Search Results (56)

Heavy metal contamination is a serious environmental problem worldwide, with substantial negative ecological and economic effects. Serine hydroxymethyltransferase (SHMT) is a key metabolic and photorespiratory enzyme in plant cells, and it is also involved in stress responses. In this study, LcSHMT4 was isolated from sheepgrass (Leymus chinensis (Trin.) Tzvel) after transcriptome sequence analysis. The transcript levels of LcSHMT4 in sheepgrass seedlings increased under Cd and Mn stresses, and subcellular localization analysis in tobacco leaves revealed that its encoded protein localizes at the mitochondria. Transgenic yeast and rice lines overexpressing LcSHMT4 showed increased tolerance to Cd and Mn, compared with that of their controls. In addition, compared with the control, transgenic rice overexpressing LcSHMT4 accumulated more Cd and Mn in brown rice grains. The transcript levels of genes encoding Cd or Mn transporters were increased in the LcSHMT4-overexpressing transgenic rice lines. We speculate that LcSHMT4 may enhance Cd and Mn tolerance by increasing the activities of antioxidant enzymes and the glutathione content and increase heavy metal accumulation by inducing the expression of genes encoding transporters. These results highlight useful genetic resources and provide a theoretical basis for further research on heavy metal tolerance and the phytoremediation of heavy-metal-contaminated soil. Full article

BRCC36, a member of the JAB1/MPN/Mov34 metalloenzymes family, exhibits distinct biochemical characteristics compared to other monomeric deubiquitinating enzymes. To function as a deubiquitinating enzyme, BRCC36 must assemble into a complex with other subunits that specifically cleaves K63-linked polyubiquitin chains. In the cytoplasm, BRCC36 forms the BRISC complex, which plays a crucial role in regulating various signaling pathways through modulating the K63-linked ubiquitination of substrate proteins. The BRISC complex can interact with the cytoplasmic SHMT2, thereby influencing diverse biological processes, including inflammation, mitosis, and hematopoiesis. Within the nucleolus, BRCC36 forms the BRCA1-A complex, which contributes to DNA damage repair. Growing evidence underscores the importance of the ubiquitin system, particularly deubiquitinating enzymes, in the initiation and progression of various diseases. In this review, we first provide a comprehensive overview of the localization, assembly, mutations, and functions of BRCC36 and its associated complexes. We then discuss recent advances in research on BRCC36 across various diseases and explore its potential as a therapeutic target. Full article

Ovarian cancer stem cells (OCSCs) possess stemness; differentiation capacity; and tolerance to oxidative, metabolic, and therapeutic stress, driving recurrence and chemoresistance. Emerging evidence highlights a synergistic interplay between redox homeostasis and amino acid metabolism in maintaining stemness and treatment resistance. This review integrates redox regulation, amino acid metabolic reprogramming, and tumor microenvironment (TME) signals into a unified “redox–amino acid–TME” framework. OCSCs balance signal transduction and antioxidant defense by fine-tuning reactive oxygen species (ROS) levels. Glutamine, serine/glycine, and sulfur amino acid metabolism collectively generate NADPH and glutathione, sustaining the GPX4/TRX antioxidant systems and suppressing ferroptosis. Branched-chain amino acid (BCAA)–mTOR and tryptophan (Trp)–aryl hydrocarbon receptor (AhR) axes couple amino acid sensing to redox signaling, stabilizing the stem-like phenotype. Under TME stress, including hypoxia, acidity, and nutrient competition, exosomes and stromal components reinforce stemness and immune evasion through metabolic and redox crosstalk. Therapeutically, targeting glutamine metabolism (ASCT2/GLS), serine biosynthesis (PHGDH/SHMT), or antioxidant defenses (xCT/GPX4) disrupts reducing power, increases oxidative stress, and enhances the efficacy of chemotherapy, PARP inhibition, and immunotherapy. Biomarkers such as xCT/GPX4 expression, PHGDH levels, Nrf2 activity, and GSH/NADPH ratios may guide patient stratification and response prediction. Overall, understanding the redox–amino acid metabolic network provides a mechanistic basis and translational opportunities for precision metabolic therapies in ovarian cancer. Full article

