Genetic, epigenetic and genomic mechanisms of methionine dependency of cancer and tumor-initiating cells: What could we learn from folate and methionine cycles

B Vitamins and One-Carbon Metabolism: Implications in Human Health and Disease

“…One-carbon metabolism is driven by the folate and methionine cycles that together regulate DNA synthesis and methylation reactions ( Figure 1). These two cycles are linked by methionine synthase (MS), the rate-limiting enzyme in one-carbon metabolism that converts homocysteine (Hcy) to methionine (Met) using 5-methyltetrahydrofolate (5-mTHF) as a methyl donor and B12 as an essential cofactor [8,17]. The key regulators of one carbon metabolism are all essential dietary requirements: Methionine, Folate (B9), and Vitamin B12.…”

“…In the methionine cycle, Met is converted to SAM by methyl-adenosyl transferase 2A (MAT2A) and SAM then acts as a substrate used by a diverse group of methyltransferases. The product of these methylation reactions is S-adenosylhomocysteine (SAH), which can be hydrolysed into homocysteine (Hcy) by S-adenosylhomocysteine hydrolase (AHCY), then resynthesized into Met by MS using 5-mTHF as a methyl donor and B12 as an essential cofactor [8,17,32]. Occasionally, the cobalt group of B12 becomes oxidized to Co(II) during its reaction [33].…”

“…Methylation is essential for many cellular processes, including protein-protein interactions and epigenetic regulation, which have important roles in embryonic development, cognitive function, and hematopoiesis [6,7]. Furthermore, perturbations in the uptake and homeostasis of B vitamins, which results in deficiency or excess of one-carbon metabolism intermediates, can lead to neurological defects, anemia, aberrant immune responses, and cancer [8][9][10]. Given the central role of vitamin B9 (folate) and vitamin B12 (B12) as direct participants of one-carbon metabolism, this review will focus on their biological roles in human health.…”

Genetic Variants in One-Carbon Metabolism Pathway Predict Survival Outcomes of Early-Stage Non-Small Cell Lung Cancer

“…Another 2 SNPs, MTR rs2853523C>A and MTHFR rs4846049G>T, were significantly associated with worse OS and worse DFS, respectively. The MTR gene encodes methionine synthase (MS) which plays a key role in the metabolic balance between folate and methionine cycles [21]. In the methionine cycle, MS cobalamin-dependently catalyzes the final step in the regeneration of methionine from homocysteine.…”

“…The increased expression of MS correlated to increased proliferation of cancer cells, and the inhibition of the activity of MS led to a decrease of SAM concentration and a dramatic reduction of cancer cell growth [22]. The MTHFR catalyzes the irreversible conversion of 5,10-methylene-THF to 5-methyl-THF, which provides its methyl group to homocysteine for the synthesis of methionine in a reaction catalyzed by MS. Methionine dependency is a common feature of cancer cells, which cannot proliferate without constant inputs of exogenous methionine even in the presence of its precursor, homocysteine, suggesting the crucial role of 1C metabolism enzymes in cancer cells [21]. Diverse mechanisms, such as somatic mutations, aberrant DNA methylation, and altered expression of genes, in 1C metabolism may cause methionine dependency [21].…”