Evolved resistance to partial GAPDH inhibition results in loss of the Warburg effect and in a different state of glycolysis

Maria V. Liberti, Annamarie E. Allen, Vijyendra Ramesh, Ziwei Dai, Katherine R. Singleton, Zufeng Guo, Jun O. Liu, Kris C. Wood, Jason W. Locasale

Research output: Contribution to journalArticlepeer-review

Abstract

Aerobic glycolysis or the Warburg effect (WE) is characterized by increased glucose uptake and incomplete oxidation to lactate. Although the WE is ubiquitous, its biological role remains controversial, and whether glucose metabolism is functionally different during fully oxidative glycolysis or during the WE is unknown. To investigate this question, here we evolved resistance to koningic acid (KA), a natural product that specifically inhibits glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a rate-controlling glycolytic enzyme, during the WE. We found that KA-resistant cells lose theWEbut continue to conduct glycolysis and surprisingly remain dependent on glucose as a carbon source and also on central carbon metabolism. Consequently, this altered state of glycolysis led to differential metabolic activity and requirements, including emergent activities in and dependences on fatty acid metabolism. These findings reveal that aerobic glycolysis is a process functionally distinct from conventional glucose metabolism and leads to distinct metabolic requirements and biological functions.

Original languageEnglish (US)
Pages (from-to)111-124
Number of pages14
JournalJournal of Biological Chemistry
Volume295
Issue number1
DOIs
StatePublished - Jan 3 2020

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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