Reprogramming is a hallmark of cancer, enabling tumour cells to sustain rapid proliferation, resist cell death, and adapt to hostile microenvironments. This review explores the expression profiles of key metabolic enzymes and transporters involved in glucose, amino acid, and lipid metabolism across the five most deadly cancers worldwide: lung, breast, colorectal, liver, and gastric cancers. Through a comparative analysis, we identify consistent upregulation of glycolytic enzymes such as LDHA, PKM2, and HK2, as well as nutrient transporters like GLUT1, ASCT2, and LAT1, which contribute to cancer progression, metastasis, and therapy resistance. The role of enzymes involved in glutaminolysis (e.g., GLS1, GDH), one-carbon metabolism (e.g., SHMT2, PHGDH), and fatty acid synthesis (e.g., FASN, ACLY) is also examined, with emphasis on their emerging relevance as diagnostic, prognostic, and predictive biomarkers. While several metabolic proteins show strong potential for clinical translation, only a few, such as tumour M2-pyruvate kinase (TuM2-PK) and serum LDH measurement, have progressed into clinical use or trials. This review addresses some of the challenges in biomarker development. Ultimately, our findings underscore the importance of metabolic proteins not only as functional drivers of malignancy but also as promising candidates for biomarker discovery. Advancing their clinical implementation could significantly enhance early detection, treatment stratification, and personalized oncology. Full article

Off-white or yellowish shoots are common in tea plants (Camellia sinensis L.), and such albino variations are often accompanied by metabolic reprogramming, including increased contents of amino acids and lower levels of polyphenols. Nonetheless, the molecular mechanisms that underlie these albino variations remain to be fully clarified. Here, we examined the ultrastructural characteristics of novel, naturally occurring, yellowish mutated tea leaves and performed metabolomic analyses on green and albino leaves and stems. Then, transcriptomic analyses were also conducted on green and albino leaves to investigate the mechanistic basis of the albino variation. As expected, the cells of albino tea leaves contained fewer and smaller chloroplasts with disorganized thylakoids and smaller starch granules. Widely targeted metabolomics analysis revealed 561 differentially abundant metabolites between green and albino leaves and stems, but there was little difference between green and albino stems. Then, RNA sequencing of green and albino leaves revealed downregulation of genes associated with light harvesting and photosynthesis, and integration of the metabolomic and transcriptomic results indicated that biosynthesis of aromatic amino acids (AAAs) was strongly upregulated in albino leaves. To gain additional insight into the molecular basis of the increased AAA levels, Oxford Nanopore long-read sequencing was performed on green and albino leaves, which enabled us to identify differences in long non-coding RNAs (lncRNAs) and alternatively spliced transcripts between green and albino leaves. Interestingly, the amino acid biosynthesis genes arogenate dehydratase/prephenate dehydratase (ADT) and serine hydroxymethyltransferase (SHMT) were highlighted in the lncRNA and alternative splicing analyses, and the transcription factor genes PLATZ, B3 Os04g0386900, and LRR RLK At1g56140 showed significant changes in both expression and alternative splicing in albino leaves. Together, our data suggest that biosynthesis of AAAs might be crucial for albino mutations in tea plants and could be coordinated with the regulation of lncRNAs and alternative splicing. This is a complex regulatory network, and further exploration of the extensive metabolic reprogramming of albino tea leaves will be beneficial. Full article

Background: Lycium chinense has been acknowledged for its substantial nutritional benefits. The “Mengqi No.1” variety of L. chinense is known for its high yield and exceptional quality. Methods: We screened twenty dominant endophytic bacterial genera based on OTUs from L. chinense fruits during three developmental stages. Results: Forty-three differential amino acid metabolites were selected from L. chinense fruits. Five endophytic bacteria (Enterococcus, Escherichia-Shigella, Bacteroides, Pseudomonas, and Bacillus) were dominant genera in green fruit (GF, 16–19 days after flowering), color-changing fruit (CCF, 22–25 days after flowering), and red-ripe fruit (RRF, 31–34 days after flowering). Four endophytic bacterial genera (Enterococcus, Bacillus, Pseudomonas, and Rhodanobacter) showed positive correlation with twenty different amino acid metabolites and negative correlation with seven different amino acid metabolites. Conclusions: Five genes (AST1, ltaE1, TAT1, SHMT2, and SHMT3) indicated positive correlation with seventeen different amino acid metabolites and negative correlation with eight different amino acid metabolites. AST1 gene had a major role in regulating arginine biosynthesis (ko00220); ltaE1, SHMT2, and SHMT3 genes were major in regulating glycine, serine, and threonine metabolism (ko00260); and TAT1 gene had a major role in regulating tyrosine metabolism (ko00350). These findings offer insights into the relationship between amino acid synthesis and endophytic bacteria in L. chinense fruits. Full article

