This review delves into the intricate relationship between excess folate (vitamin B9) intake, especially its synthetic form, namely, folic acid, and its implications on health and disease. While folate plays a pivotal role in the one-carbon cycle, which is essential for DNA synthesis, repair, and methylation, concerns arise about its excessive intake. The literature underscores potential deleterious effects, such as an increased risk of carcinogenesis; disruption in DNA methylation; and impacts on embryogenesis, pregnancy outcomes, neurodevelopment, and disease risk. Notably, these consequences stretch beyond the immediate effects, potentially influencing future generations through epigenetic reprogramming. The molecular mechanisms underlying these effects were examined, including altered one-carbon metabolism, the accumulation of unmetabolized folic acid, vitamin-B12-dependent mechanisms, altered methylation patterns, and interactions with critical receptors and signaling pathways. Furthermore, differences in the effects and mechanisms mediated by folic acid compared with natural folate are highlighted. Given the widespread folic acid supplementation, it is imperative to further research its optimal intake levels and the molecular pathways impacted by its excessive intake, ensuring the health and well-being of the global population.

Abstract In this issue of Cancer Research, Xia and colleagues show that MYC-induced metabolic reprograming results in dependency on the serine-glycine-one-carbon (SGOC) metabolic pathway in neuroblastoma. This occurs through MYCN and ATF4 activation of the SGOC biosynthetic pathway in MYCN-amplified cells. Furthermore, inhibition of de novo serine synthesis generates metabolic stress in MYCN-amplified neuroblastoma cells, causing cell-cycle arrest and autophagy. Together, these data suggest that the SGOC pathway is an attractive therapy target in neuroblastoma. See related article by Xia et al., p. 3837

Brazil has the second-highest COVID-19 death rate worldwide, and Rio de Janeiro is among the states with the highest rate in the country. Although vaccine coverage has been achieved, it is anticipated that COVID-19 will transition into an endemic disease. It is concerning that the molecular mechanisms underlying clinical evolution from mild to severe disease, as well as the mechanisms leading to long COVID-19, are not yet fully understood. NMR and MS-based metabolomics were used to identify metabolites associated with COVID-19 pathophysiology and disease outcome. Severe COVID-19 cases (n = 35) were enrolled in two reference centers in Rio de Janeiro within 72 h of ICU admission, alongside 12 non-infected control subjects. COVID-19 patients were grouped into survivors (n = 18) and non-survivors (n = 17). Choline-related metabolites, serine, glycine, and betaine, were reduced in severe COVID-19, indicating dysregulation in methyl donors. Non-survivors had higher levels of creatine/creatinine, 4-hydroxyproline, gluconic acid, and N-acetylserine, indicating liver and kidney dysfunction. Several changes were greater in women; thus, patients’ sex should be considered in pandemic surveillance to achieve better disease stratification and improve outcomes. These metabolic alterations may be useful to monitor organ (dys) function and to understand the pathophysiology of acute and possibly post-acute COVID-19 syndromes.

One-carbon metabolism is the network of biochemical pathways in which methyl groups are transferred from one compound to another for methylation processes. Expansion of the core pathway connects one-carbon metabolism to polyamine synthesis, nucleotide synthesis, redox metabolism, and the citric acid cycle. One-carbon metabolites (OCM) are methyl donors and cofactors which play key roles in the one-carbon metabolism pathway and include B-vitamins (choline, vitamin B12, vitamin B6, riboflavin, and folate), minerals (cobalt and sulfur) and amino acids (methionine, serine, and glycine). One-carbon metabolites are fundamental methyl donors for epigenetic modifications. Immediately post-fertilization, the embryonic genome undergoes epigenetic remodeling, and is the time when cell division is greatest (cell divisions/total cell number). At this time OCM supplementation may have its greatest impact on programming of offspring development, growth and postnatal performance, due to established metabolic roles in epigenetics (methyl transfer), growth (polyamine and nucleotide synthesis), and energetics. Limited data are available, however, which directly investigates the developmental effects of OCM supplementation in ruminants. In dairy cows, OCM supplementation in late gestation increased calf birth weight, nutrient sensing pathway activation, and offspring performance through the pre-weaning period. Methyl deficient diets during the pre-conception period in ewes altered the offspring hepatic methylome at 90 days of gestation, as well as the body composition and insulin tolerance of ram lambs at 22-mo of age. Bovine embryonic fibroblasts cultured in vitro with increasing OCM had greater growth rates and mitochondrial respiration parameters. Additional research into the area of one-carbon metabolism and the roles that OCM supplementation may play on postnatal function will provide new knowledge that could lead to altered management practices and increased efficiency of beef cattle. USDA is an equal opportunity provider and employer.

