Search Results (75)

Antibiotic resistance is considered to be one of the most complex health obstacles of our time. Methicillin-resistant Staphylococcus aureus (MRSA) represents a global health challenge due to its broad treatment resistance capacity, resulting in high mortality rates. The shikimate pathway (SP) is responsible for the biosynthesis of chorismate from glycolysis and pentose phosphate pathway intermediates. This pathway plays a crucial role in producing aromatic amino acids, folates, ubiquinone, and other secondary metabolites in bacteria. Notably, SP is absent in humans, which makes it a specific and potential therapeutic target to explore for discovering new antibiotics against MRSA. The present study characterized in vitro and in silico natural products as inhibitors of the shikimate dehydrogenase from methicillin-resistant S. aureus (SaSDH). The results showed that, from the set of compounds studied, phloridzin, rutin, and caffeic acid were the most potent inhibitors of SaSDH, with IC₅₀ values of 140, 160, and 240 µM, respectively. Furthermore, phloridzin showed a mixed-type inhibition mechanism, whilst rutin and caffeic acid showed non-competitive mechanisms. The structural characterization of the SaSDH–inhibitor complex indicated that these compounds interacted with amino acids from the catalytic site and formed stable complexes. In biological activity studies against MRSA, caffeic acid showed an MIC of 2.2 mg/mL. Taken together, these data encourage using these compounds as a starting point for developing new antibiotics based on natural products against MRSA. Full article

Cordycepin, a bioactive adenosine analog, holds promise in pharmaceutical and health product development. However, large-scale production remains constrained by the limitations of natural producers, Cordyceps spp. Herein, we report the reconstruction of the first genome-scale metabolic model (GSMM) for a cordycepin-producing strain of recombinant Aspergillus oryzae. The model, iNR1684, incorporated 1684 genes and 1947 reactions with 93% gene-protein-reaction coverage, which was validated by the experimental biomass composition and growth rate. In silico analyses identified key gene amplification targets in the pentose phosphate and one-carbon metabolism pathways, indicating that folate metabolism is crucial for enhancing cordycepin production. Nutrient optimization simulations revealed that chitosan, D-glucosamine, and L-aspartate preferentially supported cordycepin biosynthesis. Additionally, a carbon-to-nitrogen ratio of 11.6:1 was identified and experimentally validated to maximize production, higher than that reported for Cordyceps militaris. These findings correspond to a faster growth rate, enhanced carbon assimilation, and broader substrate utilization by A. oryzae. This study demonstrates the significant role of GSMM in uncovering rational engineering strategies and provides a quantitative framework for precision fermentation, offering scalable and sustainable solutions for industrial cordycepin production. Full article

The transsulfuration pathway plays a central role in the regulation of sulfur metabolism and contributes to the maintenance of cellular homeostasis. Starting from homocysteine, a sulfur-containing amino acid derived from methionine via the methionine cycle, this metabolic pathway supports the biosynthesis of cysteine and other downstream products, such as taurine, serine, reduced glutathione and the gasotransmitter hydrogen sulfide (H₂S). The most common disruption of this pathway leads to hyperhomocysteinemia (HHcy), a well-known risk factor for the development of cardiometabolic diseases and other pathological conditions. In this context, identifying effective pharmacological strategies is crucial. Based on both preclinical and clinical evidence, this review provides an updated overview on the role of folates in restoring transsulfuration balance in HHcy and explores the potential effects of downstream products (such as serine, taurine, and precursors of glutathione) under HHcy conditions. Finally, it examines the pharmacological properties of H₂S-donors in cultured cells exposed to HHcy and in animal models of HHcy. This summary of the literature offers new perspectives for the treatment of HHcy and the prevention of its associated multiorgan complications. Full article

