Cancer is defined as the uncontrolled growth and division of masses of cell that sometimes take the shape of an outgrown tumor. Other times, tumors remain inside the body and are detected only through medical tests such as x-rays, ultrasound, and such. The purpose of this article by Amelio et al. is to inform readers about recent developments regarding the serine/glycine biosynthetic pathway that is crucial to the abnormal growth of cells in cancerous tumors. Cancer cells thrive on proteins, lipids and nucleic acids. Serine and glycine are the precursors for these molecules.
De novo synthesis of serine, which provides precursors for various biosynthetic pathways. The typical glycolysis process provides energy for cells, and serine diverges from this process. The glycolysis intermediate 3-phosphoglycerate is converted to serine via a 3-step enzymatic reaction. Cancer cells use PHGDH and NAD to oxidize about 10% of this 3-phosphoglycerate into the serine precursor 3-phosphohydroxypyruvate. Subsequent enzymes in the pathway convert this into serine via transamination. De novo synthesis of serine hinges on the conversion of serine to hydroxymethyltrasnferase. In this regard, glycine is a major source of methyl groups.
In order to prevent abnormal cell growth, several suppressors can be used. The p53 tumor suppressor is emerging as an essential regulator of cell metabolism. It is a mediator of the cellular stress response and is associated with the capacity of cancer cells to respond to serine deprivation. Several players in the p53 family can help cancer cells cope with the oxidative stress associated with serine depletion. Thus, serine depletion represents an innovative therapeutic strategy for cancer treatment. Serine also supports aerobic glycolysis and lactate production, and cal be used to regulate these processes.
The biosynthetic cell potential is maintained by the shuttling of carbon units in the one-carbon metabolic network. Central to this is the conversion of serine to glycine that is catalyzed by hydroxymethyltransferase (SHMT). This enzyme holds a critical position at the conversion of two key pathways for chemotherapeutic intervention: serine/glycine metabolism and nucleotide biosynthesis. SHMT-mediated reactions are also essential for maintaining normal methyation patterns and DNA stability. This refuels the one-carbon metabolism.
The one-carbon metabolism cycles carbon units from different amino acids, generating several different outputs and integrating several cellular nutrient statuses. A central aspect of this is the transformation of folate in all its stages. Coupling of the folate cycle to the methionine cycle constitutes a bicyclic pathway that circulates carbon units. It is collectively referred to as the one-carbon metabolism.
De novo synthesized or imported serine and glycine refuel the one-carbon metabolism, which is comprised of two interconnected metabolic cycles: the methionine cycle and the folate cycle. In figure 2, red boxes represent various de novo or imported inputs that converge in this metabolic pathway. Blue boxes represent the multiple outputs produced in this complex process, such as proteins, lipids, and nucleotides.
Glycine metabolism is associated with cancer cell proliferation in that glycine can be directed to the biosynthesis of purines by supplying the incomplete purine ring with two carbons and one nitrogen. Glycine is also integral for maintaining the cellular redox balance. Researchers have demonstrated the link of glycine consumption and enzyme expression in the glycine metabolism to the rate of proliferation of cancer cells. Thus, glycine deprivation may be the new advancement in treating cancer.
Antimetabolites are an essential advancement in the treatment of cancer in an era where it is challenging to select pharmaceutical compounds that can provide therapeutic intervention. These drugs dampen the effect of metabolites on cellular processes. Antifolates are particularly favored by researchers, since they cater to various types of metabolisms. For example, methotrexate and pemetrexed are a major component of cancer chemotherapeutic agents and are used to treat acute lymphoblastic leukemia, breast cancer, bladder cancer, and lymphomas. Patients whose tumors show increased amounts of serine and glycine mitochondrial enzymes can be treated with antifolates; the latter show selectivity for mitochondrial folate metabolism enzymes.
Alternate approaches have been suggested by researchers, which aim to target downstream pathways of glycine/serine/one-carbon metabolism. These can regulate the epigenetic status of tumors, and these substances are in the preliminary stages of testing. Yet another novel approach to target cancer metabolism is the design of a complementary diet or nutritional modification that can be added to cancer treatment drugs. However, the relationship between diet and the one-carbon metabolism is complex; reduced administration of folate is also associated with breast and colorectal cancer.
This paper aims to explore the glycine/serine metabolism that is essential to the uncontrolled growth of cancer cells, albeit the effect of the former on the latter is indirect. Understanding of the glycine, serine, and one-carbon metabolisms can lead to innovative therapeutic methods of treating cancers through regulated control over one or more of the inputs, intermediates, or products of these metabolic pathways. Topics for further research, such as development of mathematical models exemplifying these pathways, have been suggested.
Amelio, Ivano, et al. “Serine and Glycine Metabolism in Cancer.” Trends in Biochemical Sciences, vol. 39, no. 4, 2014, pp. 191–198., doi:10.1016/j.tibs.2014.02.004.
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