Methyl-donor nutrients, including folate, vitamin B12, vitamin B6, choline, betaine, and methionine, play indispensable roles in one-carbon metabolism and govern key processes such as DNA methylation, nucleotide synthesis, and genomic maintenance. Yet despite decades of research, their relationship with cancer remains paradoxical and frequently misunderstood. Much of the confusion arises from an overreliance on epidemiological studies that use cancer incidence as a late-stage endpoint, thereby obscuring how the biological actions of methyl donors differ fundamentally across the continuum from precancerous lesions to established tumors. By synthesizing evidence from mechanistic studies, precancerous lesion research, and early-stage carcinogenic models, this review suggests that adequate methyl-donor availability may be protective during the earliest phases of cancer development. However, these same nutrients may later become substrates hijacked by neoplastic cells to fuel rapid proliferation, maintain oncogenic methylation programs, and enhance tumor progression in established malignancies and high-risk populations. Therefore, this review proposes a reframing that methyl donors may not be evaluated merely as protective or harmful, but rather as context-dependent modifiers whose influence is shaped by timing, metabolic status, and the underlying biology of the target tissue. Such a shift is promising for advancing precision nutrition and the prevention or targeted suppression of cancer.

Formyl-THF and total folate levels were similar to controls. A redistribution of folate coenzymes was not found in vitamin A-deficient rats not force fed histidine. A 43% decrease in 10-formyl-THF dehydrogenase activity, which generates both THF and the 14CO2 from the labeled substrates, and an 81% increase in 5,10-methylene-THF reductase activity, which generates 5-methyl-THF, were found in vitamin A-deficient rats. It appears that the production of severe vitamin A deficiency results in selective changes in the activities of hepatic folate-dependent enzymes, so that when a load of a one-carbon donor is given, THF concentration decreases and metabolism of the load is impaired. Published in Archives of biochemistry and biophysics (1985)

to the C6 position of the pteridine ring. A one-carbon (1C) methyl group is added to tetrahydrofolate through the action of serine hydroxymethyltransferase Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Folate is required for the body to make DNA and RNA and metabolize amino acids necessary for cell division and maturation of blood cells. As the human body cannot make folate, it is required in the diet, making it an essential nutrient. It occurs naturally in many foods. The recommended adult daily intake of folate in the U.S. All of the biological functions of folic acid are performed by THF and its methylated derivatives. Hence folic acid must first be reduced to THF. This four electron reduction proceeds in two chemical steps both catalyzed by the same enzyme, dihydrofolate reductase. Folic acid is first reduced to dihydrofolate and then to tetrahydrofolate. Each step consumes one molecule of NADPH (biosynthetically derived from vitamin B3) and produces one molecule of NADP. Mechanistically, hydride is transferred from NADPH to the C6 position of the pteridine ring. A one-carbon (1C) methyl group is added to tetrahydrofolate through the action of serine hydroxymethyltransferase (SHMT) to yield 5,10-methylenetetrahydrofolate (5,10-CH2-THF). This reaction also consumes serine and pyridoxal phosphate (PLP; vitamin B6) and produces glycine and pyridoxal. A second enzyme, methylenetetrahydrofolate dehydrogenase (MTHFD2) oxidizes 5,10-methylenetetrahydrofolate to an iminium cation which in turn is hydrolyzed to produce 5-formyl-THF and 10-formyl-THF. This series of reactions using the β-carbon atom of serine as the carbon source provide the largest part of the one-carbon units available to the cell. Alternative carbon sources include formate which by the catalytic action of formate–tetrahydrofolate ligase adds a 1C unit to THF to yield 10-formyl-THF. Glycine, histidine, and sarcosine can also directly contribute to the THF-bound 1C pool.