Serine hydroxymethyltransferases (SHMTs) are key enzymes in one-carbon metabolism, with vertebrates possessing two paralogs, cytosolic SHMT1 and mitochondrial SHMT2, implicated in nucleotide biosynthesis and glycine metabolism. In this study, we investigate the evolutionary history of animal Shmt genes and analyze the expression patterns of Shmt genes in developing amphioxus (Branchiostoma lanceolatum). Phylogenetic analyses indicate the presence of Shmt1 and Shmt2 orthologs in deuterostomes, spiralians and placozoans, which is consistent with an ancient Shmt gene duplication event predating bilaterian diversification. Gene expression analyses in developing amphioxus show that Shmt2 expression is confined to the somites and absent from neural tissues. In contrast, Shmt1 is broadly expressed across germ layers, but its transcription is restricted to tissues characterized by strong cell proliferation. Notably, Shmt1 expression in the nervous system does not match the distribution of glycinergic neuron populations, implying a negligible role in glycine neurotransmitter synthesis. Instead, the spatial correlation of Shmt1 expression with mitotically active domains suggests a primary function in nucleotide biosynthesis via one-carbon metabolism. These findings indicate that SHMTs predominantly support cell proliferation rather than neurotransmission in amphioxus. Full article

Formononetin is widely used in anti-tumor research, but its poor water solubility leads to low absorption and poor utilization efficiency in vivo, limiting further development. The triphenylphosphine cation was partially attached to the 7-position hydroxyl group of formononetin to specifically target it into the mitochondria of tumor cells to enhance the anti-tumor effect. Detailed structural characterization via ¹H-NMR and ¹³C-NMR analysis confirmed the physical properties and chemical structures of 21 newly synthesized derivatives. The effects of these derivatives on tumor cells were assessed by in vitro and computational methods. MTT results from four tumor cell lines showed that formononetin derivatives containing triphenylphosphine had stronger anti-tumor activity than formononetin and exhibited more cytotoxic effects in cancer cells than in normal cells. In particular, the final product 2c (IC₅₀ = 12.19 ± 1.52 μM) showed more potent anti-tumor activity against A549 cells. It was also superior to formononetin and 5-FU. To identify the potential biological targets, the core-expressed gene SHMT2 in lung cancer mitochondria was screened using network pharmacology technology, and molecular docking analysis confirmed the stable binding of the end products to the amino acid residues of the core genes through the formation of hydrogen bonds and via other interactions. In addition, molecular docking simulations further confirmed that the end product exhibited excellent stability when bound to SHMT2. These results suggest that triphenylphosphine-containing formononetin derivatives are worthy of further exploration in the search for novel drug candidates for the treatment of cancer. Full article

Aedes aegypti mosquitoes are critical vectors of arboviruses, responsible for transmitting pathogens that pose significant public health challenges. Serine hydroxymethyltransferase (SHMT), a key enzyme in one-carbon metabolism, plays a vital role in various biological processes, including DNA synthesis, energy metabolism, and cell proliferation. Although SHMT is expressed at low levels in the midgut of Aedes aegypti, its silencing has been shown to inhibit blood meal digestion. The precise mechanisms by which SHMT regulates midgut physiology in mosquitoes remain poorly understood. In this study, we employed small RNA sequencing and quantitative PCR to identify differentially expressed miRNAs (DEMs) following SHMT downregulation. We focused on a subset of DEMs—miR-2940-5p, miR-2940-3p, miR-2941, and miR-306-5p—to explore their potential biological functions. To further elucidate the molecular mechanisms underlying the miRNA response to SHMT downregulation, we analyzed the expression levels of key genes involved in the miRNA biogenesis pathway. Our results demonstrated that several critical enzymes, including Drosha, Dicer1, and AGO1, exhibited significant changes in expression upon SHMT silencing. This study provides new insights into the molecular mechanisms through which SHMT influences the biological functions and nutritional metabolism of the mosquito midgut. By linking SHMT activity to miRNA regulation, our findings highlight a potential pathway by which SHMT modulates midgut physiology, offering a foundation for future research into mosquito biology and vector control strategies. Full article

