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Incidence of esophageal and gastric cancer has been linked to low B‐vitamin status. We conducted matched nested case–control studies of incident esophageal squamous cell carcinoma (ESCC; 340 case–control pairs) and gastric cancer (GC; 352 case–control pairs) within the Golestan Cohort Study. The primary exposure was plasma biomarkers: riboflavin and flavin mononucleotide (FMN) (vitamin B2), pyridoxal phosphate (PLP) (B6), cobalamin (B12), para‐aminobenzoylglutamate (pABG) (folate), and total homocysteine (tHcy); and indicators for deficiency: 3‐hydroxykyurenine‐ratio (HK‐r for vitamin B6) and methylmalonic acid (MMA for B12). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression adjusting for matching factors and potential confounders. High proportions of participants had low B‐vitamin and high tHcy levels. None of the measured vitamin B levels was associated with the risk of ESCC and GC, but elevated level of MMA was marginally associated with ESCC (OR = 1.42, 95% CI = 0.99–2.04) and associated with GC (OR = 1.53, 95% CI = 1.05–2.22). Risk of GC was higher for the highest versus lowest quartile of HK‐r (OR = 1.95, 95%CI = 1.19–3.21) and for elevated versus non‐elevated HK‐r level (OR = 1.59, 95% CI = 1.13–2.25). Risk of ESCC (OR = 2.81, 95% CI = 1.54–5.13) and gastric cancer (OR = 2.09, 95%CI = 1.17–3.73) was higher for the highest versus lowest quartile of tHcy. In conclusion, insufficient vitamin B12 was associated with higher risk of ESCC and GC, and insufficient vitamin B6 status was associated with higher risk of GC in this population with prevalent low plasma B‐vitamin status. Higher level of tHcy, a global indicator of OCM function, was associated with higher risk of ESCC and GC. [ABSTRACT FROM AUTHOR]

Translation of messenger RNA (mRNA) in bacteria occurs in the steps of initiation, elongation, termination, and ribosome recycling. The initiation step comprises multiple stages and uses a special transfer RNA (tRNA) called initiator tRNA (i‐tRNA), which is first aminoacylated and then formylated using methionine and N10‐formyl‐tetrahydrofolate (N10‐fTHF), respectively. Both methionine and N10‐fTHF are produced via one‐carbon metabolism, linking translation initiation with active cellular metabolism. The fidelity of i‐tRNA binding to the ribosomal peptidyl‐site (P‐site) is attributed to the structural features in its acceptor stem, and the highly conserved three consecutive G‐C base pairs (3GC pairs) in the anticodon stem. The acceptor stem region is important in formylation of the amino acid attached to i‐tRNA and in its initial binding to the P‐site. And, the 3GC pairs are crucial in transiting the i‐tRNA through various stages of initiation. We utilized the feature of 3GC pairs to investigate the nuanced layers of scrutiny that ensure fidelity of translation initiation through i‐tRNA abundance and its interactions with the components of the translation apparatus. We discuss the importance of i‐tRNA in the final stages of ribosome maturation, as also the roles of the Shine–Dalgarno sequence, ribosome heterogeneity, initiation factors, ribosome recycling factor, and coevolution of the translation apparatus in orchestrating a delicate balance between the fidelity of initiation and/or its leakiness to generate proteome plasticity in cells to confer growth fitness advantages in response to the dynamic nutritional states. [ABSTRACT FROM AUTHOR]

Purpose: Serine is a major source of one‐carbon units needed for the synthesis of nucleotides and the production of intramitochondrial nicotinamide adenine dinucleotide phosphate (NADPH), and it plays an important role in cancer cell proliferation. The aim of this study was to develop a deuterium (2H) MRS imaging method for imaging tumor serine metabolism. Methods: Sequential (2H) spectra and spectroscopic images were used to monitor the metabolism of [2,3,3‐2H3]serine in patient‐derived glioblastoma cells in vitro and in tumors obtained by their orthotopic implantation in mouse brain. Results: [14,14‐2H2] 5,10‐methylene‐tetrahydrofolate, [2H]glycine, [2H]formate, and labeled water were detected in cell suspensions and water labeling in spectroscopic images of tumors. Studies in cells and tumors with variable mitochondrial content and inhibitor studies in cells demonstrated that most of the labeled serine was metabolized in the mitochondria. Water labeling in the cell suspensions was correlated with formate labeling; therefore, water labeling observed in tumors could be used to provide a surrogate measure of flux in the pathway of one‐carbon metabolism in vivo. Conclusion: The method has the potential to be used clinically to select patients for treatment with inhibitors of one‐carbon metabolism and subsequently to detect their early responses to such treatment. [ABSTRACT FROM AUTHOR]

SUMMARY: The metabolism of tetrahydrofolate (H4PteGlun)‐bound one‐carbon (C1) units (C1 metabolism) is multifaceted and required for plant growth, but it is unclear what of many possible synthesis pathways provide C1 units in specific organelles and tissues. One possible source of C1 units is via formate‐tetrahydrofolate ligase, which catalyzes the reversible ATP‐driven production of 10‐formyltetrahydrofolate (10‐formyl‐H4PteGlun) from formate and tetrahydrofolate (H4PteGlun). Here, we report biochemical and functional characterization of the enzyme from Arabidopsis thaliana (AtFTHFL). We show that the recombinant AtFTHFL has lower Km and kcat values with pentaglutamyl tetrahydrofolate (H4PteGlu5) as compared to monoglutamyl tetrahydrofolate (H4PteGlu1), resulting in virtually identical catalytic efficiencies for the two substrates. Stable transformation of Arabidopsis plants with the EGFP‐tagged AtFTHFL, followed with fluorescence microscopy, demonstrated cytosolic signal. Two independent T‐DNA insertion lines with impaired AtFTHFL function had shorter roots compared to the wild type plants, demonstrating the importance of this enzyme for root growth. Overexpressing AtFTHFL led to the accumulation of H4PteGlun + 5,10‐methylene‐H4PteGlun and serine, accompanied with the depletion of formate and glycolate, in roots of the transgenic Arabidopsis plants. This metabolic adjustment supports the hypothesis that AtFTHFL feeds the cytosolic C1 network in roots with C1 units originating from glycolate, and that these units are then used mainly for biosynthesis of serine, and not as much for the biosynthesis of 5‐methyl‐H4PteGlun, methionine, and S‐adenosylmethionine. This finding has implications for any future attempts to engineer one‐carbon unit‐requiring products through manipulation of the one‐carbon metabolic network in non‐photosynthetic organs. Significance Statement: This study describes the cloning and biochemical characterization of a recombinant formate‐tetrahydrofolate ligase from plants and establishes the role of this enzyme in providing formate as an important source of one‐carbon units in roots. [ABSTRACT FROM AUTHOR]

The relationship among polycystic ovary syndrome (PCOS), endometrial cancer (EC), and glycometabolism remains unclear. We explored shared genes between PCOS and EC, using bioinformatics to unveil their pathogenic connection and influence on EC prognosis. Gene Expression Omnibus datasets GSE226146 (PCOS) and GSE196033 (EC) were used. A protein–protein interaction (PPI) network was constructed to identify the central genes. Candidate markers were screened using dataset GSE54250. Differences in marker expression were confirmed in mouse PCOS and human EC tissues using RT‐PCR and immunohistochemistry. The effect of PGD on EC proliferation and migration was explored using Ki‐67 and Transwell assays. PGD's impact on the glycometabolic pathway within carbon metabolism was assessed by quantifying glucose content and lactic acid production. R software identified 31 common genes in GSE226146 and GSE196033. Gene Ontology functional classification revealed enrichment in the "purine nucleoside triphosphate metabolism process," with key Kyoto Encyclopedia of Genes and Genomes pathways related to "carbon metabolism." The PPI network identified 15 hub genes. HK2, NDUFS8, PHGDH, PGD, and SMAD3 were confirmed as candidate markers. The RT‐PCR analysis validated distinct HK2 and PGD expression patterns in mouse PCOS ovarian tissue and human EC tissue, as well as in normal and EC cells. Transfection experiments with Ishikawa cells further confirmed PGD's influence on cell proliferation and migration. Suppression of PGD expression impeded glycometabolism within the carbon metabolism of EC cells, suggesting PGD as a significant PCOS risk factor impacting EC proliferation and migration through modulation of single carbon metabolism. These findings highlight PGD's pivotal role in EC onset and prognosis. [ABSTRACT FROM AUTHOR]