Gastric intestinal metaplasia (GIM) is a precancerous lesion and the key risk factor in the development of gastric cancer (GC), but early detection and treatment remain challenging. The traditional endoscopic diagnosis of metaplastic lesions is complicated by an increased rate of inappropriateness and false negativity. Although early interventions with H. pylori eradication, as well as endoscopic therapy results, were promising, there is still a significant unmet need to control GIM progression and recurrences. Molecular alterations, such as an increased DNA methylation index, have been identified as a crucial factor in the downregulation of tumor suppressor genes, such as the caudal-type homeobox (CDX2) gene, which regulates epithelial cell proliferation and GIM progression and is associated with treatment failure. CDX2 is downregulated by promoter hypermethylation in the colonic-type epithelium, in which the methylation was correlated with reduced intake of dietary folate sources. Tumor cells alter to dietary methionine sources in the biosynthesis of S-Adenosylmethionine, a universal methyl donor for transmethylation, under the conditions of limited folate and B12 availability. The gut microbiota also exhibited a shift in microbial composition, which could influence the host’s dietary methionine metabolism. Meanwhile, activated oncogenic signaling via the PI3K/Akt/mTORC1/c-MYC pathway could promotes rewiring dietary methionine and cellular proliferation. Tumor methionine dependence is a metabolic phenotype that could be helpful in predictive screening of tumorigenesis and as a target for preventive therapy to enhance precision oncology. This review aimed to discuss the molecular alterations in GIM to shed light on the alteration of methionine metabolism, with insight into new diagnostic and treatment approaches and future research directions. Full article

Tetrahydrofolate (THF), the biologically active form of folate, serves as a crucial carrier of one-carbon units essential for synthesizing cellular components such as amino acids and purine nucleotides in vivo. It also acts as an important precursor for the production of pharmaceuticals, including folinate and L-5-methyltetrahydrofolate (L-5-MTHF). In this study, we developed an efficient enzyme cascade system for the production tetrahydrofolate from folate, incorporating NADPH recycling, and explored its application in the synthesis of L-5-MTHF, a derivative of tetrahydrofolate. To achieve this, we first screened dihydrofolate reductases (DHFRs) from various organisms, identifying SmDHFR from Serratia marcescens as the enzyme with the highest catalytic activity. We then conducted a comparative analysis of formate dehydrogenases (FDHs) from different sources, successfully establishing an NADPH recycling system. To further enhance biocatalytic efficiency, we optimized key reaction parameters, including temperature, pH, enzyme ratio, and substrate concentration. To address the challenge of pH mismatch in dual-enzyme reactions, we employed an enzymatic microenvironment regulation strategy. This involved covalently conjugating SmDHFR with a superfolder green fluorescent protein mutant carrying 30 surface negative charges (−30sfGFP), using the SpyCatcher/SpyTag system. This modification resulted in a 2.16-fold increase in tetrahydrofolate production, achieving a final yield of 4223.4 µM. Finally, we extended the application of this tetrahydrofolate synthesis system to establish an enzyme cascade for L-5-MTHF production with NADH recycling. By incorporating methylenetetrahydrofolate reductase (MTHFR), we successfully produced 389.8 μM of L-5-MTHF from folate and formaldehyde. This work provides a novel and efficient pathway for the biosynthesis of L-5-MTHF and highlights the potential of enzyme cascade systems in the production of tetrahydrofolate-derived compounds. Full article

Water-soluble B vitamins, mainly obtained through dietary intake of fruits, vegetables, grains, and dairy products, act as co-factors in various biochemical processes, including DNA synthesis, repair, methylation, and energy metabolism. These vitamins include B1 (Thiamine), B2 (Riboflavin), B3 (Niacin), B5 (Pantothenic Acid), B6 (Pyridoxine), B7 (Biotin), B9 (Folate), and B12 (Cobalamin). Recent studies have shown that besides their fundamental physiological roles, B vitamins influence oncogenic metabolic pathways, including glycolysis (Warburg effect), mitochondrial function, and nucleotide biosynthesis. Although deficiencies in these vitamins are associated with several complications, emerging evidence suggests that excessive intake of specific B vitamins may also contribute to cancer progression and interfere with therapy due to impaired metabolic and genetic functions. This review discusses the tumor-suppressive and tumor-progressive roles of B vitamins in cancer. It also explores the recent evidence on a comprehensive understanding of the relationship between B vitamin metabolism and cancer progression and underscores the need for further research to determine the optimal balance of B vitamin intake for cancer prevention and therapy. Full article

