Serine and glycine metabolism in cancer

Abstract

Serine and glycine are biosynthetically linked, and together provide the essential precursors for the synthesis of proteins, nucleic acids, and lipids that are crucial to cancer cell growth. Moreover, serine/glycine biosynthesis also affects cellular antioxidative capacity, thus supporting tumour homeostasis. A crucial contribution of serine/glycine to cellular metabolism is through the glycine cleavage system, which refuels one-carbon metabolism; a complex cyclic metabolic network based on chemical reactions of folate compounds. The importance of serine/glycine metabolism is further highlighted by genetic and functional evidence indicating that hyperactivation of the serine/glycine biosynthetic pathway drives oncogenesis. Recent developments in our understanding of these pathways provide novel translational opportunities for drug development, dietary intervention, and biomarker identification of human cancers.

Keywords: cancer metabolism; folate; glycine; one-carbon metabolism; serine.

Figure 1

De novo serine biosynthesis diverges from glycolysis. The serine synthesis pathway utilises the glycolytic intermediate 3P-glycerate, which is converted by PHGDH, PSAT-1, and PSPH into serine. Removal of exogenous serine causes activation of its biosynthetic pathway. Serine accumulation accelerates glycolytic flux, although allosteric activation of PKM2 by serine. p53, via TIGAR, and TAp73, via G6PD, facilitate activation of the PPP, promoting NADPH and nucleotide synthesis. p53-dependent activation of p21 induces transient cell cycle arrest, blocking flux to purines, thus maintaining GSH synthesis. TAp73 drives glutamine/glutamate conversion by inducing expression of GLS-2, thus pushing serine biosynthetic pathway, while it represses intracellular ROS controlling COX4i1 subunit expression. Abbreviations: 3P glycerate, glycerate-3-phosphate; PHGDH, phosphoglycerate dehydrogenase; PKM2, pyruvate kinase M2; PPP, pentose phosphate pathway; ROS, reactive oxygen species; COX4i1, cytochrome C oxidase subunit 4 isoform 1; G6PD, glucose-6-phosphate dehydrogenase; GLS-2, glutaminase-2; GSH, glutathione; PSAT-1, phosphoserine aminotransferase 1; PSPH, phosphoserine phosphatase; TIGAR, TP53-inducible glycolysis and apoptosis regulator.

Figure 2

De novo synthesised or imported serine and glycine refuel one-carbon metabolism. One-carbon metabolism comprises two interconnected metabolic cycles: the folate cycle and the methionine cycle. Different de novo or imported inputs (red boxes), including glycine derived from serine and vitamin B₁₂, converge in this bimodular metabolic pathway. The. complex process produces multiple outputs (blue boxes), including substrates for methylation reactions, proteins, lipids, nucleotides, and reducing power against reactive oxygen species (ROS).

Figure 3

The folate and the methionine cycles exist and can be modulated independently. Imported folic acid can be converted into reduced to THF and enter the folic cycle. THF is in turn converted to me-THF by SHMT. me-THF is then either converted to F-THF or reduced to mTHF by MTHFR. Demethylation of mTHF completes the folate cycle and begins the methionine cycle, converting hCysteine to methionine. Methionine is used to generate SAM, which is demethylated to form SAH. After deadenylation by SAHH, the cycle performs a full turn with the conversion of SAH in homocysteine. Abbreviations: F-THF, 10-formyltetrahydrofolate; hCysteine, homocysteine; me-THF, 5,10-methylene-THF; mTHF, 5-methyltetrahydrofolate; MTHFR, methylenetetrahydrofolate reductase; SAH, S-adenosylhomocysteine; SAHH, S-adenosyl homocysteine hydrolase; SAM, S-adenosylmethionine; SHMT, serine hydroxymethyl transferase; THF, tetrahydrofolate; MAT, methionine adenosyltransferase; Methyl-TR, methyl-transferase.