Reconstruction of Tissue-Specific Metabolic Networks Using CORDA

PLoS Comput Biol. 2016 Mar 4;12(3):e1004808. doi: 10.1371/journal.pcbi.1004808. eCollection 2016 Mar.

Abstract

Human metabolism involves thousands of reactions and metabolites. To interpret this complexity, computational modeling becomes an essential experimental tool. One of the most popular techniques to study human metabolism as a whole is genome scale modeling. A key challenge to applying genome scale modeling is identifying critical metabolic reactions across diverse human tissues. Here we introduce a novel algorithm called Cost Optimization Reaction Dependency Assessment (CORDA) to build genome scale models in a tissue-specific manner. CORDA performs more efficiently computationally, shows better agreement to experimental data, and displays better model functionality and capacity when compared to previous algorithms. CORDA also returns reaction associations that can greatly assist in any manual curation to be performed following the automated reconstruction process. Using CORDA, we developed a library of 76 healthy and 20 cancer tissue-specific reconstructions. These reconstructions identified which metabolic pathways are shared across diverse human tissues. Moreover, we identified changes in reactions and pathways that are differentially included and present different capacity profiles in cancer compared to healthy tissues, including up-regulation of folate metabolism, the down-regulation of thiamine metabolism, and tight regulation of oxidative phosphorylation.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Algorithms*
  • Computer Simulation
  • Humans
  • Metabolome*
  • Metabolomics / methods*
  • Models, Biological*
  • Neoplasm Proteins / metabolism*
  • Neoplasms / metabolism*
  • Organ Specificity
  • Proteome / metabolism
  • Signal Transduction

Substances

  • Neoplasm Proteins
  • Proteome

Grants and funding

This work was funded by: National Science Foundation (http://www.nsf.gov/awardsearch/showAward?AWD_ID=1354390&HistoricalAwards=false) grant number 1354390 (AAQ), and National Science Foundation (http://www.nsf.gov/awardsearch/showAward?AWD_ID=1150645&HistoricalAwards=false) grant number 1150645 (AAQ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.