Prenatal multivitamins, including folic acid, are commonly consumed in excess, whereas choline, an essential nutrient and an important source of labile methyl groups, is underconsumed. Here, we characterized profiles of one‐carbon metabolism and related pathways and patterns of DNA methylation in offspring exposed to excess or imbalanced micronutrients prenatally. Pregnant Wistar rats were fed either recommended 1× vitamins (RV), high 10× vitamins (HV), high 10× folic acid with recommended choline (HFolRC), or high 10× folic acid with no choline (HFolNC). Offspring were weaned to a high‐fat diet for 12 weeks. Circulating metabolites were analyzed with a focus on the hypothalamus, an area known to be under epigenetic regulation. HV, HFolRC, and HFolNC males had higher body weight (BW) and lower plasma choline and methionine consistent with lower hypothalamic S‐adenosylmethionine (SAM):S‐adenosylhomocysteine (SAH) and global DNA methylation compared with RV. HV and HFolNC females had higher BW and lower plasma 5‐methyltetrahydrofolate and methionine consistent with lower hypothalamic global DNA methylation compared with RV. Plasma dimethylglycine (DMG) and methionine were higher as with hypothalamic SAM:SAH and global DNA methylation in HFolRC females without changes in BW compared with RV. Plasma trimethylamine and trimethylamine‐N‐oxide were higher in males but lower in females from HFolRC compared with RV. Network modeling revealed a link between the folate‐dependent pathway and SAH, with most connections through DMG. Final BW was negatively correlated with choline, DMG, and global DNA methylation. In conclusion, prenatal intake of excess or imbalanced micronutrients induces distinct metabolic and epigenetic perturbations in offspring that reflect long‐term nutritional programming of health.Prenatal multivitamins including folic acid are commonly consumed in excess whereas choline is underconsumed but their health consequences remain unknown. Pregnant Wistar rats were fed either recommended 1× vitamins (RV), high 10× vitamins (HV), high 10× folic acid with recommended choline (HFolRC), or high 10× folic acid with no choline (HFolNC). We showed distinct alterations in one‐carbon metabolism and related pathways associated with DNA methylation in offspring exposed to excess or imbalanced micronutrients that reflect long‐term programming of health. [ABSTRACT FROM AUTHOR]

Cystathionine beta‐synthase‐deficient homocystinuria (HCU) is a life‐threatening disorder of sulfur metabolism. HCU can be treated by using betaine to lower tissue and plasma levels of homocysteine (Hcy). Here, we show that mice with severely elevated Hcy and potentially deficient in the folate species tetrahydrofolate (THF) exhibit a very limited response to betaine indicating that THF plays a critical role in treatment efficacy. Analysis of a mouse model of HCU revealed a 10‐fold increase in hepatic levels of 5‐methyl ‐THF and a 30‐fold accumulation of formiminoglutamic acid, consistent with a paucity of THF. Neither of these metabolite accumulations were reversed or ameliorated by betaine treatment. Hepatic expression of the THF‐generating enzyme dihydrofolate reductase (DHFR) was significantly repressed in HCU mice and expression was not increased by betaine treatment but appears to be sensitive to cellular redox status. Expression of the DHFR reaction partner thymidylate synthase was also repressed and metabolomic analysis detected widespread alteration of hepatic histidine and glutamine metabolism. Many individuals with HCU exhibit endothelial dysfunction. DHFR plays a key role in nitric oxide (NO) generation due to its role in regenerating oxidized tetrahydrobiopterin, and we observed a significant decrease in plasma NOx (NO2 + NO3) levels in HCU mice. Additional impairment of NO generation may also come from the HCU‐mediated induction of the 20‐hydroxyeicosatetraenoic acid generating cytochrome CYP4A. Collectively, our data shows that HCU induces dysfunctional one‐carbon metabolism with the potential to both impair betaine treatment and contribute to multiple aspects of pathogenesis in this disease. [ABSTRACT FROM AUTHOR]

This article, published in Molecular Oral Microbiology, explores the links between metabolism, inflammation, and oral and systemic health. It consists of a collection of research articles that cover various topics such as host-microbiome interactions, epigenetic regulation, cell death pathways, and the associations between periodontitis and systemic conditions like cerebral small vessel disease, rheumatoid arthritis, and diabetes. The articles highlight potential therapeutic interventions and treatment implications for these conditions. The authors emphasize the need for innovative interventions to improve oral health outcomes and call for further research in this field. [Extracted from the article]

Lifecourse nutrition encompasses nourishment from early development into parenthood. From preconception and pregnancy to childhood, late adolescence, and reproductive years, life course nutrition explores links between dietary exposures and health outcomes in current and future generations from a public health perspective, usually addressing lifestyle behaviours, reproductive well-being and maternal-child health strategies. However, nutritional factors that play a role in conceiving and sustaining new life might also require a molecular perspective and recognition of critical interactions between specific nutrients and relevant biochemical pathways. The present perspective summarises evidence about the links between diet during periconception and next-generation health and outlines the main metabolic networks involved in nutritional biology of this sensitive time frame. [ABSTRACT FROM AUTHOR]

Background: One‐carbon (1C) metabolism is a metabolic network that plays essential roles in biological reactions. In 1C metabolism, a series of nutrients are used to fuel metabolic pathways, including nucleotide metabolism, amino acid metabolism, cellular redox defence and epigenetic maintenance. At present, 1C metabolism is considered the hallmark of cancer. The 1C units obtained from the metabolic pathways increase the proliferation rate of cancer cells. In addition, anticancer drugs, such as methotrexate, which target 1C metabolism, have long been used in the clinic. In terms of immunotherapy, 1C metabolism has been used to explore biomarkers connected with immunotherapy response and immune‐related adverse events in patients. Methods: We collected numerous literatures to explain the roles of one‐carbon metabolism in cancer immunotherapy. Results: In this review, we focus on the important pathways in 1C metabolism and the function of 1C metabolism enzymes in cancer immunotherapy. Then, we summarise the inhibitors acting on 1C metabolism and their potential application on cancer immunotherapy. Finally, we provide a viewpoint and conclusion regarding the opportunities and challenges of targeting 1C metabolism for cancer immunotherapy in clinical practicability in the future. Conclusion: Targeting one‐carbon metabolism is useful for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

There are multiple theories of Alzheimer's disease pathogenesis. One major theory is that oxidation of amyloid beta (Aβ) promotes plaque deposition that directly contributes to pathology. A competing theory is that hypomethylation of DNA (due to altered one carbon metabolism) results in pathology through altered gene regulation. Herein, we propose a novel hypothesis involving L‐isoaspartyl methyltransferase (PIMT) that unifies the Aβ and DNA hypomethylation hypotheses into a single model. Importantly, the proposed model allows bidirectional regulation of Aβ oxidation and DNA hypomethylation. The proposed hypothesis does not exclude simultaneous contributions by other mechanisms (e.g., neurofibrillary tangles). The new hypothesis is formulated to encompass oxidative stress, fibrillation, DNA hypomethylation, and metabolic perturbations in one carbon metabolism (i.e., methionine and folate cycles). In addition, deductive predictions of the hypothesis are presented both to guide empirical testing of the hypothesis and to provide candidate strategies for therapeutic intervention and/or nutritional modification. HIGHLIGHTS: PIMT repairs L‐isoaspartyl groups on amyloid beta and decreases fibrillation.SAM is a common methyl donor for PIMT and DNA methyltransferases.Increased PIMT activity competes with DNA methylation and vice versa.The PIMT hypothesis bridges a gap between plaque and DNA methylation hypotheses. [ABSTRACT FROM AUTHOR]

We investigated the associations of one‐carbon metabolism (OCM)‐related metabolites, including choline, betaine, dimethylglycine (DMG), and methionine with fetal growth of twins. This hospital‐based cohort study included dichorionic twin gestations. Blood samples were collected at a median of 14.7 weeks of gestation. Blood plasma metabolite levels were measured using high‐performance liquid chromatography–triple quadrupole mass spectrometry. Generalized estimating equations and mixed effects models were used to explore associations between plasma metabolite levels and fetal growth. In total, 115 women with dichorionic diamniotic pregnancies were included. The maternal plasma DMG level was negatively correlated with fetal birth weight (β = −43.5, 95% confidence interval [CI] = −74.1 to −12.8, p <.05) and head circumference (β = −0.23, 95% CI = −0.39 to −0.07, p <.05). Other metabolites were not significantly associated with birth weight, body length, head circumference (HC), or chest circumference. Analysis of the relationships between plasma metabolite levels and fetal biological parameters on ultrasound revealed that the maternal choline level was negatively correlated with fetal abdominal circumference (AC) (β = −0.12, 95% CI = 0.24 to −0.004, p <.05); the maternal DMG level was negatively correlated with fetal AC (β = −0.17, 95% CI = 0.28–0.07, p <.05), femur length (β = 0.02, 95% CI = 0.04–0.003, p <.05), and estimated fetal weight (β = 26.4, 95% CI = −41.6 to −11.2, p <.05), but not with HC. The maternal methionine level was negatively correlated with HC (β = −0.08, 95% CI = −0.14 to −0.02, p <.05). The plasma level of the OCM‐related metabolite DMG during the second trimester was negatively correlated with fetal intrauterine growth and birth weight. However, further studies with larger samples are needed. [ABSTRACT FROM AUTHOR]

