Figure 3.

Protein metabolism and mediators of metabolic reprogramming. Protein metabolism in cancer cells is altered due to the immense demand generated by constant cell division, which is why amino acids are of great importance as proteogenic building blocks. Among the amino acids, glutamine is of great relevance in cancer cells. Glutamine enters the cell by different pathways, including macropinocytosis (which is increased by mutated RAS and c-SRC), entosis, degradation of cell-matrix proteins by metalloproteases, and transport by SLC1A5. Glutamine serves as a nitrogen donor and is used to synthesise nucleotides, purines, and proteins. It can also be a source of energy through glutaminolysis, which p53 and c-Myc stimulate. When there is a decrease in glutamine levels, it is synthesized by GLUL using glutamate as a substrate. Likewise, glutamine intervenes indirectly in the redox balance through glutamate. Serine is also essential, since increases in serine and 3-phosphoglycerate dehydrogenase, the first enzyme involved in its synthesis, are associated with tumor growth. Serine feeds carbon metabolism and protein synthesis, favors the synthesis of the oncometabolite 2-hydroxy-glutarate, and can act as an energy source, since it is an anaplerotic metabolite. In addition, methionine and SAM facilitate the pattern of histone methylation in monocytes/macrophages and the activation of TAMs. Depletion of exogenous methionine promotes tumor growth, metastasis, and immune evasion. SLC1A5 solute transporter family member 5; PPAT, phosphoribosyl pyrophosphate amidotransferase; PRA, phosphoribosylamine; GLS, glutaminase; GLUL, glutamine synthetase; AKG, alpha-ketoglutarate; SAMs S-adenosylmethionine; MAT, methionine adenosyltransferase; TAMs, tumor-associated macrophages.