Identification of Conserved Moieties in Metabolic Networks by Graph Theoretical Analysis of Atom Transition Networks

PLoS Comput Biol. 2016 Nov 21;12(11):e1004999. doi: 10.1371/journal.pcbi.1004999. eCollection 2016 Nov.

Abstract

Conserved moieties are groups of atoms that remain intact in all reactions of a metabolic network. Identification of conserved moieties gives insight into the structure and function of metabolic networks and facilitates metabolic modelling. All moiety conservation relations can be represented as nonnegative integer vectors in the left null space of the stoichiometric matrix corresponding to a biochemical network. Algorithms exist to compute such vectors based only on reaction stoichiometry but their computational complexity has limited their application to relatively small metabolic networks. Moreover, the vectors returned by existing algorithms do not, in general, represent conservation of a specific moiety with a defined atomic structure. Here, we show that identification of conserved moieties requires data on reaction atom mappings in addition to stoichiometry. We present a novel method to identify conserved moieties in metabolic networks by graph theoretical analysis of their underlying atom transition networks. Our method returns the exact group of atoms belonging to each conserved moiety as well as the corresponding vector in the left null space of the stoichiometric matrix. It can be implemented as a pipeline of polynomial time algorithms. Our implementation completes in under five minutes on a metabolic network with more than 4,000 mass balanced reactions. The scalability of the method enables extension of existing applications for moiety conservation relations to genome-scale metabolic networks. We also give examples of new applications made possible by elucidating the atomic structure of conserved moieties.

MeSH terms

  • Computer Simulation
  • Conserved Sequence / physiology*
  • Metabolic Networks and Pathways / physiology*
  • Models, Biological*
  • Models, Chemical*
  • Proteome / chemistry*
  • Proteome / metabolism*
  • Sequence Homology, Amino Acid

Substances

  • Proteome

Grants and funding

HSH and RMTF were supported by the U.S. Department of Energy (http://www.energy.gov/), Offices of Advanced Scientific Computing Research and the Biological and Environmental Research as part of the Scientific Discovery Through Advanced Computing program, grant #DE-SC0010429. HSH was supported by the Luxembourg National Research Fund (FNR, http://www.fnr.lu/) through the National Centre of Excellence in Research (NCER) on Parkinson’s Disease (http://ncer-pd.lu/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.