Background: Reduced folate status and elevated levels of circulating homocysteine are modifiable risk factors for cognitive decline and dementia. Disturbances in one‐carbon metabolism are associated with the pathological accumulation of phosphorylated tau, a hallmark feature of prevalent dementia, including Alzheimer's disease and subgroups of frontotemporal dementia. Methods: Here, using transgenic TAU58/2 mouse models of human tauopathy, we tested whether dietary supplementation with L‐methylfolate (the active folate form), choline and betaine can reduce tau phosphorylation and associated behavioural phenotypes. Results: TAU58/2 mice fed with the methyl donor‐enriched diet showed reduced phosphorylation of tau at the pathological S202 (CP13) and S396/S404 (PHF‐1) epitopes and alleviation of associated motor and learning deficits. Compared with mice on the control diet, the decrease in cortical phosphorylated tau levels in mice fed with the methyl donor‐enriched diet was associated with enhanced methylation of protein phosphatase 2A, the major brain tau Ser/Thr phosphatase. It also correlated with a reduction in protein levels of Fyn, a tau tyrosine kinase that plays a central role in mediating pathological tau‐induced neurodegeneration. Conversely, Fyn expression levels were increased in mice with deficiencies in folate metabolism. Conclusions: Our findings provide the first experimental evidence that boosting one‐carbon metabolism with L‐methylfolate, choline and betaine can mitigate key pathological, learning and motor deficits in a tauopathy mouse model. They give support to using a combination of methyl donors as a preventive or disease‐modifying strategy for tauopathies. [ABSTRACT FROM AUTHOR]

Suboptimal status of folate and/or interrelated B vitamins (B12, B6 and riboflavin) can perturb one‐carbon metabolism and adversely affect brain development in early life and brain function in later life. Human studies show that maternal folate status during pregnancy is associated with cognitive development in the child, whilst optimal B vitamin status may help to prevent cognitive dysfunction in later life. The biological mechanisms explaining these relationships are not clear but may involve folate‐related DNA methylation of epigenetically controlled genes related to brain development and function. A better understanding of the mechanisms linking these B vitamins and the epigenome with brain health at critical stages of the lifecycle is necessary to support evidence‐based health improvement strategies. The EpiBrain project, a transnational collaboration involving partners in the United Kingdom, Canada and Spain, is investigating the nutrition–epigenome–brain relationship, particularly focussing on folate‐related epigenetic effects in relation to brain health outcomes. We are conducting new epigenetics analysis on bio‐banked samples from existing well‐characterised cohorts and randomised trials conducted in pregnancy and later life. Dietary, nutrient biomarker and epigenetic data will be linked with brain outcomes in children and older adults. In addition, we will investigate the nutrition–epigenome–brain relationship in B vitamin intervention trial participants using magnetoencephalography, a state‐of‐the‐art neuroimaging modality to assess neuronal functioning. The project outcomes will provide an improved understanding of the role of folate and related B vitamins in brain health, and the epigenetic mechanisms involved. The results are expected to provide scientific substantiation to support nutritional strategies for better brain health across the lifecycle. [ABSTRACT FROM AUTHOR]

Sulforaphane (SFN) is a promising phytochemical with a wide range of antitumor activities. A comprehensive understanding of the effects of SFN on breast cancer based on the metabolome and microbiome is limited. Thus, we treated MCF‐7 cell‐transplanted nude mice with 50 mg/kg SFN. SFN inhibits breast cancer cell proliferation. SFN increased the levels of sulfate‐related metabolites and glutathione‐related metabolites and decreased tryptophan metabolites and methyl‐purine metabolites in urinary metabolic profile. SFN indirectly affected the activation of aryl hydrocarbon receptor by tryptophan metabolism. The ratio of SAM to methionine was decreased by SFN while the global DNA methylation was downregulated in tumor tissue. SFN decreased the sulfate‐reducing bacterium Desulfovibrio, which is related to reduced methylation capacity, and increased the genus Lactobacillus related to tryptophan metabolites with antitumor activities. In conclusion, we provide a perspective on the metabolome and microbiome to elucidate the antitumor activities of SFN. [ABSTRACT FROM AUTHOR]

BACKGROUND: Foxtail millet grain has higher folate content than other cereal crops. However, the folate metabolite content and the expression patterns of folate metabolite‐related genes are unknown. RESULTS: Liquid chromatography–mass spectrometry was used to investigate 12 folate metabolites in a foxtail millet panicle. The content of total folate and derivatives gradually decreased during panicle development. Polyglutamate 5‐formyl‐tetrahydrofolate was the major form. Twenty‐eight genes involved in the folate metabolic pathway were identified through bioinformatic analysis. These genes in Setaria italica, S. viridis and Zea mays showed genomic collinearity. Phylogenetic analysis revealed that the folate‐related genes were closely related among the C4 plants compared to C3 plants. The gene expressions were then studied at three panicle development stages. The gene expression patterns were classified into two groups, namely SiADCL1 and SiGGH as two key enzymes, which are responsible for folate synthesis and degradation; their expression levels were highest at the early panicle development stage, up to 179.11‐ and 163.88‐fold, respectively. Their expression levels had a similar downward trend during panicle development and were significantly positively correlated with the concentration of total folate and folate derivatives. However, SiSHMT3 expression levels were significantly negatively correlated with total folate concentration. CONCLUSION: Besides being the major determinants of folate and folate derivatives accumulation, SiADCL1 and SiGGH expression levels are key limiting factors in the foxtail millet panicle. Therefore, SiADCL1 and SiGGH expression levels can be targeted in genetic modification studies to improve folate content in foxtail millet seeds in the future. © 2021 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Diet regulates complex life‐history traits such as longevity. For optimal lifespan, organisms employ intricate adaptive mechanisms whose molecular underpinnings are less known. We show that Caenorhabditis elegans FLR‐4 kinase prevents lifespan differentials on the bacterial diet having higher Vitamin B12 levels. The flr‐4 mutants are more responsive to the higher B12 levels of Escherichia coli HT115 diet, and consequently, have enhanced flux through the one‐carbon cycle. Mechanistically, a higher level of B12 transcriptionally downregulates the phosphoethanolamine methyltransferase pmt‐2 gene, which modulates phosphatidylcholine (PC) levels. Pmt‐2 downregulation activates cytoprotective gene expression through the p38‐MAPK pathway, leading to increased lifespan only in the mutant. Evidently, preventing bacterial B12 uptake or inhibiting one‐carbon metabolism reverses all the above phenotypes. Conversely, supplementation of B12 to E. coli OP50 or genetically reducing PC levels in the OP50‐fed mutant extends lifespan. Together, we reveal how worms maintain adaptive capacity to diets having varying micronutrient content to ensure a normal lifespan. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate, in a case‐control design, the association between maternal genotypes for variants in 23 genes involved in folate/one‐carbon metabolism and nonsyndromic cleft lip with or without cleft palate (NSCL/P) in a Chilean population. After applying several filters to an Illumina array, we extracted 175 single nucleotide polymorphisms (SNPs) from 150 mothers of NSCL/P cases and 150 control women. Association was evaluated using computed odds ratio (OR) with a 95% confidence interval (95% CI) in additive, recessive, and dominant models. After multiple comparison correction, only SNP rs4451422 (A>C), located 237 bp downstream of the gene encoding the human folylpolyglutamate synthetase (FPGS), maintained a significant association with NSCL/P in the offspring (OR 3.03; 95% CI 1.69–5.26). The variant rs4451422 is associated with a decrease in FPGS expression according to database annotation. Our results lead to a new hypothesis that a lower activity of FPGS enzyme reduces intracellular folate levels and increases the risk of an offspring having NSCL/P. [ABSTRACT FROM AUTHOR]

Background: The risk of chronic hepatitis B (CHB) infection is influenced by aberrant DNA methylation and altered nucleotide synthesis and repair, possibly caused by polymorphic variants in one‐carbon metabolism genes. In the present study, we investigated the relationship between polymorphisms belonging to the one‐carbon metabolic pathway and CHB infection. Methods: A case–control study using 230 CHB patients and 234 unrelated healthy controls was carried out to assess the genetic association of 24 single nucleotide polymorphisins (SNPs) determined by mass spectrometry. Results: Three SNPs, comprising rs10717122 and rs2229717 in serine hydroxymethyltransferase1/2 (SHMT2) and rs585800 in betaine‐homocysteine S‐methyltransferase (BHMT), were associated with the risk of CHB. Patients with DEL allele, DEL.DEL and DEL.T genotypes of rs10717122 had a 1.40‐, 2.00‐ and 1.83‐fold increased risk for CHB, respectively. Cases inheriting TA genotype of rs585800 had a 2.19‐fold risk for CHB infection. The T allele of rs2229717 was less represented in the CHB cases (odds ratio = 0.66, 95% confidence interval = 0.48–0.92). The T allele of rs2229717 was less in patients with a low hepatitis B virus‐DNA level compared to the control group (odds ratio = 0.49, 95% confidence interval = 0.25–0.97) and TT genotype of rs2229717 had a significant correlation with hepatitis B surface antigen level (p = 0.0195). Further gene–gene interaction analysis showed that subjects carrying the rs10717122 DEL.DEL/DEL.T and rs585800 TT/TA genotypes had a 2.74‐fold increased risk of CHB. Conclusions: The results of the present study suggest that rs10717122, rs585800 and rs2229717 and gene–gene interactions of rs10717122 and rs585800 affect the outcome of CHB infection, at the same time as indicating their usefulness as a predictive and diagnostic biomarker of CHB infection. [ABSTRACT FROM AUTHOR]

