Integration of untargeted metabolomics with transcriptomics reveals active metabolic pathways

Kyuil Cho, Bradley S. Evans, B. Mc Kay Wood, Ritesh Kumar, Tobias J. Erb, Benjamin P. Warlick, John A. Gerlt, Jonathan V. Sweedler

Research output: Contribution to journalArticlepeer-review

Abstract

While recent advances in metabolomic measurement technologies have been dramatic, extracting biological insight from complex metabolite profiles remains a challenge. We present an analytical strategy that uses data obtained from high resolution liquid chromatography–mass spectrometry and a bioinformatics toolset for detecting actively changing metabolic pathways upon external perturbation. We begin with untargeted metabolite profiling to nominate altered metabolites and identify pathway candidates, followed by validation of those pathways with transcriptomics. Using the model organisms Rhodospirillum rubrum and Bacillus subtilis, our results reveal metabolic pathways that are interconnected with methionine salvage. The rubrum-type methionine salvage pathway is interconnected with the active methyl cycle in which re-methylation, a key reaction for recycling methionine from homocysteine, is unexpectedly suppressed; instead, homocysteine is catabolized by the trans-sulfuration pathway. Notably, the non-mevalonate pathway is repressed, whereas the rubrum-type methionine salvage pathway contributes to isoprenoid biosynthesis upon 5′-methylthioadenosine feeding. In this process, glutathione functions as a coenzyme in vivo when 1-methylthio-d-xylulose 5-phosphate (MTXu 5-P) methylsulfurylase catalyzes dethiomethylation of MTXu 5-P. These results clearly show that our analytical approach enables unexpected metabolic pathways to be uncovered.

Original languageEnglish (US)
Pages (from-to)503-517
Number of pages15
JournalMetabolomics
Volume11
Issue number3
DOIs
StatePublished - Jun 1 2015

Keywords

  • Active pathway detection
  • Isoprenoid biosynthesis
  • Liquid chromatography–mass spectrometry
  • Metabolomics
  • Methionine salvage
  • Quantitative real time polymerase chain reaction
  • Transcriptomics

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Clinical Biochemistry

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