2′-Deoxythymidine-5′-monophosphate, dTMP, is an essential precursor of thymine, one of the four canonical bases of DNA. In almost all living organisms, dTMP is synthesized de novo by a reductive methylation reaction of 2′-deoxyuridine-5′-monophosphate (dUMP) catalyzed by the thymidylate synthase, where the carbon used for the methylation is derived from methylenetetrahydrofolate (CH2THF). Many microbes, including human pathogens, utilize the flavin-dependent thymidylate synthase encoded by the thyX gene to generate dTMP. The mechanism of action relies on the reduced coenzyme FADH⁻, which acts both as a mediator, facilitating methylene transfer from CH2THF to dUMP, and as a reducing agent. Here, we present for the first-time crystallographic structures of ThyX from Thermotoga maritima in the reduced state alone and in complex with dUMP. ThyX flavin reduction appears to order the active site, favoring a flavin conformation that drastically deviates from that observed in the oxidized enzyme. The structures show that FADH⁻ potentially controls access to the folate site and the conformation of two active site loops, affecting the degree of accessibility of substrate pockets to the solvent. Our results provide the molecular basis for the sequential enzyme mechanism implemented by ThyX during dTMP biosynthesis. Full article

Daldinia carpinicola is a newly identified species of wood-rotting fungi, with substantial aspects of its biology and ecological function yet to be clarified. A Nanopore third-generation sequencer was employed for de novo genome assembly to examine the genetic characteristics. The genome consisted of 35.93 Mb in 46 contigs with a scaffold N50 of 4.384 Mb. Glycoside hydrolases and activities enzymes accounted for a large proportion of the 522 identified carbohydrate-active enzymes (CAZymes), suggesting a strong wood degradation ability. Phylogenetic and comparative analysis revealed a close evolutionary relationship between D. carpinicola and D. bambusicola. D. carpinicola and Hypoxylon fragiforme exhibited significant collinear inter-species genome alignment. Based on transcriptome and metabolomic analyses, D. carpinicola showed a greater ability to utilize sucrose over sawdust as a carbon source, enhancing its growth by activating glycolysis/gluconeogenesis and the citrate cycle. However, compared with sucrose, sawdust as a carbon source activated D. carpinicola amino acid biosynthesis and the production of various secondary metabolites, including diterpenoid, indole alkaloid, folate, porphyrin, and biotin metabolism. The study establishes a theoretical basis for research and applications in biological processes, demonstrating a strategy to modulate the production of secondary metabolites by altering its carbon sources in D. carpinicola. Full article

The incidence of cognitive disorders is increasing globally, with a reported prevalence of over 50 million individuals affected, and current interventions offer limited efficacy. This study investigates the effects of sunflower oil fortified with sunflower lecithin, vitamin D, and vitamin A on scopolamine-induced cognitive dysfunction in mice and explores the underlying mechanisms. The incidence of cognitive disorders, such as Alzheimer’s disease, is increasing yearly, and current interventions offer limited efficacy. Therefore, this research aims to evaluate the cognitive improvement effects of the three added functional factors on mice with learning and memory impairments, along with the associated molecular mechanisms. Behavioral tests, biochemical assays, and real-time quantitative polymerase chain reaction (RT-qPCR) were utilized to examine the intervention effects of these functional factors on scopolamine-induced cognitive impairment in mice. The results revealed that the groups treated with sunflower lecithin and vitamin D significantly enhanced the mice’s exploratory behavior, working memory, and spatial memory, with increases of 1.6 times and 4.5 times, respectively, in the open field and novel object recognition tests (VD group). Additionally, these treatments reduced levels of inflammatory markers and IL-6, increased antioxidant GSH levels, and decreased oxidative stress marker MDA levels, with all effects showing significant differences (p < 0.01). The effects were further enhanced when vitamin A was combined with these treatments. Transcriptomic analysis demonstrated that the intervention groups had markedly improved learning and memory abilities through upregulation of key gene expression levels in the PI3K-AKT signaling pathway, cholinergic pathway, and folate biosynthesis pathway. These findings provide a theoretical basis for the development of nutritionally fortified edible oils with added sunflower lecithin, vitamin D, and vitamin A, which may help prevent and ameliorate cognitive disorders. Full article