Here we sought metabolic alterations specifically associated with MYCN amplification as nodes to indirectly target the MYCN oncogene. Liquid chromatography‐mass spectrometry‐based proteomics identified seven proteins consistently correlated with MYCN in proteomes from 49 neuroblastoma biopsies and 13 cell lines. Among these was phosphoglycerate dehydrogenase (PHGDH), the rate‐limiting enzyme in de novo serine synthesis. MYCN associated with two regions in the PHGDH promoter, supporting transcriptional PHGDH regulation by MYCN. Pulsed stable isotope‐resolved metabolomics utilizing 13C‐glucose labeling demonstrated higher de novo serine synthesis in MYCN‐amplified cells compared to cells with diploid MYCN. An independence of MYCN‐amplified cells from exogenous serine and glycine was demonstrated by serine and glycine starvation, which attenuated nucleotide pools and proliferation only in cells with diploid MYCN but did not diminish these endpoints in MYCN‐amplified cells. Proliferation was attenuated in MYCN‐amplified cells by CRISPR/Cas9‐mediated PHGDH knockout or treatment with PHGDH small molecule inhibitors without affecting cell viability. PHGDH inhibitors administered as single‐agent therapy to NOG mice harboring patient‐derived MYCN‐amplified neuroblastoma xenografts slowed tumor growth. However, combining a PHGDH inhibitor with the standard‐of‐care chemotherapy drug, cisplatin, revealed antagonism of chemotherapy efficacy in vivo. Emergence of chemotherapy resistance was confirmed in the genetic PHGDH knockout model in vitro. Altogether, PHGDH knockout or inhibition by small molecules consistently slows proliferation, but stops short of killing the cells, which then establish resistance to classical chemotherapy. Although PHGDH inhibition with small molecules has produced encouraging results in other preclinical cancer models, this approach has limited attractiveness for patients with neuroblastoma. Whats's new? Molecular alterations in neuroblastoma influence disease aggressiveness and relapse risk. In particular, molecular amplification of the oncogene MYCN is a major determinant of patient outcome. Here, shotgun proteomics was combined with metabolomics to investigate alterations in MYCN as potential therapeutic targets in neuroblastoma. A strong correlation was detected between MYCN amplification and proteins involved in serine synthesis, including the rate‐limiting enzyme PHGDH, and one‐carbon metabolism. Targeting PHGDH by genetic knockout and small molecule inhibitors stalled proliferation but did not kill neuroblastoma cells. Chemotherapeutic resistance was evident in mice with patient‐derived neuroblastoma xenografts following treatment with PHGDH inhibitors and cisplatin. [ABSTRACT FROM AUTHOR]

Mitochondrial serine hydroxymethyltransferase 2 (SHMT2) is an important drug target in the one‐carbon metabolic pathway, since its activity is critical for purine and pyrimidine biosynthesis. Additionally, it plays a prominent role during metabolic reprogramming of cancer cells, and SHMT2 inhibitors have proven useful as anticancer drugs. Compared to drugs targeting one‐carbon metabolic enzymes (mainly dihydrofolate reductase and thymidylate synthase) that have been used for clinical treatment of cancer, efficient SHMT2‐specific inhibitors are lacking. Therefore, we established a direct system for virtual screening, protein expression, and identification of inhibitors targeting SHMT2. First, 27 compounds qualifying as potential SHMT2 inhibitors were selected for biological activity verification through virtual screening of the 210 thousand compounds registered in the Specs database. Second, these 27 hits were subjected to quick screening by an in vitro non‐competitive kinetic assay of SHMT2 single‐enzyme catalysis. This allowed us to identify three compounds featuring medium‐strength and non‐competitive inhibition of SHMT2: AM‐807/42004511 (IC50 = 14.52 ± 4.1665 μM), AM‐807/40675298 (IC50 = 12.74 ± 5.8991 μM), and AM‐807/42004633 (IC50 = 9.43 ± 0.5646 μM). We describe a quick screening method for the identification of inhibitors targeting SHMT2, providing a basis for subsequent identification and screening of new inhibitors. [ABSTRACT FROM AUTHOR]

Single nucleotide polymorphisms and pre‐ and peri‐conception folic acid (FA) supplementation and dietary data were used to identify one‐carbon metabolic factors associated with pregnancy outcomes in 3196 nulliparous women. In 325 participants, we also measured circulating folate, vitamin B12 and homocysteine. Pregnancy outcomes included preeclampsia (PE), gestational hypertension (GHT), small for gestational age (SGA), spontaneous preterm birth (sPTB) and gestational diabetes mellitus (GDM). Study findings show that maternal genotype MTHFR A1298C(CC) was associated with increased risk for PE, whereas TCN2 C766G(GG) had a reduced risk for sPTB. Paternal MTHFR A1298C(CC) and MTHFD1 G1958A(AA) genotypes were associated with reduced risk for sPTB, whereas MTHFR C677T(CT) genotype had an increased risk for GHT. FA supplementation was associated with higher serum folate and vitamin B12 concentrations, reduced uterine artery resistance index and increased birth weight. Women who supplemented with <800 μg daily FA at 15‐week gestation had a higher incidence of PE (10.3%) compared with women who did not supplement (6.1%) or who supplemented with ≥800 μg (5.4%) (P <.0001). Higher serum folate levels were found in women who later developed GDM compared with women with uncomplicated pregnancies (Mean ± SD: 37.6 ± 8 nmol L−1 vs. 31.9 ± 11.2, P =.007). Fast food consumption was associated with increased risk for developing GDM, whereas low consumption of green leafy vegetables and fruit were independent risk factors for SGA and GDM and sPTB and SGA, respectively. In conclusion, maternal and paternal genotypes, together with maternal circulating folate and homocysteine concentrations, and pre‐ and early‐pregnancy dietary factors, are independent risk factors for pregnancy complications. [ABSTRACT FROM AUTHOR]

Purpose: To investigate impact of the one‐carbon metabolism (OCM) on oocyte maturity and embryo development. Methods: This prospective study analyzed 18 women who agreed to participate. We measured the OCM biomarkers' concentrations including Vitamin B12 (VB12), folic acid (FA), and homocysteine (Hcy) in serum and follicular fluid (FF), and assessed their correlation. We also evaluated the influence of such OCM biomarker concentrations in mono‐FF on oocyte maturation, fertilization, embryo quality, and consequent pregnancy after embryo transfers. Results: All biomarkers showed a high concentration variability in different follicles of each woman, but their mean levels correlated with the serum levels. Among the 106 collected oocytes, 92 were mature, 59 were fertilized, and 16 yielded good‐quality embryos. We performed 26 single embryo transfers, and 7 patients achieved clinical pregnancies. VB12 concentration (FF) was significantly lower in fertilized than unfertilized oocytes by univariate analysis. In multivariate logistic analysis, a significant correlation was found between FA concentration (FF) <14.25 ng/mL and good‐quality embryos and between Hcy concentration (FF) <4.9 nmol/mL and clinical pregnancy. Conclusion: OCM in FF may affect fertilization, embryo quality, and clinical pregnancy. [ABSTRACT FROM AUTHOR]

Background: Depression is a heterogeneous disorder and is thought to develop as a result of complex interactions between genetic and environmental factors. One‐carbon metabolism that includes vitamin B12, folic acid, and homocysteine has been investigated in psychiatric disorders like depression. In recent years, vitamin D has also been considered to contribute to psychiatric disorders. In this study, serum levels of folate, vitamin B12, and homocysteine related to one‐carbon metabolism and vitamin D were investigated in children and adolescents with depression and to assess possible roles in depression pathogenesis. Methods: The study included 89 children and adolescents with depression (69 female, 20 male; mean age ± SD = 15.08 ± 1.46) and 43 control subjects (31 female, 12 male; mean age ± SD = 14.41 ± 2.32) without any DSM‐5 diagnosis. Each subject completed a sociodemographic form, Childhood Depression Inventory, State‐Trait Anxiety Inventory 1‐2 and measured serum folate, vitamin B12, homocysteine, and 25‐OH vitamin D levels. Results: There was no significant difference between the groups in terms of folate levels (p =.052). In the patient group, the vitamin B12 and vitamin D levels were clearly low (p values for both levels were <.001), while homocysteine levels were found to be remarkably high (p <.001). In addition, there was a negative correlation between depression severity and vitamin B12 and vitamin D, while a positive correlation was found with homocysteine. Conclusions: The results of the study show that vitamin B12 deficiency or insufficiency and elevated homocysteine may contribute to the etiopathogenesis of depression. Additionally, it was shown that lower vitamin D levels may be associated with depression. Key Practitioner Message: Depression of children and adolescents is associated with the interaction of environmental and genetic factors.Homocysteine, vitamin B12, and folate related to one‐carbon metabolism are associated with psychiatric disorders such as depression in adulthood.Vitamin D also contributes to psychiatric disorders pathogenesis.There are not enough studies in the literature about these parameters in children with depression.Low vitamin B12 and vitamin D levels and increased homocysteine levels may play a role in the pathogenesis of depression in children and adolescents.Investigation of vitamin B12, folate, homocysteine, and vitamin D levels are recommended in children and adolescents with depression. [ABSTRACT FROM AUTHOR]

