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A GlcNAc switch

Science 337, 975–980 (2012)

O-GlcNAcylation, or the modification of proteins with β-N-acetylglucosamine, has been shown to link nutrient sensing with cell signaling. Yi et al. now investigate a further role for the modification in regulating cellular metabolism. The authors first observed that global increases in O-GlcNAcylation lowered rates of glucose metabolism owing to a substantial decrease in phosphofructokinase 1 (PFK1) activity. Labeling of PFK1 using a biotin or PEG tag established that PFK1 itself is O-GlcNAcylated and that the population of modified protein increases during the hypoxic conditions found in many tumors. MS further identified Ser529 as the site of modification, a residue already known to be important for PFK1 regulation by the activator fructose-2,6-bisphosphate. Analysis of PFK1 in multiple cell lines and human tissue also showed that O-GlcNAcylation was increased in tumor cells compared to nontumorigenic cells. As decreasing glycolytic flux can increase flux through the oxidative pentose phosphate pathway (the metabolites of which are necessary for DNA synthesis and protection from oxidative stress), the authors suspected this modification would be not only more prevalent in cancer cells but also necessary for their growth, as supported by impaired formation of tumors in a mouse model system harboring a S529A mutation as compared to the parent sequence. This work highlights a new regulatory mechanism in glycolysis with important implications for cancer treatment.


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Goodman, C. A GlcNAc switch. Nat Chem Biol 8, 809 (2012).

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