Thus, in the case of PDAC, targeting glutamine metabolism while taking into account these adaptive responses may yield clinical benefits for patients. in discussing the transporters and transaminases that mediate amino acid uptake and synthesis, we identify potential metabolic liabilities as targets for therapeutic intervention. expression120,121. The functional role of LAT1 in cancer, at least in part, is its ability to take in leucine with high affinity. Leucine is a well-known activator of mTOR signaling122,123 (Fig. ?(Fig.4a),4a), and pharmacologic inhibition of LAT1 suppresses mTOR signaling and tumor growth (e.g., non-small cell lung cancer, oral cancer)124,125. LAT1-mediated leucine influx is coupled with another amino acid antiporter, ASCT2, which is encoded by (Fig. ?(Fig.4a4a)126. ASCT2 mediates the Na+-coupled influx of neutral amino acids (alanine, serine, cysteine, and glutamine) in mandatory exchange for the Na+-coupled efflux of other amino acids126. In the functional coupling between LAT1 and ASCT2, glutamine enters the cancer cell through ASCT2, which then effluxes out of the cell via LAT1 coupled to the entry of leucine115 (Fig. ?(Fig.4a).4a). Consequently, genetic or pharmacological inhibition of ASCT2 impedes LAT1-mediated leucine uptake, leading to inactivation of mTOR signaling in cancer cells127,128. Notably, is also a target for c-MYC111,112, implying that cancer cells induce the two transporters (LAT1 and ASCT2) in a coordinated manner to enhance the functional coupling necessary for proliferation. expression is decreased by the tumor suppressor RB, supporting its role in cancer growth129. The amino acid transport system x?c (xCT), which JZL195 is encoded by and em SLC7A2 /em , respectively (Fig. ?(Fig.4a).4a). In a cancer setting, CAT1s ability to transport arginine, rather than lysine, appears to be more relevant to tumor growth and survival. CAT1 suppression reduces arginine uptake and NO production, resulting in apoptotic cell death in breast cancer cells134. Unlike essential amino acids whose source is solely the extracellular environment, nonessential amino acids can be produced, in most cases, through transamination reactions, which transfer the amino group from glutamate to a sugar precursor and generate -KG. Aspartate aminotransferase (AST, also known as glutamic oxaloacetic transaminase (GOT), GOT1 in the cytosol and GOT2 in the mitochondria) generates aspartate from oxaloacetate and glutamate (Fig. ?(Fig.4b).4b). Interestingly, recent studies have discovered an important role for aspartate synthesis in maintaining reducing potential. GOT1 consumes aspartate in the cytosol and transfers electrons into the mitochondria, which are accepted by the electron transport chain (ETC) and consume nicotinamide adenine dinucleotide (NADH) to regenerate NAD+135,136 (Fig. ?(Fig.4b).4b). NAD+ can then be utilized for OAA generation and aspartate biosynthesis135,136. In PDAC, GOT1-derived oxaloacetate (OAA) fuels the TCA cycle, which is further converted to malate and pyruvate to produce NADPH from NADP+ to maintain the cellular redox state25. Pathophysiologically, GOT is closely related to alanine aminotransferase (ALT). ALT generates alanine from pyruvate and the nitrogen of glutamate. Under normal physiology, the AST (GOT)/ALT ratio is 1, but upon liver damage, Serpinf2 including hepatocellular carcinoma (HCC), AST levels become higher than ALT (AST/ALT ratio 1). In addition to serving as a liver damage marker, ALT has implications for tumor growth. Inhibition of ALT induces oxidative phosphorylation and a subsequent increase in mitochondrial ROS, suggesting ALT as a putative target to promote JZL195 mitochondrial metabolism and inhibit tumor growth137. A transaminase for serine synthesis is phosphoserine aminotransferase 1 (PSAT1) (Fig. ?(Fig.4b).4b). It transfers nitrogen JZL195 from glutamate to 3-phosphohydroxypyruvate to make phosphoserine. Similar to other transaminases, PSAT1 is associated with tumor aggressiveness, especially in breast cancer. Both the mRNA and protein levels of PSAT1 in ER-positive primary tumors are associated with poor clinical outcomes following tamoxifen treatment, suggesting that combination with a regimen targeting PSAT1 might enable therapeutic efficacy in this subset of breast cancer26. Some amino acids are produced by non-transaminase reactions. The best-known non-transaminase NEAA-synthesizing enzyme would be glutaminase (GLS). This amidohydrolase generates glutamate and ammonia from glutamine. GLS activity has been shown to be critical for most cancer cell growth, at.