PT  - JOURNAL ARTICLE
AU  - Maria V. Liberti
AU  - Annamarie E. Allen
AU  - Vijyendra Ramesh
AU  - Ziwei Dai
AU  - Katherine R. Singleton
AU  - Zufeng Guo
AU  - Jun O. Liu
AU  - Kris C. Wood
AU  - Jason W. Locasale
TI  - Evolved resistance to GAPDH inhibition results in loss of the Warburg Effect but retains a different state of glycolysis
AID  - 10.1101/602557
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 602557
4099  - http://biorxiv.org/content/early/2019/04/09/602557.short
4100  - http://biorxiv.org/content/early/2019/04/09/602557.full
AB  - Aerobic glycolysis or the Warburg Effect (WE) is characterized by increased glucose uptake and incomplete oxidation to lactate. Although ubiquitous, the biological role of the WE remains controversial and whether glucose metabolism is functionally different during fully oxidative glycolysis or during the WE is unknown. To investigate this question, we evolved resistance to koningic acid (KA), a natural product shown to be a specific inhibitor of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a rate-controlling glycolytic enzyme during the WE. We find that KA-resistant cells lose the WE but conduct glycolysis and surprisingly remain dependent on glucose and central carbon metabolism. Consequentially this altered state of glycolysis leads to differential metabolic activity and requirements including emergent activities in and dependencies on fatty acid metabolism. Together, these findings reveal that, contrary to some recent reports, aerobic glycolysis is a functionally distinct entity from conventional glucose metabolism and leads to distinct metabolic requirements and biological functions.