Creative Proteomics Blog

One-carbon metabolism, mediated by the folate cofactor, is a group of biochemical reactions with a special set of enzymes and coenzymes. It is referred to as one-carbon metabolism because what they have in common is the transfer of one-carbon groups. One-carbon metabolism plays an important role in multiple physiological processes, including biosynthesis (purines and thymidine), amino acid homeostasis (glycine, serine, and methionine), epigenetic maintenance, and redox defense.

One-carbonmetabolic pathway

One-carbon metabolism contains three critical reactions: the folate cycle, the methionine cycle, and the trans-sulfuration pathway. In the folate cycle, glycine and serine fuel mitochondrial enzymes through purine production. In the methionine cycle, S-adenocyl methionine (SAM) serves both hydrocarbons and polyamines. The trans-sulphuration pathway is essential for the synthesis of glutathione, which is involved in the production of reactive oxygen species(ROS). 

Source of carbon

One-carbon pool refers to the pool of the methyl groups that are available for the methylation of a variety of compounds, including protein, DNA, RNA, etc. Serine, glycine, formate, histidine, and the choline-derived methyl-glycine species (sarcosine and dimethylglycine) can all directly contribute to the tetrahydrofolate (THF)-bound one-carbon pool. Among them, only three (histidine, serine, and formate) can directly feed into the cytosolic folate-bound one-carbon pool. In the mitochondrial, one-carbon units can be made from serine, glycine, sarcosine, or dimethylglycine and excreted into the cytosol as formate. Histidine degradation generates 5-formimino-THF, which is converted into 5, 10-methylene-THF in the cytosol by formimidoyltransferase cyclodeaminase. Serine, which can be synthesized from glucose but under typical conditions in mammals mainly comes from dietary protein intake, can directly feed the cytosolic 1C pool via SHMT1. In rapidly proliferating cultured cells, however, the main direct source of cytosolic 1C units is the formate released from their mitochondria.

One carbon metabolism in cancer

One-carbon units can be used for nucleotide synthesis, methylation, and reductive metabolism, which support the high proliferative rate of cancer cells. Aminoacids (like serine) are major one-carbon sources, and cancer cells are particularly susceptible to the deprivation of one-carbon units by serine restriction or inhibition of de novo serine synthesis. In tumor cells, the processes of cell growth and proliferation require the construction of building blocks for new cellular components from substances associated with a redox status. In addition,one-carbon metabolism plays a critical role in the regulation of the redox state by producing glutathione. Therefore, antifolates and drugs that target one-carbon metabolism, have been used for treating cancers. C1 metabolism is critical for the maintenance of genomic stability through nucleotide metabolism as well as for the epigenetic control of DNA and histones, altered expression of which is a characteristic attribution of tumor cells.

Recently, C1 metabolic enzymes have been shown to be novel therapeutic targets for cancer. As shown in table 1, dihydrofolate reductase (DHFR), serine hydroxymethyltransferase (SHMT), and thymidylate synthase (TYMS) have been used as targets to develop antifolate antineoplastic agents. One-carbon units contribute to multiple downstream pathways that are known to or are likely to benefit cancer cell survival. Traditional antifolate chemotherapeutics have many deleterious side effects due to the importance of folate pathways in healthy proliferating cells and resistance of cancer cells to antifolates is a common problem. Future therapeutics may better target one-carbon metabolism in cancer cells by moreselectively inhibiting individual one-carbon pathway enzymes.

Table 1: Established anti-folate antineoplastic agents (Newman A C and Maddocks O D K, 2017)

Drug name	Targets	Therapeutic uses
Aminopterin	DHFR	Initially found to reduce leukaemic cells in children; no longer in use
Methotrexate	DHFR	Used to treat a wide range of neoplastic disease
Pemetrexed	DHFR, TYMS (and SHMT)	Non-small cell lung carcinoma; pleural mesothelioma
Pralatrexate	DHFR	Peripheral T-cell lymphoma
Raltitrexed	DHFR and TYMS	Metastatic colorectal cancer
5-Fluoruoracil	TYMS	Used to treat a wide range of neoplastic disease

One-carbon metabolism plays a significant role in physiological and pathological process. The increasing interest in one-carbon metabolism in research filed and industrial field will demand a powerful profiling analytical platform. At CreativeProteomics, we have established a sensitive, reliable, and accurate platform for simultaneous determination of multiple components of one-carbon metabolism in large-scale studies. Our HPLC-MS/MS method can be used for quantification of various one-carbon metabolism metabolites compounds, such as folate, homocysteine, S-adenosylmethionine, and so on.

References:

1. Kalhan S C. One-carbon metabolism, fetal growth and long-term consequences//Maternal and Child Nutrition: The First 1,000 Days.Karger Publishers, 2013, 74: 127-138.
2. Ducker G S, Rabinowitz J D. One-carbonmetabolism in health and disease. Cell metabolism, 2017, 25(1): 27-42.
3. Konno M, Asai A, Kawamoto K, et al. Theone-carbon metabolism pathway highlights therapeutic targets forgastrointestinal cancer. International journal of oncology, 2017, 50(4):1057-1063.
4. Newman A C, Maddocks O D K. One-carbonmetabolism in cancer. British journal of cancer, 2017, 116(12): 1499.