The gut–liver axis is essential in animal disease and health. However, the role of the gut–liver axis in the anti-disease mechanism of disease-resistant grass carp (DRGC) derived from the backcross of female gynogenetic grass carp (GGC) and male grass carp (GC) remains unclear. This study analyzed the changes in gut histopathology, fecal intestinal microflora and metabolites, and liver transcriptome between GC and DRGC. Histological analysis revealed significant differences in the gut between DRGC and GC. In addition, microbial community analyses indicated that hybridization induced gut microbiome variation by significantly increasing the proportion of Firmicutes and Bacteroidota in DRGC. Metabolomic data revealed that the hybridization-induced metabolic change was probably characterized by being related to taurocholate and sphinganine in DRGC. Transcriptome analysis suggested that the enhanced disease resistance of DRGC was primarily attributed to immune-related genes (SHMT2, GOT1, ACACA, DLAT, GPIA, TALDO1, G6PD, and FASN). Spearman’s correlation analysis revealed a significant association between the gut microbiota, immune-related genes, and metabolites. Collectively, the gut–liver axis, through the interconnected microbiome–metabolite–gene pathway, may play a crucial role in the mechanism of greater disease resistance in DRGC, offering valuable insights for advancing the grass carp cultivation industry. Full article

To investigate the effect of tannic acid (TA) on the growth, disease resistance, and intestinal health of Chinese soft-shelled turtles, individual turtles were fed with 0 g/kg (CG), 0.5 g/kg, 1 g/kg, 2 g/kg, and 4 g/kg TA diets for 98 days. Afterwards, the turtles’ disease resistance was tested using Aeromonas hydrophila. The results showed that 0.5–4 g/kg of dietary TA increased the growth performance and feed utilization (p < 0.05), with 2.38 g/kg being the optimal level for the specific growth rate (SGR). The addition of 0.5–4 g/kg of TA in diets increased the mucosal fold height and submucosa thickness of the small intestine, which reached a maximum of 2 g/kg. The addition of 0.5–2 g/kg of TA effectively reduced the cumulative mortality that had been induced by A. hydrophila, with the 2 g/kg dosage leading to the lowest mortality. Additionally, 1–4 g/kg of TA improved the T-SOD, CAT, and GSH-Px activities during infection, while 2 g/kg of dietary TA enhanced the richness and diversity of the microbiota, for example, by increasing Actinobacteria but inhibiting Firmicutes. The transcriptome demonstrated that the predominant differentially expressed genes (DEGs) in TA2 were mainly enriched in the PPAR signaling pathway (Acsl5, Apoa2, Apoa5, Fabp1, Fabp2, and Fabp6); in glycine, serine, and threonine metabolism (Chdh, Gatm, and Shmt1); and in steroid biosynthesis (Cel, Hsd17b7, Soat2, and Sqle). The main differentially expressed metabolites (DEMs) that were discovered by means of metabolome analysis included cholylhistidine, calcipotriol, 13-O-tetradecanoylphorbol 12-acetate, and hexahomomethionine in CG vs. TA2. Integrative analyses of two omics revealed that 2 g/kg of TA mitigated inflammation by activating the PPAR signaling pathway and regulating the lipid metabolism via multiple pathways, such as steroid biosynthesis and α-linolenic acid metabolism. In general, the inclusion of 2 g/kg of TA in turtle diets can optimally promote growth and bacterial resistance by maintaining intestinal health and improving antioxidant capacity. Full article

Objective: This study aims to identify whether the development of insulin resistance (IR) induced by high selenium (Se) is related to serine deficiency via the inhibition of the de novo serine synthesis pathway (SSP) by the administrations of 3-phosphoglycerate dehydrogenase (PHGDH) inhibitor (NCT503) or exogenous serine in mice. Method: forty-eight male C57BL/6J mice were randomly divided into four groups: adequate-Se (0.1 mgSe/kg), high-Se (0.8 mgSe/kg), high-Se +serine (240 mg/kg/day), and high-Se +NCT503 (30 mg/kg, twice a week) for 5 months. The glucose tolerance test (GTT) and insulin tolerance test (ITT) were used to confirm the development of IR in mice with high-Se intake, and fasting blood glucose levels were measured monthly. The Se contents in plasma and tissues were detected by ICP-MS. The levels of insulin (INS), homocysteine (HCY), and serine in plasma were tested by ELISA. Western blot analyses were conducted to evaluate the protein expressions of glutathione peroxidase 1 (GPX1), selenoprotein P (SELENOP) and PHGDH, the PI3K-AKT-mTOR pathway, folate cycle (SHMT1, MTHFR), and methionine cycle (MS). Results: An IR model was developed in mice from the high-Se group with elevated fasting blood glucose and INS levels, impaired glucose tolerance, and reduced insulin sensitivity, but not in both the high-Se +serine group and the high-Se +NCT503 group. Compared with the high-Se and high-Se +serine groups, the expressions of GPX1 and SELENOP significantly decreased for the high-Se +NCT503 group in the liver, muscle, and pancreas tissues. The expression of PHGDH of high-Se group was significantly higher than that of the adequate-Se group in the liver (p < 0.05) and pancreas (p < 0.001). Also, the expected high expression of PHGDH was effectively inhibited in mice from the high-Se +serine group but not from the high-Se +NCT503 group. The expression of p-AKT (Ser-473) for the high-Se group was significantly lower than that of the adequate-Se group in the liver, muscle, and pancreas. Conclusions: The IR induced by high-Se intake in the body has been confirmed to be partially due to serine deficiency, which led to the initiation of SSP to produce endogenous serine. The supplementations of exogenous serine or inhibitors of PHGDH in this metabolic pathway could be used for the intervention. Full article

