Figure 1.

Overview of glutamine metabolism. Glutamine (Gln) is imported into the cytosol through various transporters (ASCT2, SNAT1, SNAT2). In the cytosol Gln acts as precursor for biosynthesis of asparagine (Asn), hexosamine and nucleotides. SLC1A5_var transports Gln into the mitochondria, where Gln is converted to glutamate (Glu) by glutaminase (GLS). Glu in the mitochondrial matrix is converted to α-ketoglutarate (αKG), either by glutamate dehydrogenase 1 (GLUD1) or by mitochondrial transaminases (GPT2, GOT2). Glu deamidation by GLUD1 is associated to production of ammonia (NH4+), whereas the conversion of Glu to αKG via transaminases is coupled to synthesis of non-essential amino acids (NEAA), aspartate (Asp) and alanine (Ala). GLS and transaminases are present both into the cytosol and into the mitochondria. The αKG enters the tricarboxylic acid (TCA) cycle, fuels the electron transport chain (ETC), and provides energy (ATP). Various mitochondrial carriers export Glu and αKG back to the cytosol. Cytosolic Glu is exported in exchange for cystine (Cys) by antiporter xCT. Cys and Glu are substrates for the synthesis of glutathione (GSH). Cytosolic isocitrate dehydrogenase IDH1 converts α-KG into isocitrate by oxidizing NADPH to NADP, whereas mitochondrial IDH2 converts isocitrate to αKG, and produces NADPH. Both IDH1 and IDH2 can catalyze the conversion between isocitrate and αKG, and the reverse reaction. Glutamine synthetase (GS) synthetize glutamine de novo through condensation of glutamate and NH4+ in the cytosol. αKG α-ketoglutarate; ETC electron transport chain; GLS glutaminase; GLUD1 glutamate dehydrogenase 1; GOT2 glutamic-oxaloacetic transaminase 2; GPT2 glutamic-pyruvic transaminase 2; GS glutamine synthetase; GSH reduced glutathione; IDH isocitrate dehydrogenase; NEAA non-essential amino acids; TCA tricarboxylic acid cycle; TME tumor microenvironment; xCT cystine-glutamate antiporter.