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Compartment and hub definitions tune metabolic networks for metabolomic interpretations.

ABSTRACT: BACKGROUND:Metabolic networks represent all chemical reactions that occur between molecular metabolites in an organism's cells. They offer biological context in which to integrate, analyze, and interpret omic measurements, but their large scale and extensive connectivity present unique challenges. While it is practical to simplify these networks by placing constraints on compartments and hubs, it is unclear how these simplifications alter the structure of metabolic networks and the interpretation of metabolomic experiments. RESULTS:We curated and adapted the latest systemic model of human metabolism and developed customizable tools to define metabolic networks with and without compartmentalization in subcellular organelles and with or without inclusion of prolific metabolite hubs. Compartmentalization made networks larger, less dense, and more modular, whereas hubs made networks larger, more dense, and less modular. When present, these hubs also dominated shortest paths in the network, yet their exclusion exposed the subtler prominence of other metabolites that are typically more relevant to metabolomic experiments. We applied the non-compartmental network without metabolite hubs in a retrospective, exploratory analysis of metabolomic measurements from 5 studies on human tissues. Network clusters identified individual reactions that might experience differential regulation between experimental conditions, several of which were not apparent in the original publications. CONCLUSIONS:Exclusion of specific metabolite hubs exposes modularity in both compartmental and non-compartmental metabolic networks, improving detection of relevant clusters in omic measurements. Better computational detection of metabolic network clusters in large data sets has potential to identify differential regulation of individual genes, transcripts, and proteins.

SUBMITTER: Waller TC

PROVIDER: S-EPMC6977586 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Compartment and hub definitions tune metabolic networks for metabolomic interpretations.

Waller T Cameron TC Berg Jordan A JA Lex Alexander A Chapman Brian E BE Rutter Jared J

GigaScience 20200101 1

<h4>Background</h4>Metabolic networks represent all chemical reactions that occur between molecular metabolites in an organism's cells. They offer biological context in which to integrate, analyze, and interpret omic measurements, but their large scale and extensive connectivity present unique challenges. While it is practical to simplify these networks by placing constraints on compartments and hubs, it is unclear how these simplifications alter the structure of metabolic networks and the inter ...[more]

PMID: 31972021

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Project description:Network representations are becoming increasingly popular for analyzing kinetic data from techniques like Milestoning, Markov State Models, and Transition Path Theory. Mapping continuous phase space trajectories into a relatively small number of discrete states helps in visualization of the data and in dissecting complex dynamics to concrete mechanisms. However, not only are molecular networks derived from molecular dynamics simulations growing in number, they are also getting increasingly complex, owing partly to the growth in computer power that allows us to generate longer and better converged trajectories. The increased complexity of the networks makes simple interpretation and qualitative insight of the molecular systems more difficult to achieve. In this paper, we focus on various network representations of kinetic data and algorithms to identify important edges and pathways in these networks. The kinetic data can be local and partial (such as the value of rate coefficients between states) or an exact solution to kinetic equations for the entire system (such as the stationary flux between vertices). In particular, we focus on the Milestoning method that provides fluxes as the main output. We proposed Global Maximum Weight Pathways as a useful tool for analyzing molecular mechanism in Milestoning networks. A closely related definition was made in the context of Transition Path Theory. We consider three algorithms to find Global Maximum Weight Pathways: Recursive Dijkstra's, Edge-Elimination, and Edge-List Bisection. The asymptotic efficiency of the algorithms is analyzed and numerical tests on finite networks show that Edge-List Bisection and Recursive Dijkstra's algorithms are most efficient for sparse and dense networks, respectively. Pathways are illustrated for two examples: helix unfolding and membrane permeation. Finally, we illustrate that networks based on local kinetic information can lead to incorrect interpretation of molecular mechanisms.

Dataset Information

Compartment and hub definitions tune metabolic networks for metabolomic interpretations.

Publications

Compartment and hub definitions tune metabolic networks for metabolomic interpretations.

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