Ralser Markus, Wamelink Mirjam M, Struys Eduard A, Joppich Christian, Krobitsch Sylvia, Jakobs Cornelis, Lehrach Hans
Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany.
Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):17807-11. doi: 10.1073/pnas.0803090105. Epub 2008 Nov 11.
The glucose analogue 2-deoxy-D-glucose (2-DG) restrains growth of normal and malignant cells, prolongs the lifespan of C. elegans, and is widely used as a glycolytic inhibitor to study metabolic activity with regard to cancer, neurodegeneration, calorie restriction, and aging. Here, we report that separating glycolysis and the pentose phosphate pathway highly increases cellular tolerance to 2-DG. This finding indicates that 2-DG does not block cell growth solely by preventing glucose catabolism. In addition, 2-DG provoked similar concentration changes of sugar-phosphate intermediates in wild-type and 2-DG-resistant yeast strains and in human primary fibroblasts. Finally, a genome-wide analysis revealed 19 2-DG-resistant yeast knockouts of genes implicated in carbohydrate metabolism and mitochondrial homeostasis, as well as ribosome biogenesis, mRNA decay, transcriptional regulation, and cell cycle. Thus, processes beyond the metabolic block are essential for the biological properties of 2-DG.
葡萄糖类似物2-脱氧-D-葡萄糖（2-DG）可抑制正常细胞和恶性细胞的生长，延长秀丽隐杆线虫的寿命，并且作为一种糖酵解抑制剂被广泛用于研究癌症、神经退行性变、热量限制及衰老方面的代谢活性。在此，我们报告称，将糖酵解与磷酸戊糖途径分开可显著提高细胞对2-DG的耐受性。这一发现表明，2-DG并非仅通过阻止葡萄糖分解代谢来阻断细胞生长。此外，2-DG在野生型和2-DG抗性酵母菌株以及人原代成纤维细胞中引发了类似的糖磷酸中间体浓度变化。最后，全基因组分析揭示了19个与碳水化合物代谢、线粒体稳态以及核糖体生物发生、mRNA衰变、转录调控和细胞周期相关的2-DG抗性酵母基因敲除。因此，代谢阻断之外的过程对于2-DG的生物学特性至关重要。
