L-methionine and the L-type Ca2+ channel agonist BAY K 8644 collaboratively contribute to the reduction of depressive-like behavior in mice.

The L-type Ca2+ channel (LTCC, also known as Cav1,2) is involved in the regulation of key neuronal functions, such as dendritic information integration, cell survival, and neuronal gene expression. Clinical studies have shown an association between L-type calcium channels and the onset of depression, although the precise mechanisms remain unclear. The development of depression results from a combination of environmental and genetic factors. DNA methylation, a significant epigenetic modification, plays a regulatory role in the pathogenesis of psychiatric disorders such as posttraumatic stress disorder (PTSD), depression, and autism. In our study, we observed reduced Dnmt3a expression levels in the hippocampal DG region of mice with LPS-induced depression compared to control mice. The antidepressant Venlafaxine was able to increase Dnmt3a expression levels. Conversely, Bay K 8644, an agonist of the L-type Ca2+ channel, partially ameliorated depression-like behaviors but did not elevate Dnmt3a expression levels. Furthermore, when we manipulated DNA methylation levels during Bay K 8644 intervention in depression-like models, we found that enhancing the expression of Dnmt3a could improve LPS-induced depression/anxiety-like behaviors, while inhibiting DNA methylation exacerbated anxiety-like behaviors, the combined use of BAY K 8644 and L-methionine can better improve depressive-like behavior. These findings indicate that DNA methylation plays a role in the regulation of depression-like behaviors by the L-type Ca2+ channel, and further research is needed to elucidate the interactions between DNA methylation and L-type Ca2+ channels.

Multi-protein assemblies orchestrate co-translational enzymatic processing on the human ribosome.

Nascent chains undergo co-translational enzymatic processing as soon as their N-terminus becomes accessible at the ribosomal polypeptide tunnel exit (PTE). In eukaryotes, N-terminal methionine excision (NME) by Methionine Aminopeptidases (MAP1 and MAP2), and N-terminal acetylation (NTA) by N-Acetyl-Transferase A (NatA), is the most common combination of subsequent modifications carried out on the 80S ribosome. How these enzymatic processes are coordinated in the context of a rapidly translating ribosome has remained elusive. Here, we report two cryo-EM structures of multi-enzyme complexes assembled on vacant human 80S ribosomes, indicating two routes for NME-NTA. Both assemblies form on the 80S independent of nascent chain substrates. Irrespective of the route, NatA occupies a non-intrusive 'distal' binding site on the ribosome which does not interfere with MAP1 or MAP2 binding nor with most other ribosome-associated factors (RAFs). NatA can partake in a coordinated, dynamic assembly with MAP1 through the hydra-like chaperoning function of the abundant Nascent Polypeptide-Associated Complex (NAC). In contrast to MAP1, MAP2 completely covers the PTE and is thus incompatible with NAC and MAP1 recruitment. Together, our data provide the structural framework for the coordinated orchestration of NME and NTA in protein biogenesis.

The Association of the Essential Amino Acids Lysine, Methionine, and Threonine with Clinical Outcomes in Patients at Nutritional Risk: Secondary Analysis of a Randomized Clinical Trial.

Lysine, methionine, and threonine are essential amino acids with vital functions for muscle and connective tissue health, metabolic balance, and the immune system. During illness, the demand for these amino acids typically increases, which puts patients at risk for deficiencies with harmful clinical consequences. In a secondary analysis of the Effect of Early Nutritional Support on Frailty, Functional Outcomes, and Recovery of Malnourished Medical Inpatients Trial (EFFORT), which compared individualized nutritional support to usual care nutrition in patients at nutritional risk, we investigated the prognostic impact of the lysine, methionine, and threonine metabolism. We had complete clinical and amino acid data in 237 patients, 58 of whom reached the primary endpoint of death at 30 days. In a model adjusted for comorbidities, sex, nutritional risk, and trial intervention, low plasma methionine levels were associated with 30-day mortality (adjusted HR 1.98 [95% CI 1.16 to 3.36], p = 0.01) and with a decline in functional status (adjusted OR 2.06 [95% CI 1.06 to 4.01], p = 0.03). The results for lysine and threonine did not show statistically significant differences regarding clinical outcomes. These findings suggest that low levels of methionine may be critical during hospitalization among patients at nutritional risk. Further studies should investigate the effect of supplementation of methionine in this patient group to improve outcomes.

