The importance of serine metabolism in cancer

Abstract

Serine metabolism is frequently dysregulated in cancers; however, the benefit that this confers to tumors remains controversial. In many cases, extracellular serine alone is sufficient to support cancer cell proliferation, whereas some cancer cells increase serine synthesis from glucose and require de novo serine synthesis even in the presence of abundant extracellular serine. Recent studies cast new light on the role of serine metabolism in cancer, suggesting that active serine synthesis might be required to facilitate amino acid transport, nucleotide synthesis, folate metabolism, and redox homeostasis in a manner that impacts cancer.

Figure 1.

The metabolic fates of serine. This schematic illustrates the products in mammalian cells where serine is a biosynthetic precursor.

Figure 2.

Serine and one-carbon metabolism. Serine can be cleaved into glycine and CH₂-THF, a one-carbon unit, in either the cytosol or the mitochondria in a reaction catalyzed by SHMT1 or SHMT2, respectively. Cytosolic CH₂-THF is needed for the biosynthesis of thymidine, and cytosolic 10-formyl-tetrahydrofolate (CHO-THF) is used in purine synthesis. One-carbon units produced by the action of SHMT2 in the mitochondria can be transported as formate to the cytosol and produce CHO-THF and CH₂-THF. CH⁺-THF, 5,10-methenyltetrahydrofolate.

Figure 3.

Pathways of serine synthesis and catabolism. Serine is synthesized from the glycolytic intermediate (3-PG) by the sequential action of PHGDH, PSAT, and PSPH. Serine can be catabolized directly to pyruvate or converted to glycerate in two steps.