Four Key Steps Control Glycolytic Flux in Mammalian Cells

Cell Syst. 2018 Jul 25;7(1):49-62.e8. doi: 10.1016/j.cels.2018.06.003. Epub 2018 Jun 27.

Abstract

Altered glycolysis is a hallmark of diseases including diabetes and cancer. Despite intensive study of the contributions of individual glycolytic enzymes, systems-level analyses of flux control through glycolysis remain limited. Here, we overexpress in two mammalian cell lines the individual enzymes catalyzing each of the 12 steps linking extracellular glucose to excreted lactate, and find substantial flux control at four steps: glucose import, hexokinase, phosphofructokinase, and lactate export (and not at any steps of lower glycolysis). The four flux-controlling steps are specifically upregulated by the Ras oncogene: optogenetic Ras activation rapidly induces the transcription of isozymes catalyzing these four steps and enhances glycolysis. At least one isozyme catalyzing each of these four steps is consistently elevated in human tumors. Thus, in the studied contexts, flux control in glycolysis is concentrated in four key enzymatic steps. Upregulation of these steps in tumors likely underlies the Warburg effect.

Keywords: GLUT; MCT1; PFK; PFKFB; flux control; glycolysis; metabolic control analysis; metabolism; metabolomics; optogenetics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport
  • Cell Line
  • Genes, ras / genetics
  • Genes, ras / physiology
  • Glucose / metabolism
  • Glycolysis / genetics
  • Glycolysis / physiology*
  • HEK293 Cells
  • Hexokinase / genetics
  • Hexokinase / metabolism*
  • Humans
  • Isoenzymes / metabolism
  • Lactic Acid / biosynthesis
  • Mammals
  • Mice
  • Models, Biological
  • NIH 3T3 Cells
  • Neoplasms / enzymology
  • Phosphofructokinase-1 / metabolism*

Substances

  • Isoenzymes
  • Lactic Acid
  • Hexokinase
  • Phosphofructokinase-1
  • Glucose