Metabolization of Free and Peptide-Bound Oxidized Methionine Derivatives by Saccharomyces cerevisiae in a Model System.

In the brewing process, methionine is a decisive amino acid for (off-)flavor formation. A significant part of methionine is oxidized to methionine sulfoxide (MetSO) in malt. We hypothesized that MetSO and MetSO2 are metabolized to volatile compounds during yeast fermentation and examined whether the yeast Saccharomyces cerevisiae is able to catabolize l-MetSO and l-MetSO2 in free and dipeptide-bound forms. We also investigated the stability of l-methionine sulfoximine and S-methylmethionine. Cell viability in the presence of the test compounds was at least 90%. Both free and peptide-bound test substances were metabolized by Saccharomyces cerevisiae. l-MetSO was degraded most rapidly as the free amino acid, while l-MetSO2 was degraded most rapidly bound in dipeptides. We observed a different degradation behavior of the (R) and (S) diastereoisomers for l-MetSO and l-methionine sulfoximine. Furthermore, we detected methionol as the only metabolite of MetSO. Methionol sulfoxide was not formed. MetSO2 was not converted to methionol or methionol sulfone but to the respective α-hydroxy acid. We conclude that the reduction of MetSO to methionine proceeds faster than transamination. The occurrence of MetSO or MetSO2 in brewing malt will not lead to the formation of hitherto unknown volatile metabolites of the Ehrlich pathway.

Late-Stage Glycosylation of Peptides by Methionine-Directed ß-C(sp3)-H Functionalization with 1-Iodoglycals.

Using l-methionine (Met) as the endogenous directing group, we developed Pd-catalyzed ß-C(sp3)-H glycosylation of peptides with 1-iodoglycals. A wide range of tri- to hexapeptides containing the Ala-Met motifs underwent Ala C-H glycosylation under the standard conditions to give the glycopeptides smoothly. 15 proteinogenic amino acids (with easily removable protecting groups) were well tolerated. Control experiments indicated that Met acted as a N,S-bidentate directing group and exhibited an effect superior to other amino acid residues such as l-aspartic acid (Asp), l-asparagine (Asn), and S-protected l-cysteine (Cys). In addition, further transformation by HFIP-promoted 1,4-elimination furnished another type of glycopeptide with the 1,3-diene motif, which provides a handle for further derivatization.

Simultaneous determination of total homocysteine, methionine, methylmalonic acid and 2-methylcitric acid in dried blood spots by ultra-performance liquid chromatography-tandem mass spectrometry.

Homocysteine, methionine, methylmalonic acid and 2-methylcitric acid are clinically relevant markers in the methionine, propionate, and cobalamin metabolism. This study aimed to develop and validate an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for simultaneously determining total homocysteine, methionine, methylmalonic acid and 2-methylcitric acid in dried blood spots. Three 3.2 mm discs were punched from each calibrator, quality control, and sample dried blood spot into a 96-well U-plate. Each sample was spiked with internal standards and extracted. Then the supernatant was transferred to another 96-well U-plate. After nitrogen drying, the dried residues were reconstituted, centrifuged, and the resulting supernatant was transferred to another 96-well plate for analysis. The method was performed using UPLC-MS/MS within 3 min, validated according to guidance documents, and applied to 72 samples from confirmed patients with methionine, propionate, and cobalamin metabolism disorders. The UPLC-MS/MS method provided satisfactory separation of the four analytes. The R2 values were ≥ 0.9937 for all analytes. The recoveries ranged from 94.17 to 114.29 %, and the coefficients of variation for intraday and interday precision were 0.19 % to 5.23 % and 1.02 % to 6.89 %, respectively. No significant carry-over was detected for the four analytes, and most of confirmed samples exhibited biomarker patterns characteristic of the relevant disorders. A simple and fast UPLC-MS/MS method was successfully developed, validated, and applied to clinical samples for the simultaneous determination of total homocysteine, methionine, methylmalonic acid, and 2-methylcitric acid in dried blood spots.

