MYC-regulated metabolic pathways in cancer. MYC-regulated metabolic pathways in cancer. Glucose is taken up by glucose transporters (GLUT) and phosphorylated by hexokinase (HK) to form glucose-6-phosphate (glucose-6-P). Glucose-6-P can then either enter glycolysis or the pentose phosphate pathway, which supports nucleotide synthesis by yielding two NADPH-reducing equivalents and one ribose per molecule of glucose. The serine biosynthesis pathway branches off glycolysis, producing serine and glycine that likewise support nucleotide synthesis. Serine hydroxymethyltransferase 2 (SHMT2) converts serine to glycine, which, in a series of coupled reactions, can be used to create the nucleotide and epigenetic methyl donor 5,10-CH2-tetrahydrofolate and mitochondrial NADPH for redox control. LDHA can regenerate NAD+ by converting glycolysis-derived pyruvate to lactate, which is then exported out of the cell by monocarboxylate transporters (MCT1-4). Alternatively, pyruvate can enter the tricarboxylic acid (TCA) cycle in a pyruvate dehydrogenase (PDH)–dependent conversion to acetyl-CoA. TCA cycle citrate can be exported to the cytoplasm where it is converted to acetyl-CoA by ATP citrate lyase (ACLY). Cytoplasmic acetyl-CoA can then be channeled into lipogenesis. In addition to glucose, glutamine is an important fuel source in cancers. Glutamine is transported across the membrane by the glutamine transporter (SLC1A5/ASCT2) and converted to glutamate by glutaminase (GLS or GLS2). Glutamate can then be converted to the TCA cycle intermediate α-ketoglutarate (αKG) by glutamate dehydrogenase (GLUD) or aminotransferases. Zachary E. Stine et al. Cancer Discovery 2015;5:1024-1039 ©2015 by American Association for Cancer Research