Serine and one-carbon metabolism in cancer

Abstract

The non-essential amino acid serine supports several metabolic processes that are crucial for the growth and survival of proliferating cells, including protein, amino acid and glutathione synthesis. As an important one-carbon donor to the folate cycle, serine contributes to nucleotide synthesis, methylation reactions and the generation of NADPH for antioxidant defence. Many cancer cells are highly dependent on serine, a trait that provides several novel therapeutic opportunities, either through the inhibition of de novo serine synthesis or by limiting the availability or uptake of exogenous serine.

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

“…Glycine is next added by glutathione synthetase (GSS; not shown in the figure). Additionally, glutamate can contribute to glycine through transamination by PSAT1 into phosphoserine (pSer) and α-ketoglutarate (αKG) and subsequent conversion to glycine through serine hydroxymethyltransferase (SHMT; not shown in the figure) as part of the one-carbon metabolism pathway, which has been shown in numerous studies to be critical in cancer metabolism and is also reviewed in this Focus Issue by Dr. Karen Vousden 139,140,213 . GLS, kidney-type glutaminase; GLS2, liver-type glutaminase; GLUD, glutamate dehydrogenase; OAA, oxaloacetate.…”

Nuclear magnetic resonance spectroscopy as a new approach for improvement of early diagnosis and risk stratification of prostate cancer

“…One characteristic of cancer cells is the switch from aerobic oxygen-consuming energy production to glycolytic metabolism, known as the Warburg effect (Warburg, 1956). Changes in glycolytic metabolites and related amino acids are amongst the most promising for cancer detection: high lactate levels indicating enhanced anaerobic energy metabolism; enhanced serine and glycine levels as result of de novo synthesis of serine via a side branch of glycolysis in highly proliferative cancer cells (Yang and Vousden, 2016). Serine is crucial for the growth and survival of many cancer cells and is closely related to the folate cycle as a donor of one-carbon units.…”

“…Therefore, the enzymes involved in serine de novo synthesis, i.e. phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH), may be good targets for therapeutic intervention (Yang and Vousden, 2016).…”

Balance your folate or the yin and yang of folate in hematopoiesis

“…Generally, folate coenzymes, such as vitamin B9 and vitamin B12, act as acceptors and donors of one-carbon units in a variety of reactions critical to nucleic acids synthesis (including thymine, but also purine bases), amino acids and DNA methylation reactions, and hence epigenetic mechanisms. 6 An inadequate low folate status during early pregnancy increases the risk of congenital abnormalities. Notably, neural tube defects have been linked to inadequate levels of folate provided to the fetus in the first trimester of development.…”