Do Microplastics Have Neurological Implications in Relation to Schizophrenia Zebrafish Models? A Brain Immunohistochemistry, Neurotoxicity Assessment, and Oxidative Stress Analysis.

The effects of exposure to environmental pollutants on neurological processes are of increasing concern due to their potential to induce oxidative stress and neurotoxicity. Considering that many industries are currently using different types of plastics as raw materials, packaging, or distribution pipes, microplastics (MPs) have become one of the biggest threats to the environment and human health. These consequences have led to the need to raise the awareness regarding MPs negative neurological effects and implication in neuropsychiatric pathologies, such as schizophrenia. The study aims to use three zebrafish models of schizophrenia obtained by exposure to ketamine (Ket), methionine (Met), and their combination to investigate the effects of MP exposure on various nervous system structures and the possible interactions with oxidative stress. The results showed that MPs can interact with ketamine and methionine, increasing the severity and frequency of optic tectum lesions, while co-exposure (MP+Met+Ket) resulted in attenuated effects. Regarding oxidative status, we found that all exposure formulations led to oxidative stress, changes in antioxidant defense mechanisms, or compensatory responses to oxidative damage. Met exposure induced structural changes such as necrosis and edema, while paradoxically activating periventricular cell proliferation. Taken together, these findings highlight the complex interplay between environmental pollutants and neurotoxicants in modulating neurotoxicity.

Bacteria modulate microalgal aging physiology through the induction of extracellular vesicle production to remove harmful metabolites.

The bloom and bust patterns of microalgae in aquatic systems contribute massively to global biogeochemical cycles. The decline of algal blooms is mainly caused by nutrient limitation resulting in cell death, the arrest of cell division and the aging of surviving cells. Nutrient intake can re-initiate proliferation, but the processes involved are poorly understood. Here we characterize how the bloom-forming diatom Coscinodiscus radiatus recovers from starvation after nutrient influx. Rejuvenation is mediated by extracellular vesicles that shuttle reactive oxygen species, oxylipins and other harmful metabolites out of the old cells, thereby re-enabling their proliferation. By administering nutrient pulses to aged cells and metabolomic monitoring of the response, we show that regulated pathways are centred around the methionine cycle in C. radiatus. Co-incubation experiments show that bacteria mediate aging processes and trigger vesicle production using chemical signalling. This work opens new perspectives on cellular aging and rejuvenation in complex microbial communities.

A methionine-choline-deficient diet induces nonalcoholic steatohepatitis and alters the lipidome, metabolome, and gut microbiome profile in the C57BL/6J mouse.

The methionine-choline-deficient (MCD) diet-induced non-alcoholic steatohepatitis (NASH) in mice is a well-established model. Our study aims to elucidate the factors influencing liver pathology in the MCD mouse model by examining physiological, biochemical, and molecular changes using histology, molecular techniques, and OMICS approaches (lipidomics, metabolomics, and metagenomics). Male C57BL/6J mice were fed a standard chow diet, a methionine-choline-sufficient (MCS) diet, or an MCD diet for 10 weeks. The MCD diet resulted in reduced body weight and fat mass, along with decreased plasma triglyceride, cholesterol, glucose, and insulin levels. However, it notably induced steatosis, inflammation, and alterations in gene expression associated with lipogenesis, inflammation, fibrosis, and the synthesis of apolipoproteins, sphingolipids, ceramides, and carboxylesterases. Lipid analysis revealed significant changes in plasma and tissues: most ceramide non-hydroxy-sphingosine lipids significantly decreased in the liver and plasma but increased in the adipose tissue of MCD diet-fed animals. Oxidized glycerophospholipids mostly increased in the liver but decreased in the adipose tissue of the MCD diet-fed group. The gut microbiome of the MCD diet-fed group showed an increase in Firmicutes and a decrease in Bacteroidetes and Actinobacteria. Metabolomic profiling demonstrated that the MCD diet significantly altered amino acid biosynthesis, metabolism, and nucleic acid metabolism pathways in plasma, liver, fecal, and cecal samples. LC-MS data indicated higher total plasma bile acid intensity and reduced fecal glycohyodeoxycholic acid intensity in the MCD diet group. This study demonstrates that although the MCD diet induces hepatic steatosis, the mechanisms underlying NASH in this model differ from those in human NASH pathology.

