Serine, glycine and one-carbon units: cancer metabolism in full circle

Abstract

One-carbon metabolism involving the folate and methionine cycles integrates nutritional status from amino acids, glucose and vitamins, and generates diverse outputs, such as the biosynthesis of lipids, nucleotides and proteins, the maintenance of redox status and the substrates for methylation reactions. Long considered a 'housekeeping' process, this pathway has recently been shown to have additional complexity. Genetic and functional evidence suggests that hyperactivation of this pathway is a driver of oncogenesis and establishes a link to cellular epigenetic status. Given the wealth of clinically available agents that target one-carbon metabolism, these new findings could present opportunities for translation into precision cancer medicine.

Figure 1. One carbon metabolism is an integrator of nutrient status

Nutrient sources involving amino acids are either imported or synthesized de novo and enter one carbon metabolism. One carbon metabolism can be viewed as a set of two modular units (i.e. two pathways existing separately from one another) involing the Folate Cycle and Methionine Cycle. Through these metabolic cycles, nutrients are processed. Upon processing, multiple outputs can be generated including nucleotides, proteins, lipids, reducing power, and substrates for methylation reactions.

Figure 2. Folate and methionine metabolism comprise one carbon metabolism

The folate cycle and the methionine comprise of two metabolic pathways that exist independently and thus in modules. The folate cycle: Folate is imported in cells and reduced to tetrahydrofolate (THF). THF is converted to 5,10-methylene-THF (me-THF) by serine hydroxymethyl transferase (SHMT). Vitamin B6 appears to have an influence on this reaction but the interaction is likely indirect. This product is then either reduced to 5-methyltetrahydrofolate (mTHF) by methylenetetrahydrofolate reductase (MTHFR) or converted to 10-Formyltetrahydrofolate (F-THF) through a sequence of steps.. mTHF is demethylated to complete the folate cycle. With the demethylation of mTHF, the carbon is donated into the methionine cycle through the methylation of homocysteine by methionine synthase and its cofactor Vitamin B12. The methionine cycle: The methionine cycle begins with homocysteine that accepts the carbon from the folate pool through mTHF to generate methionine. Methionine, through methionine adenyltransferase (MAT) is used to generate S-adenosylmethionine (SAM), which is demethylated to form S-adenosylhomocysteine (SAH). After deadenylation by S-adenosyl homocysteine hydrolase (SAHH), SAH is converted back to homocysteine resulting in a full turn of the methionine cycle. Another modular unit of one carbon metabolism is the transsulfuration pathway. This pathway is connected to the methionine cycle through the intermediate homocysteine. Serine can condense enzymatically with homocysteine to generate cystathione by cystathionine synthase (CBS). Cystathionine is then cleaved by cystathione lyase (CGL) to generate alpha-ketobutyrate (αKB) and cysteine, which can be shunted into glutathione production and taurine metabolism. The metabolism of cysteine can also lead to its desulfhydration and production of hydrogen sulfide through CBS and CGL. Abbreviations: SAM – S-adenosylmethionine, SAH – S-adenosylhomomocysteine, hCYS – homocysteine, THF – Tetrahydrofolate, mTHF – 5-methyltetrahydrofolate, Me-THF – 5,10 Methylenetetrahydrofolate, F-THF – 10 Formyltetrahydrofolate, DMG – Dimethylglycine, GLDC – Glycine Decarboxylase, TS – Thymidylate Synthase, MT – Methionine Synthase, B12 – Vitamin B12, MAT – Methionine adenyltransferase, SAHH – S-adenosyl homocysteine hydrolase, GNMT – Glycine N-methyltransferase, BHMT – Betaine hydroxymethyltransferase, SHMT – Serine hydroxymethyltransferase MTHFR – Methyltetrahydrofolate Reductase, DHFR –Dihydrofolate reductase, CDO – Cysteine Dioxygenase. Bi-directional arrows denote reversible steps. Dotted arrows denote multiple biochemical steps.

Figure 3. Nutrients that fuel one carbon metabolism

Serine and glycine metabolism is generated de novo from glycolysis through the oxidation of intermediate 3-phosphoglycerate. Serine and glycine are also transported into cells. Sarcosine and possibly threonine can also enter cells and be converted to glycine. The question mark denotes that threonine catabolism has been found to be utizilized in mammals including mice. Its analog in humans has not been identified. Dashed arrows denote multiple biochemical steps. Bi-directional arrows denote reversible steps. Abbreviations: PHGDH – phosphoglycerate dehydrogenase, GLDC – Glycine Decarboxylase, SHMT – Serine hydroxymethyltransferase, GNMT – Glycine N-methyltransferase, THF – Tetrahydrofolate, Me-THF – 5,10 Methylenetetrahydrofolate.

Figure 4. One carbon metabolism and cancer pathology and intervention

Schematic of one-carbon metabolism and the transsulfuration pathway. Recent findings have identified roles for these pathways in cancer. Genetic mutations and functional evidence for the existence of a cause of cancer (driver) at this point in the pathway (red), currently available drugs (yellow), and biomarker development (green) are highlighted. The specifics are indicated in Tables 1, 2 and 3. Causality is defined as either the presence of a genetic lesion or functional evidence (e.g. overexpression of a pathway component) that enhanced activity at this point in the pathway promotes oncogenesis. The biological outputs of the pathway are in a bold-italic red font. Abbreviations: SAM – S-adenosylmethionine, SAH – S-adenosylhomomocysteine, hCYS – homocysteine, THF – Tetrahydrofolate, mTHF – 5-methyltetrahydrofolate, Me-THF – 5,10 Methylenetetrahydrofolate, F-THF – 10 Formyltetrahydrofolate, DMG – Dimethylglycine, PC – Phosphatidylcholine; PHGDH – phosphoglycerate dehydrogenase, GLDC – Glycine Decarboxylase, TS – Thymidylate Synthase, MAT – Methionine Synthase, B12 – Vitamin B12, GNMT – Glycine N-methyltransferase, MTHFR – Methylenetetrahydrofolate Reductase, TDH/GCAT – Threonine Dehydrogenase/Glycine C-acetyltransferase, ROS – Reactive Oxygen Species. Bidirectional arrows denote reversible steps.