The fungus Magnaporthe oryzae causes blast, the most devastating disease of cultivated rice. After penetrating the leaf cuticle, M. oryzae grows as a biotroph in intimate contact with living rice epidermal cells before necrotic lesions develop. Biotrophic growth requires maintaining metabolic homeostasis while suppressing plant defenses, but the metabolic connections and requirements involved are largely unknown. Here, we characterized the M. oryzae nucleoside diphosphate kinase‐encoding gene NDK1 and discovered it was essential for facilitating biotrophic growth by suppressing the host oxidative burst—the first line of plant defense. NDK enzymes reversibly transfer phosphate groups from tri‐ to diphosphate nucleosides. Correspondingly, intracellular nucleotide pools were perturbed in M. oryzae strains lacking NDK1 through targeted gene deletion, compared to WT. This affected metabolic homeostasis: TCA, purine and pyrimidine intermediates, and oxidized NADP+, accumulated in Δndk1. cAMP and glutathione were depleted. ROS accumulated in Δndk1 hyphae. Functional appressoria developed on rice leaf sheath surfaces, but Δndk1 invasive hyphal growth was restricted and redox homeostasis was perturbed, resulting in unsuppressed host oxidative bursts that triggered immunity. We conclude Ndk1 modulates intracellular nucleotide pools to maintain redox balance via metabolic homeostasis, thus quenching the host oxidative burst and suppressing rice innate immunity during biotrophy. [ABSTRACT FROM AUTHOR]

Summary: Metabolites are the essential substrates for epigenetic modification enzymes to write or erase the epigenetic blueprint in cells. Hence, the availability of nutrients and activity of metabolic pathways strongly influence the enzymatic function. Recent studies have shed light on the choreography between metabolome and epigenome in the control of immune cell differentiation and function, with a major focus on histone modifications. Yet, despite its importance in gene regulation, DNA methylation and its relationship with metabolism is relatively unclear. In this review, we will describe how the metabolic flux can influence epigenetic networks in innate and adaptive immune cells, with a focus on the DNA methylation cycle and the metabolites S‐adenosylmethionine and α‐ketoglutarate. Future directions will be discussed for this rapidly emerging field. [ABSTRACT FROM AUTHOR]

Deficient intake of micronutrients involved in one‐carbon metabolism (eg, choline, methionine, vitamin B12 and folic acid) leads to hepatocellular carcinoma (HCC) development in rodents, but is under‐investigated in humans. We investigated the association between one‐carbon metabolism‐related micronutrient intake and HCC risk in a prospective cohort of 494 860 participants with 16 years of follow‐up in the NIH‐AARP study. Dietary intakes and supplement use were ascertained at baseline using a food‐frequency questionnaire. Total intake (diet plus supplements) of the following one‐carbon metabolism‐related micronutrients were calculated: folate, methionine and vitamins B2 (riboflavin), B3 (niacin), B6 and B12. These micronutrients were examined both individually and simultaneously, with adjustment for covariates. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over the 16‐year follow‐up period, 647 incident HCC cases were diagnosed. When examined individually, higher total vitamin B3 intake was associated with a lower HCC risk (HRQ5 vs Q1 = 0.60; 95% CI = 0.42‐0.85; Ptrend =.008), and the association remained significant when all six micronutrients were examined simultaneously (HRQ5 vs Q1 = 0.32; 95% CI = 0.18‐0.55; Ptrend <.0001). Among participants with >3 years of follow‐up, higher total vitamin B3 intake was again associated with lower risk (HRQ5 vs Q1 = 0.37; 95% CI = 0.20‐0.68; Ptrend =.001), whereas higher total vitamin B6 intake was associated with higher risk (HRQ5 vs Q1 = 2.04; 95% CI = 1.02‐4.07; Ptrend =.04). Restricted cubic spline analyses showed a dose‐response inverse association between total vitamin B3 intake and HCC risk, and dose‐response positive association between total vitamin B6 intake and HCC risk. The study suggests that higher vitamin B3 intake is associated with lower HCC risk, whereas higher vitamin B6 intake is associated with increased risk. What's new? Dietary micronutrients such as methionine and B vitamins are critical for DNA methylation, owing to methyl groups derived via one‐carbon metabolism. In the liver, deficiency of these methyl donors leads to hypomethylation and altered gene expression, potentially fueling hepatic tumorigenesis. Here, comprehensive investigation of one‐carbon metabolism‐related micronutrient intake and risk of hepatocellular carcinoma (HCC) shows that relatively high vitamin B3 intake is associated with reduced HCC risk. By comparison, elevated vitamin B6 intake was linked to increased HCC risk. The findings suggest that dietary modifications emphasizing healthy vitamin B3 intake while limiting vitamin B6 levels could enhance HCC prevention strategies. [ABSTRACT FROM AUTHOR]

Fatty liver disease is increasing along with the prevalence of obesity and type‐2 diabetes. Hepatic fibrosis is a major health complication for which there are no efficacious treatment options available. A better understanding of the fundamental mechanisms that contribute to the accumulation of fibrosis is needed. Glycine‐N‐methyltransferase (GNMT) is a critical enzyme in one‐carbon metabolism that serves to regulate methylation and remethylation reactions. GNMT knockout (GNMT‐/‐) mice display spontaneous hepatic fibrosis and later develop hepatocellular carcinoma. Previous literature supports the idea that hypermethylation as a consequence of GNMT deletion contributes to the hepatic phenotype observed. However, limited metabolomic information is available and the underlying mechanisms that contribute to hepatic fibrogenesis in GNMT‐/‐ mice are still incomplete. Therefore, our goals were to use dietary intervention to determine whether increased lipid load exacerbates steatosis and hepatic fibrosis in this model and to employ both targeted and untargeted metabolomics to further understand the metabolic consequences of GNMT deletion. We find that GNMT mice fed high‐fat diet do not accumulate more lipid or fibrosis in the liver and are in fact resistant to weight gain. Metabolomics analysis confirmed that pan‐hypermethylation occurs in GNMT mice resulting in a depletion of nicotinamide intermediate metabolites. Further, there is a disruption in tryptophan catabolism that prevents adequate immune cell activation in the liver. The chronic cellular damage cannot be appropriately cleared due to a lack of immune checkpoint activation. This mouse model is an excellent example of how a disruption in small molecule metabolism can significantly impact immune function. [ABSTRACT FROM AUTHOR]

Maternal obesity during pregnancy can adversely affect adult offspring vascular endothelial function. This study examined whether maternal exercise during pregnancy and lactation mitigates the adverse effects of maternal obesity on offspring vascular endothelial function. Female (C57BL/6N) mice were fed from weaning a control diet (10% kcal fat) or western diet (45% kcal fat) to induce excess adiposity (maternal obesity). After 13 weeks, the female mice were bred and maintained on the diets, with and without access to a running wheel (exercise), throughout breeding, pregnancy, and lactation. Offspring were weaned onto the control or western diet and fed for 13 weeks; male offspring were studied. Maternal exercise prevented the adverse effects of maternal obesity on offspring vascular endothelial function. However, this was dependent on offspring diet and the positive effect of maternal exercise was only observed in offspring fed the western diet. This was accompanied by alterations in aorta and liver one‐carbon metabolism, suggesting a role for these pathways in the improved endothelial function observed in the offspring. Obesity and exercise had no effect on endothelial function in the dams but did affect aorta and liver one‐carbon metabolism, suggesting the phenotype observed in the offspring may be due to obesity and exercise‐induced changes in one‐carbon metabolism in the dams. Our findings demonstrate that maternal exercise prevented vascular dysfunction in male offspring from obese dams and is associated with alterations in one‐carbon metabolism. [ABSTRACT FROM AUTHOR]

Objective: People who are ill with anorexia nervosa (AN) show altered availability of key plasma nutrients. However, little is known about the patterning of alterations that occurs across diverse nutrients during active phases of illness or about the persistence of any such alterations following remission of illness. Method: We compared plasma levels of one‐carbon metabolism nutrients across women with active AN (AN‐Active: n = 53), in remission from AN (AN‐Remitted: n = 40), or who had no eating‐disorder history (NED: n = 36). We also tested associations between body mass index (BMI) changes and changes in pre‐ to posttreatment nutrient levels, and explored the association between nutrient levels, on the one hand, and BMI and eating symptoms, on the other. Choline, betaine, and methionine were analyzed using mass spectrometry. Folate and B12 were analyzed using the AccuBind® ELISA kit. Eating‐disorder symptoms were assessed by interview and self‐report. Results: Compared to NED individuals, AN‐Active individuals exhibited significantly elevated B12 and (less‐reliably) betaine. In AN‐Active individuals, lower BMI was associated with higher B12. Discussion The observed alterations run contrary to the intuition that plasma nutrient levels should be directly responsive to nutritional status and suggest, instead, the existence of compensatory adaptations to malnutrition in individuals with active AN. Further study is required to clarify mechanisms that underlie such effects. [ABSTRACT FROM AUTHOR]

