Division of Bioinformatics and Surveillance, Department of Radiation Oncology, The Cancer Institute of New Jersey and University of Medicine and Dentistry of New Jersey, Robert-Wood Johnson Medical School, New Brunswick, New Jersey, United States of America.
PLoS One. 2011;6(11):e25881. doi: 10.1371/journal.pone.0025881. Epub 2011 Nov 2.
Previous experimental evidence indicates that some cancer cells have an alternative glycolysis pathway with net zero ATP production, implying that upregulation of glycolysis in these cells may not be related to the generation of ATP. Here we use a genome-scale model of human cell metabolism to investigate the potential metabolic alterations in cells using net zero ATP glycolysis. We uncover a novel pathway for ATP generation that involves reactions from serine biosynthesis, one-carbon metabolism and the glycine cleavage system, and show that the pathway is transcriptionally upregulated in an inducible murine model of Myc-driven liver tumorigenesis. This pathway has a predicted two-fold higher flux rate in cells using net zero ATP glycolysis than those using standard glycolysis and generates twice as much ATP with significantly lower rate of lactate - but higher rate of alanine secretion. Thus, in cells using the standard - or the net zero ATP glycolysis pathways a significant portion of the glycolysis flux is always associated with ATP generation, and the ratio between the flux rates of the two pathways determines the rate of ATP generation and lactate and alanine secretion during glycolysis.
先前的实验证据表明，一些癌细胞具有净零 ATP 产生的替代糖酵解途径，这意味着这些细胞中糖酵解的上调可能与 ATP 的产生无关。在这里，我们使用人类细胞代谢的基因组规模模型来研究使用净零 ATP 糖酵解的细胞中潜在的代谢变化。我们发现了一种新的 ATP 生成途径，涉及丝氨酸生物合成、一碳代谢和甘氨酸裂解系统的反应，并表明该途径在诱导型 Myc 驱动的肝肿瘤发生的鼠模型中转录上调。与使用标准糖酵解的细胞相比，该途径在使用净零 ATP 糖酵解的细胞中的通量预测高出两倍，并且产生的 ATP 量是两倍，而乳酸盐的产生率较低，但丙氨酸的分泌率较高。因此，在使用标准或净零 ATP 糖酵解途径的细胞中，糖酵解通量的很大一部分总是与 ATP 的产生相关，并且两条途径的通量率之比决定了糖酵解过程中 ATP 的产生以及乳酸盐和丙氨酸的分泌率。
