available at ( 29 ).…”

ALifelikeguided journey through the pathophysiology of pulmonary hypertension - from measured metabolites to the mechanism of action of drugs

“…Because currency metabolites, e.g. ATP, NAD(P)H and H + , can artificially connect metabolic reactions and pathways in network analyses [43, 44] we labeled such compounds plus the regulatory protein ubiquitin accordingly (Currency nodes) and thereby excluded them from all analyses. Finally, the database was transformed into an ArangoDB graph database consisting of 1,703,054 nodes and 3,368,926 edges, available at [29].…”

Building blocks needed for mechanistic modeling of bioprocesses: A critical review based on protein production by CHO cells

“…Metabolic reconstructions at the genomic scale are complex and often challenging to study in great detail. Recently, an interesting approach proposed by Martínez et al (2022) simplifies the model by choosing subsystems based on the topology of the metabolic model, thus preserving the essential biochemical reactions.…”