Alleviating effect of methionine on intestinal mucosal injury induced by heat stress.

Climate change is an increasing concern of stakeholders worldwide. The intestine is severely impacted by the heat stress. This study aimed to investigate the alleviating effects of methionine on the intestinal damage induced by heat stress in mice. The mice were divided into four groups: control group (C), methionine deficiency group (MD), methionine + heat stress group (MH), and methionine deficiency + heat stress group (MDH). Histopathological techniques, PAS-Alcian blue staining, immunohistochemistry method, biochemical quantification method, ELISA, and micro method were used to study the changes in the intestinal mucosal morphology, the number of goblet cells, the expression of tight junction proteins, the peroxide product contents and antioxidant enzyme activities, the intestinal mucosal damage, the content of immunoglobulins and HSP70, the activity of Na+/K+-ATPase. The results showed that methionine can improve intestinal mucosal morphology (increase the villi height, V/C value, and muscle layer thickness, decrease crypt depth), increase the expression of tight junction proteins (Claudin-1, Occludin, ZO-1) and the content of DAO, decrease the content of intestinal mucosa damage markers (ET, FABP2) and peroxidation products (MDA), increase the activity of antioxidant enzymes (GR, GSH-Px, SOD), the number of goblet cells, the contents of immunoglobulins (sIgA, IgA, IgG, IgM) and stress protein (HSP70), and the activity of Na+/K+-ATPase. It is suggested that methionine can alleviate intestinal damage in heat-stressed mice.

Investigation of guanidino acetic acid and rumen-protected methionine induced improvements in longissimus lumborum muscle quality in beef cattle.

This study examined the impact of dietary guanidino acetic acid (GAA) and rumen-protected methionine (RPM) on beef quality in Simmental bulls. For 140 days, forty-five bulls (453.43 ± 29.05 kg) were randomly divided into control (CON), 0.1% GAA (GAA), and 0.1% GAA + 0.1% RPM (GAM) groups with 15 bulls in each group and containing 3 pen with 5 bulls in each pen. Significant improvements in eye muscle area, pH48h, redness (a*) value, and crude protein (CP) content of longissimus lumborum (LL) muscles were observed in the GAA and GAM groups (P < 0.05). Conversely, the lightness (L*) value, drip loss, cooking loss, and moisture contents decreased (P < 0.05). Additionally, glutathione (GSH) and glutathione peroxidase (GSH-PX) concentrations of LL muscles in GAM were higher (P < 0.05), while malondialdehyde (MDA) content of LL muscles in GAA and GAM groups were lower (P < 0.05). Polyunsaturated fatty acids (PUFA) profiles were enriched in beef from GAM group (P < 0.05). The addition of GAA and RPM affected the expression of genes in LL muscle, such as HMOX1, EIF4E, SCD5, and NOS2, which are related to hypoxia metabolism, protein synthesis, and unsaturated fatty acid synthesis-related signaling pathways. In addition, GAA and RPM also affected the content of a series of metabolites such as L-tyrosine, L-tryptophan, and PC (O-16:0/0:0) involved in amino acid and lipid metabolism-related signaling pathways. In summary, GAA and RPM can improve the beef quality and its nutritional composition. These changes may be related to changes in gene expression and metabolic pathways related to protein metabolism and lipid metabolism in beef.

