Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710; Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853.
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710.
J Biol Chem. 2020 Jan 3;295(1):111-124. doi: 10.1074/jbc.RA119.010903. Epub 2019 Nov 20.
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.
有氧糖酵解或瓦博格效应（WE）的特征是葡萄糖摄取增加和不完全氧化为乳酸。尽管 WE 普遍存在，但它的生物学作用仍存在争议，并且在完全氧化的糖酵解或 WE 期间，葡萄糖代谢是否在功能上不同尚不清楚。为了研究这个问题，我们在这里进化出了对金雀异黄素（KA）的抗性，KA 是一种天然产物，专门抑制甘油醛-3-磷酸脱氢酶（GAPDH），一种限速糖酵解酶，在 WE 期间。我们发现，KA 抗性细胞失去了 WE，但继续进行糖酵解，令人惊讶的是，它们仍然依赖葡萄糖作为碳源，也依赖于中心碳代谢。因此，这种改变的糖酵解状态导致了不同的代谢活性和需求，包括脂肪酸代谢中的新兴活性和依赖性。这些发现表明，有氧糖酵解是一个与传统葡萄糖代谢在功能上不同的过程，并导致不同的代谢需求和生物学功能。