We and others have reported associations between B vitamins principally involved in one‐carbon metabolism and increased lung cancer risk; however, results for women have been inconsistent. Here we report on the association of supplemental vitamins B6, folic acid and B12 intake and lung cancer risk using data from the Women's Health Initiative (WHI) study of postmenopausal women. Between 1993 and 1998, 161,808 women were recruited to participate in the WHI at 40 clinical centers in the US. After exclusions, 159,232 women were available for analysis and followed prospectively for an average of 18.3 years. Among them, 3,836 incident lung cancer cases were diagnosed. At baseline, supplemental B vitamins from multivitamins, vitamin mixtures and individual supplements were assessed. Adjusted Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between supplemental B vitamin intake and lung cancer risk. Relative to no intake, women who took ≥50 mg/day of vitamin B6 had 16% (HR 0.84, 95% CI: 0.71–0.99) reduced lung cancer risk. Associations did not differ significantly by smoking status or lung cancer histology. Intakes of folic acid and vitamin B12 were not associated with risk. There is a need for replication of our findings from other large, prospective studies with similar high‐quality measurement of supplement intakes before any recommendations can be made at present on B6 supplementation for lung cancer prevention in women. What's new? Although the association between dietary intakes of B vitamins and lung cancer risk has been investigated, very few studies have examined the role of B vitamins from supplemental sources, especially in women. Based on data from the Women's Health Initiative prospective cohort of postmenopausal women, this study is thus far the largest and best powered to examine associations of B vitamins intake from dietary supplements with lung cancer risk in women. Although the findings suggest a 16% reduced lung cancer risk associated with ≥50 mg/d of vitamin B6 (over 30 times the Recommended Dietary Allowance), this work requires replication. [ABSTRACT FROM AUTHOR]

Summary: The multienzyme glycine cleavage system (GCS) converts glycine and tetrahydrofolate to the one‐carbon compound 5,10‐methylenetetrahydrofolate, which is of vital importance for most if not all organisms. Photorespiring plant mitochondria contain very high levels of GCS proteins organised as a fragile glycine decarboxylase complex (GDC). The aim of this study is to provide mass spectrometry‐based stoichiometric data for the plant leaf GDC and examine whether complex formation could be a general property of the GCS in photosynthesizing organisms. The molar ratios of the leaf GDC component proteins are 1L2‐4P2‐8T‐26H and 1L2‐4P2‐8T‐20H for pea and Arabidopsis, respectively, as determined by mass spectrometry. The minimum mass of the plant leaf GDC ranges from 1550 to 1650 kDa, which is larger than previously assumed. The Arabidopsis GDC contains four times more of the isoforms GCS‐P1 and GCS‐L1 in comparison with GCS‐P2 and GCS‐L2, respectively, whereas the H‐isoproteins GCS‐H1 and GCS‐H3 are fully redundant as indicated by their about equal amounts. Isoform GCS‐H2 is not present in leaf mitochondria. In the cyanobacterium Synechocystis sp. PCC 6803, GCS proteins concentrations are low but above the complex formation threshold reported for pea leaf GDC. Indeed, formation of a cyanobacterial GDC from the individual recombinant GCS proteins in vitro could be demonstrated. Presence and metabolic significance of a Synechocystis GDC in vivo remain to be examined but could involve multimers of the GCS H‐protein that dynamically crosslink the three GCS enzyme proteins, facilitating glycine metabolism by the formation of multienzyme metabolic complexes. Data are available via ProteomeXchange with identifier PXD018211. Significance Statement: This work provides first mass spectrometry‐based stoichiometric data for glycine decarboxylase complexes from two plant species in comparison with a cyanobacterial glycine cleavage system and examines whether complex formation could be a general property of this important ubiquitous multienzyme system. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidence suggests that breastfeeding exclusivity and duration are positively associated with child cognition. This study investigated whether DNA methylation, an epigenetic mechanism modified by nutrient intake, may contribute to the link between breastfeeding and child cognition. The aim was to quantify the relationship between global DNA methylation and cognition and behavior at 4 years of age. Methods: Child behavior and cognition were measured at age 4 years using the Wechsler Preschool and Primary Scale of Intelligence, third version (WPPSI‐III), and Child Behavior Checklist (CBC). Global DNA methylation (%5‐methylcytosines (%5mC)) was measured in buccal cells at age 4 years, using an enzyme‐linked immunosorbent assay (ELISA) commercial kit. Linear regression models were used to quantify the statistical relationships. Results: Data were collected from 73 children recruited from the Women and Their Children's Health (WATCH) study. No statistically significant associations were found between global DNA methylation levels and child cognition or behavior (p >.05), though the estimates of effect were consistently negative. Global DNA methylation levels in males were significantly higher than in females (median %5mC: 1.82 vs. 1.03, males and females, respectively, (p <.05)). Conclusion: No association was found between global DNA methylation and child cognition and behavior; however given the small sample, this study should be pooled with other cohorts in future meta‐analyses. [ABSTRACT FROM AUTHOR]

Feeding plant‐based diet through smoltification of Atlantic salmon requires verification of the optimal level of 1C nutrients. Here, we fed Atlantic salmon plant‐based diets containing three different surplus amounts of the 1C nutrients; methionine, cobalamin (vitamin B12), pyridoxine (vitamin B6) and folic acid during 6 weeks in fresh water, through smoltification, followed by 3 months on‐growing period in salt water. The three diets were fed to fish dispersed in triplicate tanks throughout the experiment. Mean start body weight was 32 g. Dietary methionine levels in the diets were 6.7, 9.2 and 11.7 g/kg. Dietary B6 was 6.75, 8.45 and 11 mg/kg. Cobalamin was 0.16, 0.18 and 0.20 mg/kg. While dietary folic acid was 2.9, 4.8 and 6.3 mg/kg, diets are referred to as low, medium and high 1C diet. All other amino acids were similar between diets. The results showed no differences in growth or feed utilization in the fresh water period, but following the on‐growing salt water period, differences between diets occurred. The fish fed the medium 1C diet showed better growth, as compared to fish fed the low or high 1C diet (p =.009). The medium 1C fed fish showed a relative lower liver weight compared with fish fed low or high 1C diet (p =.025). Condition factor was better in fish fed the medium and high 1C diet as compared to those fed the low 1C diet (p =.0006). As expected, free methionine in liver, plasma and muscle increased by dietary methionine inclusion. Surplus vitamins only had minor effect on tissue concentrations. Based on these findings, we conclude that the micronutrient and methionine level presented in the medium 1C diet improved the growth, liver size and condition factor; however, more research is needed to evaluate the optimal requirement level for each of the 1C nutrients. [ABSTRACT FROM AUTHOR]

Trisomy 21 causes Down syndrome (DS), the most common human genetic disorder and the leading genetic cause of intellectual disability. The alteration of one‐carbon metabolism was described as the possible metabolic cause of the intellectual disability development in subjects with DS. One of the biochemical pathways involved in the one‐carbon group transfer is the folate cycle. The cytotoxic drug methotrexate (MTX) is a folic acid (FA) analogue which inhibits the activity of dihydrofolate reductase enzyme involved in the one‐carbon metabolic cycle. Trisomy 21 cells are more sensitive to the MTX effect than euploid cells, and in 1986 Jérôme Lejeune and Coll. demonstrated that MTX was twice as toxic in trisomy 21 lymphocytes than in control cells. In the present work, the rescue effect on MTX toxicity mediated by FA and some of its derivatives, tetrahydrofolate (THF), 5‐formyl‐THF, and 5‐methyl‐THF, in both normal and trisomy 21 skin fibroblast cells, was evaluated. A statistically significant rescue effect was obtained by 5‐formyl‐THF, 5‐methyl‐THF, and their combination, administered together with MTX. In conclusion, trisomy 21 fibroblast cell lines showed a good response to the rescue effects of 5‐formyl‐THF and 5‐methyl‐THF on the MTX toxicity almost as normal cell lines. [ABSTRACT FROM AUTHOR]