Methionine represses gray mold of tomato by keeping nitric oxide at an appropriate level via ethylene synthesis and signal transduction.

Methionine (Met) can inhibit plant diseases caused by phytopathogens. However, the effect of Met on gray mold resulted from Botrytis cinerea in tomato is still unclear. This study showed 5 mM Met alleviated disease development of gray mold, enhanced chitinase (CHI) and ß-1, 3-glucanase (GNS) activities and the expression of SlCHI, SlGNS, SlPR1 and SlNPR1 in tomatoes, rather than inhibited the growth of B. cinerea directly. Moreover, ethylene biosynthesis and signal transduction before pathogen inoculating were induced by 5 mM Met. Interestingly, Met reduced the nitrosylation levels of ACS4 and ACO6, enhanced the activities of nitric oxide synthase, nitrite reductase (NR) and S-nitrosoglutathione reductase (GSNOR) and the expression of SlNR and SlGSNOR. Tomatoes treated with aminoethoxyvinylglycine and carboxy-PTIO exhibited lower resistance to B. cinerea. These results indicate 5 mM Met promoted ethylene biosynthesis and signal transduction to facilitate NO synthesis and metabolism, enhancing the resistance of tomatoes to B. cinerea.

Conserved gatekeeper methionine regulates the binding and access of kinase inhibitors to ATP sites of MAP2K1, 4, and 7: Clues for developing selective inhibitors.

Mitogen-activated protein kinase kinases (MAP2Ks) 1, 4, and 7 are potential targets for treating various diseases. Here, we solved the crystal structures of MAP2K1 and MAP2K4 complexed with covalent inhibitor 5Z-7-oxozeaenol (5Z7O). The elucidated structures showed that 5Z7O was non-covalently bound to the ATP binding site of MAP2K4, while it covalently attached to cysteine at the DFG-1 position of the deep ATP site of MAP2K1. In contrast, we previously showed that 5Z7O covalently binds to MAP2K7 via another cysteine on the solvent-accessible edge of the ATP site. Structural analyses and molecular dynamics calculations indicated that the configuration and mobility of conserved gatekeeper methionine located at the central ATP site regulated the binding and access of 5Z7O to the ATP site of MAP2Ks. These structural features provide clues for developing highly potent and selective inhibitors against MAP2Ks. Abbreviations: ATP, adenosine triphosphate; FDA, Food and Drug Administration; MAP2Ks, mitogen-activated protein kinase kinases; MD, molecular dynamics; NSCLC, non-small cell lung cancer; 5Z7O, 5Z-7-oxozeaenol; PDB, protein data bank; RMSD, root-mean-square deviation.

Alterations in one­carbon metabolism and protein synthesis signals due to methionine supplementation and lipopolysaccharide challenge in Holstein fetal liver explants.

One­carbon metabolism (OCM) fueled by methionine (Met), choline, and folic acid is key for embryo development and fetal growth. We investigated effects of lipopolysaccharide (LPS) to induce inflammation in fetal liver tissue with or without Met on components of OCM and protein synthesis activity. Fetal liver harvested at slaughter from six multiparous pregnant Holstein dairy cows (37 ± 6 kg milk/d, 100 ± 3 d gestation) were incubated (0.2 ± 0.02 g) for 4 h at 37 °C with each of the following: ideal profile of amino acids (control; Lysine:Met 2.9:1), control plus LPS (1 µg/mL), increased Met supply (Met, Lys:Met 2.5:1), and Met+LPS. Data were analyzed as a 2 × 2 factorial (PROC MIXED, SAS 9.4). Ratios of mechanistic target of rapamycin (p-mTOR:mTOR) and eukaryotic elongation factor 2 (p-eEF2:eEF2) protein were lowest (P < 0.0 5) with LPS and highest with Met. Tissue amino acid concentrations were lowest (P < 0.0 5) with Met regardless of LPS suggesting enhanced use via mTOR. The marked increase (P = 0.02) in phosphorylation of S6 ribosomal protein (p-RPS6) with LPS suggested a pro-inflammatory response that was partly alleviated with Met+LPS. No effect (P = 0.4 5) on methionine adenosyl transferase 1 A (MAT1A) protein abundance was detected. Activity of betaine-homocysteine S-methyltransferase (BHMT) was greatest with Met, but Met+LPS dampened this effect (P = 0.0 5). Overall, fetal liver responds to inflammatory challenges and Met supply. The latter can stimulate protein synthesis via mTOR and alter some OCM reactions while having a modest anti-inflammatory effect.

