Serine, glycine and one‑carbon metabolism in cancer (Review)

Abstract

Serine/glycine biosynthesis and one‑carbon metabolism are crucial in sustaining cancer cell survival and rapid proliferation, and of high clinical relevance. Excessive activation of serine/glycine biosynthesis drives tumorigenesis and provides a single carbon unit for one‑carbon metabolism. One‑carbon metabolism, which is a complex cyclic metabolic network based on the chemical reaction of folate compounds, provides the necessary proteins, nucleic acids, lipids and other biological macromolecules to support tumor growth. Moreover, one‑carbon metabolism also maintains the redox homeostasis of the tumor microenvironment and provides substrates for the methylation reaction. The present study reviews the role of key enzymes with tumor‑promoting functions and important intermediates that are physiologically relevant to tumorigenesis in serine/glycine/one‑carbon metabolism pathways. The related regulatory mechanisms of action of the key enzymes and important intermediates in tumors are also discussed. It is hoped that investigations into these pathways will provide new translational opportunities for human cancer drug development, dietary interventions, and biomarker identification.

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

Figure 1

The Serine-glycine biosynthesis pathway. The glycolysis pathway and glutamine catabolism provide an intermediate metabolite, 3-PG, which is gradually catalyzed into serine by PHGDH, PSAT1 and PSPH. Finally, serine is converted into glycine by SHMT1/2. Yellow ovals represent metabolic enzymes. 3-PG, 3-phosphoglycerate; 3-PHP, 3-phosphate hydroxypyruvate; 3-Pser, 3-phosphoserine; α-KG, α-ketoglutarate; OAA, oxaloacetate; PHGDH, phosphoglycerate dehydrogenase; PSAT, phosphoserine aminotransferase; PSPH, phosphoserine phosphatase; SHMT, serine hydroxymethyltransferase; TCA, tricarboxylic acid.

Figure 2

Overview of one-carbon metabolism around the folate cycle, methionine cycle and trans-sulfuration pathway. The folate cycle provides one carbon for the methionine cycle, as well as homocysteine, an intermediate product of the methionine cycle, which can be converted into GSH through the trans-sulfuration pathway. Yellow ovals represent metabolic enzymes. 3-PG, 3-phosphoglycerate; BHMT, betaine homocysteine methyltransferase; CBS, cystathionine β-synthase; CTH, cystathionase; DHFR, dihydrofolate reductase; DMG, dimethylglycine; F-THF, 10-formyltetrahydrofolate; GLDC, glycine dehydrogenase; GSH, glutathione; HMT, histone methyl transferase; MAT, methionine adenosyltransferase; me-THF, 5,10-methylenetetrahydrofolate; mTHF, 5-methyl-tetrahydrofolate; MTHFD, methylenetetrahydrofolate dehydrogenase; MTHFR, methylenetetrahydrofolate reductase; MTR, methionine synthase; SAH, S-adenosyl homocysteine; SAHH, SAH hydrolase; SAM, S-adenosylmethionine; SHMT, serine hydroxymethyltransferase; SSP, serine synthesis pathway; THF, tetrahydrofolate.

Figure 3

One-carbon metabolism integrates nutrient status and cellular functions with appropriate equilibrium in inputs and outputs. One-carbon metabolism can be viewed as a set of two modular units including the folate cycle and methionine cycle. The different nutrient sources and amino acids (serine, glycine, threonine, choline, betaine, methionine and vitamins) are inputted into the one-carbon metabolism and converted into a wide variety of outputs, such as nucleotide metabolism, redox control and post-translational modification. GSH, glutathione; ROS, reactive oxygen species.