2,6-Dichloro-1,4-benzoquinone (2,6-DCBQ) is an emerging chlorinated disinfection byproduct (DBP) in bodies of water. However, this compound poses an unknown toxic effect on cyanobacteria. In this study, the toxicological mechanisms of 2,6-DCBQ in Microcystis aeruginosa (M. aeruginosa) were investigated through physiological and nontargeted metabolomic assessments. The results show that 2,6-DCBQ inhibited the growth of M. aeruginosa, reduced its photosynthetic pigment and protein contents, increased the levels of reactive oxygen species, damaged the antioxidant defense system, and aggravated the cytomembrane. Meanwhile, 2,6-DCBQ stimulated the production and release of microcystin-LR (MC-LR) and altered the transcripts of genes associated with its synthesis (mcyA, mcyD) and transport (mcyH). In addition, nontargeted metabolomics of M. aeruginosa cells exposed to 0.1 mg/L 2,6-DCBQ identified 208 differential metabolites belonging to 10 metabolic pathways and revealed the considerable interference caused by 2,6-DCBQ among ABC transporters, the two-component system, and folate biosynthesis. This study deepens the understanding of the physiological and nontargeted metabolomic responses of M. aeruginosa exposed to 2,6-DCBQ, offers insights into the toxic effect of 2,6-DCBQ on M. aeruginosa, and provides a theoretical basis for the ecological risk assessment of emerging DBPs in accordance with water quality criteria. Full article

Maize (Zea mays) is a critical global crop, serving as a source of food, livestock feed, and industrial raw materials. Climate changes, driven by rising atmospheric carbon dioxide (CO₂) levels, have substantial effects on maize physiology, growth, and nutrient content. This review investigates the impact of elevated CO₂ on maize, with a particular focus on photosynthesis enhancement as it improves water use efficiency (WUE), which can lead to increased biomass production. Despite this, elevated CO₂ results in a decreased concentration of essential nutrients, including nitrogen, phosphorus, potassium, and folate. The reduction in folate, which is vital for both plant development and human nutrition, poses challenges, especially for population heavily reliant on maize. Additionally, biofortification through traditional breeding and genetic engineering is proposed as a strategy to enhance folate level in maize to mitigate nutritional deficiencies. Elevated CO₂ stimulates lignin production, improving stress resistance and carbon sequestration capacity. However, the increase in guaiacyl-rich lignin may negatively affect biomass degradability and efficiency in biofuel production. The findings emphasize the importance of balancing maize’s stress resilience, nutrient profile, and lignin composition to address future climate challenges. This balance is essential for optimizing maize cultivation for food security, biofuel production, and environmental sustainability. Full article

Background: ALDH1L1 plays a crucial role in folate metabolism, regulating the flow of one-carbon groups through the conversion of 10-formyltetrahydrofolate to tetrahydrofolate and CO₂ in a NADP⁺-dependent reaction. The downregulation of ALDH1L1 promotes malignant tumor growth, and silencing of ALDH1L1 is commonly observed in many cancers. In a previous study, Aldh1l1 knockout (KO) mice were found to have an altered liver metabotype, including significant alterations in glycine and serine. Serine and glycine play crucial roles in pathways linked to cancer initiation and progression, including one-carbon metabolism. Objective/Methods: To further investigate the metabolic role of ALDH1L1, an untargeted metabolomic analysis was conducted on the liver and plasma of both KO and wild-type (WT) male and female mice. Since ALDH1L1 affects glycine- and serine-coupled metabolites and metabolic pathways, correlation analyses between liver glycine and serine with other liver or plasma metabolites were performed for both WT and KO mice. Significantly correlated metabolites were input into MetaboAnalyst 5.0 for pathway analysis to uncover metabolic pathways coupled with serine and glycine in the presence or absence of ALDH1L1 expression. Results: This analysis showed substantial alterations in pathways associated with glycine and serine following ALDH1L1 loss, including the amino acid metabolism, antioxidant pathways, fatty acid oxidation, and vitamin B5 metabolism. These results indicate the glycine- and serine-linked metabolic reprogramming following ALDH1L1 loss to support macromolecule biosynthesis and antioxidant defense. Additional research is required to further explore the correlation between specific alterations in these pathways and tumor growth, as well as to identify potential dietary interventions to mitigate the detrimental effects of ALDH1L1 loss. Full article