Re-routing MAP kinase signaling for penetration peg formation in predator yeasts.

Saccharomycopsis yeasts are natural organic sulfur auxotrophs due to lack of genes required for the uptake and assimilation of sulfate/sulfite. Starvation for methionine induces a shift to a predatory, mycoparasitic life strategy that is unique amongst ascomycetous yeasts. Similar to fungal plant pathogens that separated from Saccharomycopsis more than 400 million years ago, a specialized infection structure called penetration peg is used for prey cell invasion. Penetration pegs are highly enriched with chitin. Here we demonstrate that an ancient and conserved MAP kinase signaling pathway regulates penetration peg formation and successful predation in the predator yeast S. schoenii. Deletion of the MAP kinase gene SsKIL1, a homolog of the Saccharomyces cerevisiae ScKSS1/ScFUS3 and the rice blast Magnaporthe oryzae MoPMK1 genes, as well as deletion of the transcription factor SsSTE12 generate non-pathogenic mutants that fail to form penetration pegs. Comparative global transcriptome analyses using RNAseq indicate loss of the SsKil1-SsSte12-dependent predation response in the mutant strains, while a methionine starvation response is still executed. Within the promoter sequences of genes upregulated during predation we identified a cis-regulatory element similar to the ScSte12 pheromone response element. Our results indicate that, re-routing MAP-kinase signaling by re-wiring Ste12 transcriptional control towards predation specific genes contributed to the parallel evolution of this predacious behaviour in predator yeasts. Consequently, we found that SsSTE12 is dispensable for mating.

First-line Chemotherapy in Combination With Oral Recombinant Methioninase and a Low-methionine Diet for a Stage IV Inoperable Pancreatic-Cancer Patient Resulted in 40% Tumor Reduction and an 86% CA19-9 Biomarker Decrease.

BACKGROUND/AIM: Pancreatic cancer has a very poor prognosis with a 5-year survival rate of less than 5% among patients with distant metastasis, a figure that has not improved over many decades. Only 10 to 20% patients are candidates for curative surgery at presentation due to the aggressive nature and asymptomatic progression of pancreatic cancer. Although first-line chemotherapy, such as FOLFIRINOX and gemcitabine + nab paclitaxel, improved the median survival from 8.5 to 11.1 months, more effective treatments are immediately needed. The aim of the present study was to evaluate the efficacy of methionine restriction with oral rMETase (o-rMETase) and a low-methionine diet combined with first-line chemotherapy on a patient with stage IV metastatic pancreatic cancer. CASE REPORT: A 63-year-old female was diagnosed with metastatic pancreatic cancer in October 2023. The patient started FOLFIRINOX as first-line chemotherapy in combination with methionine restriction, which comprised o-rMETase 250 units twice a day and a low-methionine diet. The patient was monitored using computed tomography and CA19-9 blood tests. After five months from the start of combination therapy, the size of the primary tumor decreased by 40% along with liver-metastasis regression. The CA19-9 blood marker decreased by 86%. The patient sustains a high performance status and continues the combination therapy without severe side effects. CONCLUSION: Methionine restriction consisting of o-rMETase and a low-methionine diet, in combination with first-line chemotherapy, was highly effective in a patient with inoperable stage IV pancreatic cancer.

