Metabolic effects of an aspartate aminotransferase-inhibitor on two T-cell lines

PLoS One. 2018 Dec 7;13(12):e0208025. doi: 10.1371/journal.pone.0208025. eCollection 2018.

Abstract

An emerging method to help elucidate the mode of action of experimental drugs is to use untargeted metabolomics of cell-systems. The interpretations of such screens are however complex and more examples with inhibitors of known targets are needed. Here two T-cell lines were treated with an inhibitor of aspartate aminotransferase and analyzed with untargeted GC-MS. The interpretation of the data was enhanced by the use of two different cell-lines and supports aspartate aminotransferase as a target. In addition, the data suggest an unexpected off-target effect on glutamate decarboxylase. The results exemplify the potency of metabolomics to provide insight into both mode of action and off-target effects of drug candidates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aspartate Aminotransferases / antagonists & inhibitors*
  • Aspartate Aminotransferases / metabolism
  • Drug Evaluation, Preclinical / methods
  • Enzyme Inhibitors / pharmacology*
  • Gas Chromatography-Mass Spectrometry
  • Glutamate Decarboxylase / metabolism
  • Humans
  • Hydrazines / pharmacology*
  • Jurkat Cells
  • Metabolome / drug effects*
  • Metabolomics
  • Succinates / pharmacology*
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / metabolism

Substances

  • Enzyme Inhibitors
  • Hydrazines
  • Succinates
  • hydrazinosuccinic acid
  • Aspartate Aminotransferases
  • Glutamate Decarboxylase

Grants and funding

This study was funded by The Swedish Research Council, grant 350-2012-6611 (M.S.), and grant 2014-04495 (H.A), the Swedish Cancer Society, grant CAN 2016/741 (H.A.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.