Vitamin B12 (cobalamin, Cbl) is a nutrient essential to human health. Due to its complex structure and dual cofactor forms, Cbl undergoes a complicated series of absorptive and processing steps before serving as cofactor for the enzymes methylmalonyl‐CoA mutase and methionine synthase. Methylmalonyl‐CoA mutase is required for the catabolism of certain (branched‐chain) amino acids into an anaplerotic substrate in the mitochondrion, and dysfunction of the enzyme itself or in production of its cofactor adenosyl‐Cbl result in an inability to successfully undergo protein catabolism with concomitant mitochondrial energy disruption. Methionine synthase catalyzes the methyl‐Cbl dependent (re)methylation of homocysteine to methionine within the methionine cycle; a reaction required to produce this essential amino acid and generate S‐adenosylmethionine, the most important cellular methyl‐donor. Disruption of methionine synthase has wide‐ranging implications for all methylation‐dependent reactions, including epigenetic modification, but also for the intracellular folate pathway, since methionine synthase uses 5‐methyltetrahydrofolate as a one‐carbon donor. Folate‐bound one‐carbon units are also required for deoxythymidine monophosphate and de novo purine synthesis; therefore, the flow of single carbon units to each of these pathways must be regulated based on cellular needs. This review provides an overview on Cbl metabolism with a brief description of absorption and intracellular metabolic pathways. It also provides a description of folate‐mediated one‐carbon metabolism and its intersection with Cbl at the methionine cycle. Finally, a summary of recent advances in understanding of how both pathways are regulated is presented. [ABSTRACT FROM AUTHOR]

Nutrients involved in one‐carbon metabolism may play a role in carcinogenesis through DNA replication, repair and methylation mechanisms. Most studies on urothelial cell carcinoma (UCC) have focused on folate. We sought to examine the association between B‐group vitamins and methionine intake and UCC risk, overall and by subtype, and to test whether these associations are different for population subgroups whose nutritional status may be compromised. We followed participants in the Melbourne Collaborative Cohort Study (N = 41,513) for over 20 years and observed 500 UCC cases (89% originating in the bladder; superficial: 279, invasive: 221). Energy‐adjusted dietary intakes of B vitamins (B1, B2, B3, B5, B6, B8, B9 and B12) and methionine were estimated from a 121‐item food frequency questionnaire administered at baseline (1990–1994), using the residuals method. We used Cox regression models to compute hazard ratios (HRs) of UCC risk per standard deviation (SD) of log‐transformed nutrient intakes and 95% confidence intervals, adjusted for potential confounders. We investigated associations by tumor subtype, and tested interactions with sex, country of birth, smoking and alcohol drinking. The risk of UCC appeared not to be associated with intake of B‐group vitamins or methionine, and findings were consistent across tumor subtypes and across demographic and lifestyle characteristics of the participants. A potential interaction between vitamin B1 and alcohol drinking was observed (all participants: HR per 1 SD = 0.99 (0.91–1.09), never drinkers: HR = 0.81 (0.69–0.97), p‐interaction = 0.02), which needs to be confirmed by other studies. Our findings do not indicate that dietary intake of nutrients involved in one‐carbon metabolism are associated with UCC risk. [ABSTRACT FROM AUTHOR]

Abstract: Folate‐mediated one‐carbon metabolism (FOCM) is a key pathway essential for nucleotide synthesis, DNA methylation, and repair. This pathway is a critical target for 5‐fluorouracil (5‐FU), which is predominantly used for colorectal cancer (CRC) treatment. A comprehensive assessment of polymorphisms in FOCM‐related genes and their association with prognosis has not yet been performed. Within 1,739 CRC cases aged ≥30 years diagnosed from 2003 to 2007 (DACHS study), we investigated 397 single nucleotide polymorphisms (SNPs) and 50 candidates in 48 FOCM‐related genes for associations with overall‐ (OS) and disease‐free survival (DFS) using multiple Cox regression (adjusted for age, sex, stage, grade, BMI, and alcohol). We investigated effect modification by 5‐FU‐based chemotherapy and assessed pathway‐specific effects. Correction for multiple testing was performed using false discovery rates (FDR). After a median follow‐up time of 5.0 years, 585 patients were deceased. For one candidate SNP in MTHFR and two in TYMS, we observed significant inverse associations with OS (MTHFR: rs1801133, C677T: HRhet = 0.81, 95% CI: 0.67–0.97; TYMS: rs1001761: HRhet = 0.82, 95% CI: 0.68–0.99 and rs2847149: HRhet = 0.82, 95% CI: 0.68–0.99). After FDR correction, one polymorphism in paraoxonase 1 (PON1; rs3917538) was significantly associated with OS (HRhet = 1.28, 95% CI: 1.07–1.53; HRhzv = 2.02, 95% CI:1.46–2.80; HRlogAdd = 1.31, pFDR = 0.01). Adjusted pathway analyses showed significant associations for pyrimidine biosynthesis (P = 0.04) and fluorouracil drug metabolism (P < 0.01) with significant gene–chemotherapy interactions, including PON1 rs3917538. This study supports the concept that FOCM‐related genes could be associated with CRC survival and may modify effects of 5‐FU‐based chemotherapy in genes in pyrimidine and fluorouracil metabolism, which are relevant targets for therapeutic response and prognosis in CRC. These results require confirmation in additional clinical studies. [ABSTRACT FROM AUTHOR]

Abstract: Formaldehyde (FA) is a common environmental toxin that is also produced naturally in the body through a wide range of metabolic and epigenetic processes, motivating the development of new technologies to monitor this reactive carbonyl species (RCS) in living systems. Herein, we report a pair of first‐generation chemiluminescent probes for selective formaldehyde detection. Caging phenoxy‐dioxetane scaffolds bearing different electron‐withdrawing groups with a general 2‐aza‐Cope reactive formaldehyde trigger provides chemiluminescent formaldehyde probes 540 and 700 (CFAP540 and CFAP700) for visible and near‐IR detection of FA in living cells and mice, respectively. In particular, CFAP700 is capable of visualizing FA release derived from endogenous folate metabolism, providing a starting point for the use of CFAPs and related chemical tools to probe FA physiology and pathology, as well as for the development of a broader palette of chemiluminescent activity‐based sensing (ABS) probes that can be employed from in vitro biochemical to cell to animal models. [ABSTRACT FROM AUTHOR]

Previous studies have found associations between one-carbon metabolism nutrients and risk of several cancers, but little is known regarding upper gastrointestinal tract (UGI) cancer. We analyzed prediagnostic serum concentrations of several one-carbon metabolism nutrients (vitamin B12, folate, vitamin B6, riboflavin and homocysteine) in a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of male smokers, which was undertaken in Finland between 1985 and 1988. We conducted a nested case-control study including 127 noncardia gastric adenocarcinoma (NCGA), 41 esophagogastric junctional adenocarcinoma and 60 esophageal squamous cell carcinoma incident cases identified within ATBC. Controls were matched to cases on age, date of serum collection and follow-up time. One-carbon nutrient concentrations were measured in fasting serum samples collected at baseline (up to 17 years prior to cancer diagnosis). Odds ratios and 95% confidence intervals (CI) were calculated using conditional logistic regression. Lower prediagnostic vitamin B12 concentrations at baseline were associated with a 5.8-fold increased risk of NCGA (95% CI = 2.7-12.6 for lowest compared to highest quartile, p-trend <0.001). This association remained in participants who developed cancer more than 10 years after blood collection, and after restricting the analysis to participants with clinically normal serum vitamin B12 (>300 pmol/L). In contrast, pepsinogen I, a known serologic marker of gastric atrophy, was not associated with NCGA in this population. As vitamin B12 absorption requires intact gastric mucosa to produce acid and intrinsic factor, our findings suggest vitamin B12 as a possible serologic marker for the atrophic gastritis that precedes NCGA, one more strongly associated with subsequent NCGA than pepsinogen. [ABSTRACT FROM AUTHOR]

Folate functions as a coenzyme to transfer one-carbon units that are necessary for deoxythymidylate synthesis, purine synthesis, and various methylation reactions. Ingested folate becomes a functional molecule through intestinal absorption, circulation, transport to cells, and various modifications to its structure. Associations between nutritional folate status and chronic diseases such as cardiovascular disease, cancer, and cognitive dysfunction have been reported. It has also been reported that maternal folate nutritional status is related to the risk of neural tube defects (NTDs) in the offspring. It has also been recommended that folate be consumed in the diet to promote the maintenance of good health. To reduce the risk of NTDs, supplementation with folic acid (a synthetic form of folate) during the periconceptional period has also been recommended. This paper describes the basic features and nutritional role of folate. [ABSTRACT FROM AUTHOR]

Here, we found that formate, an essential one-carbon metabolite, activates superoxide ( [ABSTRACT FROM AUTHOR]

Reduced oxygen availability (hypoxia) leads to increased production of reactive oxygen species ( ROS) by the electron transport chain. Here, I review recent work delineating mechanisms by which hypoxia-inducible factor 1 ( HIF-1) mediates adaptive metabolic responses to hypoxia, including increased flux through the glycolytic pathway and decreased flux through the tricarboxylic acid cycle, in order to decrease mitochondrial ROS production. HIF-1 also mediates increased flux through the serine synthesis pathway and mitochondrial one-carbon (folate cycle) metabolism to increase mitochondrial antioxidant production ( NADPH and glutathione). Dynamic maintenance of ROS homeostasis is required for induction of the breast cancer stem cell phenotype in response to hypoxia or cytotoxic chemotherapy. Consistently, inhibition of phosphoglycerate dehydrogenase, the first enzyme of the serine synthesis pathway, in breast cancer cells impairs tumor initiation, metastasis, and response to cytotoxic chemotherapy. I discuss how these findings have important implications for understanding the logic of the tumor microenvironment and for improving therapeutic responses in women with breast cancer. [ABSTRACT FROM AUTHOR]