[11C]Methionine PET vs. [18F]Fluorodeoxyglucose PET Whole-body Imaging to Determine the Extent of Methionine-addiction Compared to Glucose-addiction of Primary and Metastatic Cancer of the Trunk in Patients.

BACKGROUND/AIM: Positron emission tomography (PET) is an important imaging modality, especially in oncology. [18F]fluorodeoxyglucose PET (FDG-PET) is the most used cancer PET imaging. However, since the elevated glucose use by cancers, termed the Warburg effect, is usually only moderate, FDG often does not provide a strong or well-delineated signal. Malignancies have a stronger addiction to methionine, known as the Hoffman effect, and thus [11C]methionine PET (MET-PET) has demonstrated superiority over FDG-PET in gliomas and other brain tumors. Our team is pioneering the use of MET-PET for tumors of the trunk for both better detection of cancer and to determine candidates for methionine-restriction therapy. The present study provides examples of cancers of organs in the trunk in which MET-PET outperforms FDG-PET in detecting and delineating primary and metastatic cancer. PATIENTS AND METHODS: In all cases, MET-PET and FDG-PET were performed simultaneously. An evaluation of the images was conducted by a nuclear medicine physician. RESULTS: Four cases, including prostate, bladder, esophageal, and breast cancer demonstrated the superiority of MET-PET compared to FDG-PET. CONCLUSION: MET-PET can out-perform FDG PET for accurate detection of primary and metastatic cancer in the trunk and can determine the extent of methionine addiction of cancer, thereby indicating whether cancer patients can benefit from methionine-restriction therapy.

Exposure to prenatal excess or imbalanced micronutrients leads to long-term perturbations in one-carbon metabolism, trimethylamine-N-oxide and DNA methylation in Wistar rat offspring.

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.

Sulfur starvation-induced autophagy in Saccharomyces cerevisiae involves SAM-dependent signaling and transcription activator Met4.

Autophagy is a key lysosomal degradative mechanism allowing a prosurvival response to stresses, especially nutrient starvation. Here we investigate the mechanism of autophagy induction in response to sulfur starvation in Saccharomyces cerevisiae. We found that sulfur deprivation leads to rapid and widespread transcriptional induction of autophagy-related (ATG) genes in ways not seen under nitrogen starvation. This distinctive response depends mainly on the transcription activator of sulfur metabolism Met4. Consistently, Met4 is essential for autophagy under sulfur starvation. Depletion of either cysteine, methionine or SAM induces autophagy flux. However, only SAM depletion can trigger strong transcriptional induction of ATG genes and a fully functional autophagic response. Furthermore, combined inactivation of Met4 and Atg1 causes a dramatic decrease in cell survival under sulfur starvation, highlighting the interplay between sulfur metabolism and autophagy to maintain cell viability. Thus, we describe a pathway of sulfur starvation-induced autophagy depending on Met4 and involving SAM as signaling sulfur metabolite.

Effect of amino acids on the formation and distribution of volatile aldehydes in high oleic sunflower oil during frying.

This research aims to assess the effect of amino acids as lipid antioxidants in reducing the formation of volatile aldehydes in frying oil. Methionine, histidine, and glycine at concentrations of 2.5, 5, and 10 mM were added to high oleic sunflower oil (HOSO) to investigate their effects on the distribution and formation of saturated, monounsaturated, and polyunsaturated volatile aldehydes. The results showed that the proportion of saturated volatile aldehydes was greater than that of unsaturated ones; Methionine exhibited the best inhibitory effect, after 12 h of frying, 10 mM methionine reduced the content of saturated volatile aldehydes by 24.21 %, monounsaturated by 52.4 %, and polyunsaturated by 54.73 % compared to the control. Methionine's sulfur-containing side chain was also proven to have strong antioxidant activity. Combined with the results of this study, this can also provide insights for using amino acids as lipid antioxidants.