Preeclampsia (PE) is a serious complication of pregnancy linked to endothelial dysfunction and an imbalance in the gut microbiota. While Akkermansia muciniphila (AKK) has shown promise in alleviating PE symptoms, the use of live bacteria raises safety concerns. This study explored the potential of pasteurized A. muciniphila (pAKK) as a safer alternative for treating PE, focusing on its effects on endothelial function and metabolic regulation. A PE mouse model was induced via the nitric oxide synthase inhibitor L-NAME, followed by treatment with either pAKK or live AKK. Fecal metabolomic profiling was performed via liquid chromatography–tandem mass spectrometry (LC-MS/MS), and in vivo and in vitro experiments were used to assess the effects of pAKK on endothelial function and metabolic pathways. pAKK exhibited therapeutic effects comparable to those of live AKK in improving L-NAME-induced PE-like phenotypes in mice, including enhanced gut barrier function and reduced endotoxemia. pAKK also promoted placental angiogenesis by restoring endothelial nitric oxide synthase (eNOS) activity and nitric oxide (NO) production. The in vitro experiments further confirmed that pAKK alleviated L-NAME-induced NO reduction and endothelial dysfunction in human umbilical vein endothelial cells (HUVECs). Metabolomic analysis revealed that both pAKK and live AKK reversed metabolic disturbances in PE by modulating key metabolites and pathways related to unsaturated fatty acid biosynthesis, folate, and linoleic acid metabolism. As a postbiotic, pAKK may support existing treatments for preeclampsia by improving gut barrier function, restoring endothelial function, and regulating metabolic dysregulation, offering a safer alternative to live bacteria. These findings highlight the potential clinical value of pAKK as an adjunctive therapy in managing PE. Full article

One-carbon (1C) metabolism is a complex network of metabolic reactions closely related to producing 1C units (as methyl groups) and utilizing them for different anabolic processes, including nucleotide synthesis, methylation, protein synthesis, and reductive metabolism. These pathways support the high proliferative rate of cancer cells. While drugs that target 1C metabolism (like methotrexate) have been used for cancer treatment, they often have significant side effects. Therefore, developing new drugs with minimal side effects is necessary for effective cancer treatment. Methionine, glycine, and serine are the main three precursors of 1C metabolism. One-carbon metabolism is vital not only for proliferative cells but also for non-proliferative cells in regulating energy homeostasis and the aging process. Understanding the potential role of 1C metabolism in aging is crucial for advancing our knowledge of neoplastic progression. This review provides a comprehensive understanding of the molecular complexities of 1C metabolism in the context of cancer and aging, paving the way for researchers to explore new avenues for developing advanced therapeutic interventions for cancer. Full article

Cellular metabolism is crucial for various physiological processes, with folate-dependent one-carbon (1C) metabolism playing a pivotal role. Folate, a B vitamin, is a key cofactor in this pathway, supporting DNA synthesis, methylation processes, and antioxidant defenses. In dividing cells, folate facilitates nucleotide biosynthesis, ensuring genomic stability and preventing carcinogenesis. Additionally, in neurodevelopment, folate is essential for neural tube closure and central nervous system formation. Thus, dysregulation of folate metabolism can contribute to pathologies such as cancer, severe birth defects, and neurodegenerative diseases. Epidemiological evidence highlights folate’s impact on disease risk and its potential as a therapeutic target. In cancer, antifolate drugs that inhibit key enzymes of folate-dependent 1C metabolism and strategies targeting folate receptors are current therapeutic options. However, folate’s impact on cancer risk is complex, varying among cancer types and dietary contexts. In neurodegenerative conditions, including Alzheimer’s and Parkinson’s diseases, folate deficiency exacerbates cognitive decline through elevated homocysteine levels, contributing to neuronal damage. Clinical trials of folic acid supplementation show mixed outcomes, underscoring the complexities of its neuroprotective effects. This review integrates current knowledge on folate metabolism in cancer and neurodegeneration, exploring molecular mechanisms, clinical implications, and therapeutic strategies, which can provide crucial information for advancing treatments. Full article