PII Protein-Derived FRET Sensors for Quantification and Live-Cell Imaging of 2-Oxoglutarate

Sci Rep. 2017 May 3;7(1):1437. doi: 10.1038/s41598-017-01440-w.

Abstract

The citric acid cycle intermediate 2-oxoglutarate (2-OG, a.k.a. alpha-ketoglutarate) links the carbon and nitrogen metabolic pathways and can provide information on the metabolic status of cells. In recent years, it has become exceedingly clear that 2-OG also acts as a master regulator of diverse biologic processes in all domains of life. Consequently, there is a great demand for time-resolved data on 2-OG fluctuations that can't be adequately addressed using established methods like mass spectrometry-based metabolomics analysis. Therefore, we set out to develop a novel intramolecular 2-OG FRET sensor based on the signal transduction protein PII from Synechococcus elongatus PCC 7942. We created two variants of the sensor, with a dynamic range for 2-OG from 0.1 µM to 0.1 mM or from 10 µM to 10 mM. As proof of concept, we applied the sensors to determine in situ glutamine:2-oxoglutarate aminotransferase (GOGAT) activity in Synechococcus elongatus PCC 7942 cells and measured 2-OG concentrations in cell extracts from Escherichia coli in vitro. Finally, we could show the sensors' functionality in living human cell lines, demonstrating their potential in the context of mechanistic studies and drug screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biosensing Techniques*
  • Cell Line, Tumor
  • Chlamydomonas reinhardtii / genetics
  • Chlamydomonas reinhardtii / metabolism
  • Citric Acid Cycle / genetics
  • Cloning, Molecular
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Escherichia coli K12 / genetics
  • Escherichia coli K12 / metabolism
  • Fluorescence Resonance Energy Transfer
  • Gene Expression
  • Gene Expression Regulation, Bacterial*
  • Genetic Vectors / chemistry
  • Genetic Vectors / metabolism
  • Glutamate Synthase / genetics*
  • Glutamate Synthase / metabolism
  • Humans
  • Ketoglutaric Acids / analysis*
  • Ketoglutaric Acids / metabolism
  • Neuroglia / cytology
  • Neuroglia / metabolism
  • PII Nitrogen Regulatory Proteins / genetics*
  • PII Nitrogen Regulatory Proteins / metabolism
  • Protein Engineering*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Synechococcus / genetics
  • Synechococcus / metabolism

Substances

  • Ketoglutaric Acids
  • PII Nitrogen Regulatory Proteins
  • Recombinant Proteins
  • Glutamate Synthase