Background Valproic acid (VPA) is prescribed therapeutically for multiple conditions, including epilepsy. When taken during pregnancy, VPA is teratogenic, increasing the risk of several birth and developmental defects including neural tube defects (NTDs). The mechanism by which VPA causes NTDs remains controversial and how VPA interacts with folic acid (FA), a vitamin commonly recommended for the prevention of NTDs, remains uncertain. We sought to address both questions by applying untargeted metabolite profiling analysis to neural tube closure (NTC) stage mouse embryos. Methods Pregnant SWV dams on either a 2 ppm or 10 ppm FA supplemented diet were injected with a single dose of VPA on gestational day E8.5. On day E9.5, the mouse embryos were collected and evaluated for NTC status. Liquid chromatography coupled to mass spectrometry metabolomics analysis was performed to compare metabolite profiles of NTD-affected VPA-exposed whole mouse embryos with profiles from embryos that underwent normal NTC from control dams. Results NTDs were observed in all embryos from VPA-treated dams and penetrance was not diminished by dietary FA supplementation. The most profound metabolic perturbations were found in the 10ppm FA VPA-exposed mouse embryos, compared with the other three treatment groups. Affected metabolites included amino acids, nucleobases and related phosphorylated nucleotides, lipids, and carnitines. Conclusion Maternal VPA treatment markedly perturbed purine and pyrimidine metabolism in E9.5 embryos. In combination with a high FA diet, VPA treatment resulted in gross metabolic changes, likely caused by a multiplicity of mechanisms, including an apparent disruption of mitochondrial beta-oxidation. Birth Defects Research 109:106-119, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Here, we report that choline and dimethylglycine can stimulate reactive oxygen species ( ROS) production in liver mitochondria. Choline stimulated O2˙−/H2O2 formation at a concentration of 5 μ m. We also observed that Complex II and III inhibitors, atpenin A5 and myxothiazol, collectively induced a 95% decrease in O2˙−/H2O2 production indicating both sites serve as the main sources of ROS during choline oxidation. Dimethylglycine, an intermediate of choline oxidation, was a more effective ROS generator. Rates of production were ~ 43% higher than choline-mediated O2˙−/H2O2 production. The main site for dimethylglycine-mediated ROS production was via reverse electron transfer to Complex I. Our results demonstrate that metabolism of essential metabolites involved in methionine and folic acid biosynthesis can stimulate mitochondrial ROS production. [ABSTRACT FROM AUTHOR]

The sequence of the human genome together with sequence similarity analyses has advanced the discovery of missing steps in the mitochondrial one-carbon metabolism pathway. That together with the revived interest in cancer metabolism has brought the research on one-carbon metabolism back under the spotlight. Here, we present a brief review of recent advances in the field of one-carbon metabolism, with a bias towards its relevance to cell growth and proliferation in human cancers. We will address the requirements of one-carbon metabolism for biosynthesis and the major sources to satisfy that demand. We will also discuss some recent discoveries indicating a role of one-carbon metabolism beyond biosynthesis. We conclude with a concise enumeration of some fundamental questions that remain unanswered. [ABSTRACT FROM AUTHOR]

One-carbon metabolism is a metabolic network that integrates nutrient status from the environment to yield multiple biological functions. The folate and methionine cycles generate S-adenosylmethionine (SAM), which is the universal methyl donor for methylation reactions, including histone and DNA methylation. Histone methylation is a crucial part of the epigenetic code and plays diverse roles in the establishment of chromatin states that mediate the regulation of gene expression. The activities of histone methyltransferases (HMTs) are dependent on intracellular levels of SAM, which fluctuate based on cellular nutrient availability, providing a link between cell metabolism and histone methylation. Here we discuss the biochemical properties of HMTs, their role in gene regulation, and the connection to cellular metabolism. Our emphasis is on understanding the specificity of this intriguing link. [ABSTRACT FROM AUTHOR]

In vivo, as an advanced catalytic strategy, transient non-covalently bound multi-enzyme complexes can be formed to facilitate the relay of substrates, i. e. substrate channeling, between sequential enzymatic reactions and to enhance the throughput of multi-step enzymatic pathways. The human thymidylate synthase and dihydrofolate reductase catalyze two consecutive reactions in the folate metabolism pathway, and experiments have shown that they are very likely to bind in the same multi-enzyme complex in vivo. While reports on the protozoa thymidylate synthasedihydrofolate reductase bifunctional enzyme give substantial evidences of substrate channeling along a surface "electrostatic highway," attention has not been paid to whether the human thymidylate synthase and dihydrofolate reductase, if they are in contact with each other in the multienzyme complex, are capable of substrate channeling employing surface electrostatics. This work utilizes protein-protein docking, electrostatics calculations, and Brownian dynamics to explore the existence and mechanism of the substrate channeling between the human thymidylate synthase and dihydrofolate reductase. The results show that the bound human thymidylate synthase and dihydrofolate reductase are capable of substrate channeling and the formation of the surface "electrostatic highway." The substrate channeling efficiency between the two can be reasonably high and comparable to that of the protozoa. [ABSTRACT FROM AUTHOR]

Maternal intake of dietary methyl-micronutrients (e.g. folate, choline, betaine and vitamin B-12) during pregnancy is essential for normal maternal and fetal methionine metabolism, and is critical for important metabolic processes including those involved in developmental programming. Maternal obesity and nutrient excess during pregnancy influence developmental programming potentially predisposing adult offspring to a variety of chronic health problems. In the present study, we hypothesized that maternal obesity would dysregulate the maternal and fetal methionine cycle. To test this hypothesis, we developed a nulliparous baboon obesity model fed a high fat, high energy diet (HF-HED) prior to and during gestation, and examined methionine cycle biomarkers (e.g., circulating concentrations of homocysteine, methionine, choline, betaine, key amino acids, folate, and vitamin B-12). Animals were group housed allowing full physical activity and social interaction. Maternal prepregnancy percent body fat was 5% in controls and 19% in HF-HED mothers, while fetal weight was 16% lower in offspring of HF-HED mothers at term. Maternal and fetal homocysteine were higher, while maternal and fetal vitamin B-12 and betaine were lower in the HF-HED group. Elevations in circulating maternal folate were evident in the HF-HED group indicating impaired folate metabolism (methyl-trap) as a consequence of maternal vitamin B-12 depletion. Finally, fetal methionine, glycine, serine, and taurine were lower in the HF-HED fetuses. These data show that maternal obesity disturbs the methionine cycle in primate pregnancy, providing a mechanism for the epigenetic changes observed among obese pregnant women and suggesting diagnostic and therapeutic opportunities in human pregnancies complicated by obesity. [ABSTRACT FROM AUTHOR]

Background: Investigations of folate-mediated one-carbon metabolism (FOCM) genes and gene-nutrient interactions with respect to colorectal cancer (CRC) risk are limited to candidate polymorphisms and dietary folate. This study comprehensively investigated associations between genetic variants in FOCM and CRC risk and whether the FOCM nutrient status modified these associations.Methods: Two hundred eighty-eight candidate and tagging single-nucleotide polymorphisms (SNPs) in 30 FOCM genes were genotyped for 821 incident CRC case-control matched pairs in the Women's Health Initiative Observational Study cohort. FOCM biomarkers (red blood cell [RBC] folate, plasma folate, pyridoxal-5'-phosphate [PLP], vitamin B12, and homocysteine) and self-reported alcohol consumption were measured at the baseline. Conditional logistic regression was implemented; effect modification was examined on the basis of known enzyme-nutrient relations.Results: Statistically significant associations were observed between CRC risk and functionally defined candidate SNPs of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1; K134R), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR; P450R), and PR domain containing 2 with ZNF domain (PRDM2; S450N) and a literature candidate SNP of thymidylate synthase (TYMS; g.676789A>T; nominal P < .05). In addition, suggestive associations were noted for tagging SNPs in cystathionine-β-synthase (CBS), dihydrofolate reductase (DHFR), DNA (cytosine-5-)-methyltransferase 3β (DNMT3B), methionine adenosyltransferase I α (MAT1A), MTHFD1, and MTRR (nominal P < .05; adjusted P, not significant). Significant interactions between nutrient biomarkers and candidate polymorphisms were observed for 1) plasma/RBC folate and folate hydrolase 1 (FOLH1), paraoxonase 1 (PON1), transcobalamin II (TCN2), DNMT1, and DNMT3B; 2) plasma PLP and TYMS TS3; 3) plasma B12 and betaine-homocysteine S-methyltransferase 2 (BHMT2); and 4) homocysteine and methylenetetrahydrofolate reductase (MTHFR) and alanyl-transfer RNA synthetase (AARS).Conclusions: Genetic variants in FOCM genes are associated with CRC risk among postmenopausal women. FOCM nutrients continue to emerge as effect modifiers of genetic influences on CRC risk. [ABSTRACT FROM AUTHOR]