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

Journal Article (Journal Article)

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 the WE but 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.

Full Text

Duke Authors

Cited Authors

  • Liberti, MV; Allen, AE; Ramesh, V; Dai, Z; Singleton, KR; Guo, Z; Liu, JO; Wood, KC; Locasale, JW

Published Date

  • January 3, 2020

Published In

Volume / Issue

  • 295 / 1

Start / End Page

  • 111 - 124

PubMed ID

  • 31748414

Pubmed Central ID

  • PMC6952593

Electronic International Standard Serial Number (EISSN)

  • 1083-351X

Digital Object Identifier (DOI)

  • 10.1074/jbc.RA119.010903

Language

  • eng

Conference Location

  • United States