Fig. 6.

The potential inhibitors that target cancer metabolic process. Glucose is taken up into the cell by glucose transporters GLUT1/4 and phosphorylated by hexokinases HK1 and HK2. Glucose 6-phosphate (P) and its downstream intermediates can either be converted to pyruvate or fuel biosynthesis through different pathways, such as the pentose phosphate pathway which provides ribose 5-P for nucleotide synthesis. Fructose-6-P is involved in the hexosamine biosynthesis pathway. Glycerol 3-P production contributes to the serine and glycine biosynthesis pathways which are regulated by the key enzymes PHGDH and SHMT1/2. Moreover, serine biosynthesis plays an essential role in amino acid metabolism and nucleotide metabolism by regulating one-carbon metabolism which is mediated by the methylenetetrahydrofolate dehydrogenase MTHFD1. Pyruvate can be converted to lactate by LDH and exported through the monocarboxylate transporter MCT-1. Besides, pyruvate can enter the TCA cycle as acetyl-CoA through the mitochondrial pyruvate carrier and pyruvate dehydrogenase. Various pathways influence the production of the mitochondrial acetyl-CoA, including fatty acid β-oxidation, glucose metabolism, and other sources that can condense with oxaloacetate to form citrate, which can then be exported from the mitochondrion. Citrate via ACLY is a vital source of cytoplasmic acetyl-CoA which forms malonyl-CoA by acetyl-CoA carboxylase ACC1 and ACC2. Subsequently, malonyl-CoA is cyclically extended by the addition of carbons from acetyl-CoA by FASN to make saturated fatty acids. Fatty acid catabolism is initiated with the formation of fatty acyl-CoA which is then converted by CPT1 to an acylcarnitine. Pyrimidine synthesis, a multistep process regulated by key enzymes such as CAD and DHODH, can produce pyrimidine nucleotides from glutamine, carbonate, and aspartate. Meanwhile, glutamine is taken up by transporters SLC1A5. Glutamate produced from glutamine by glutaminase enzymes can be used in glutathione synthesis. In addition, the complex V (ATP synthase) and the electron transport chain consisting of four complexes including complex I/II/III/IV (CI–IV), are promising targets for drug development. Inhibitors (red), key enzymes or transporters (blue), and key metabolites (purple) are shown. ACC acetyl-CoA carboxylase, ACLY ATP-citrate lyase, BP bisphosphate, CAD carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase, CoA coenzyme A, CI–IV, complex I/II/III/IV, CV complex V, CPT1 carnitine palmitoyltransferase 1, DHODH dihydroorotate dehydrogenase, FASN fatty acid synthase, GLUT1/GLUT4 glucose transporter 1/4, HK hexokinase, IDH1 isocitrate dehydrogenase 1, LDHA/B lactate dehydrogenase A/B, MCT-1 monocarboxylate transporter 1, MTHFD1 methylenetetrahydrofolate dehydrogenase 1, P phosphate, PHGDH phosphoglycerate dehydrogenase, PKM2 pyruvate kinase M2, SHMT serine hydroxymethyl transferase, SLC1A5 solute carrier family 1 member 5, TCA tricarboxylic acid