Melon (Cucumis melo L.) is a significant cash crop globally and is cherished for its sweet and flavorful fruits, as well as its high nutritional values. However, its yield and quality are limited by various factors, including drought, salinity, and low temperatures. Low temperatures are one of the primary factors influencing the growth and development of melons, diminishing the viability, germination, and growth rate of melon seeds. Concurrently, low temperatures also reduce light absorption efficiency and fruit yields, thereby affecting melon growth and development. Serine hydroxymethyltransferase (SHMT), a conserved phosphopyridoxal-dependent enzyme, plays a crucial role in plant resistance to abiotic stressors. In this study, eight CmSHMT family genes were identified from the melon genome. We predicted their chromosomal locations, physicochemical properties, gene structures, evolutionary relationships, conserved motifs, cis-acting elements of promoters, and tissue-specific expression patterns. The expression levels of CmSHMT family genes in response to low-temperature stress was then analyzd using qRT-PCR. The phylogenetic results indicated that these CmSHMT genes were classified into four subfamilies and were unevenly distributed across five chromosomes, with relatively high conservation among them. Furthermore, our investigation revealed that the promoter regions of the CmSHMT family genes contain many cis-acting elements related to phytohormones, growth, and various stress responses. The relative expression levels of CmSHMT3, CmSHMT4, CmSHMT6, and CmSHMT7 were higher under low-temperature stress compared to the control group. Notably, the promoter region of CmSHMT3 contains cis-acting elements associated with low-temperature response (LTR) and abscisic acid response (ABRE). It is suggested that the mechanism through which CmSHMT3 responds to low-temperature stress treatments may be associated with hormonal regulation. These findings provide a foundation for the further exploration of CmSHMT family genes in melon and their functional roles in response to low-temperature stress, and they provide a theoretical basis for the targeted breeding of superior melon varieties with enhanced tolerance to low temperatures. Full article

Hypoxia is a characteristic feature of malignancy; however, its effect on metabolism remains unclear. In this study, Hepa1-6 cells were cultured under hypoxic conditions and their metabolites were analyzed. Elevated levels of L-serine along with increased glycolytic activity are prominent features of hypoxia. Transcriptome sequencing revealed the downregulation of genes involved in L-serine synthesis and metabolism, which was confirmed by PCR analysis and comparison with public databases. Further experimental evidence indicates that the accumulation of L-serine under hypoxic conditions is attributable not only to enhanced glycolysis but also to a reduction in the catabolism of L-serine mediated by serine hydroxymethyltransferase 2 (SHMT2). Full article

Serine and folate metabolism play critical roles in erythroid development in both embryonic and adult mice; however, the precise roles of these metabolic pathways in erythropoiesis and the pathophysiology of anemia remain inadequately characterized in the literature. To delineate the contributions of serine and folate metabolism to erythroid differentiation, we focused on serine hydroxymethyltransferase 2 (SHMT2), a key regulatory enzyme within these metabolic pathways. Using gene-editing techniques, we created fetal and adult mouse models with targeted deletion of Shmt2 in the hematopoietic system. Our findings demonstrated that the deletion of Shmt2 within the hematopoietic system led to the distinctive anemia phenotype in both fetal and adult mice. Detailed progression analysis of anemia revealed that Shmt2 deletion exerts stage-specific effects on the development and maturation of erythroid cells. Specifically, Shmt2 deficiency promoted erythroid differentiation in the R2 (CD71⁺ Ter119⁻) cell population residing in the bone marrow while concurrently inhibiting the proliferation and erythroid differentiation of the R3 (CD71⁺ Ter119⁺) cell population. This disruption resulted in developmental arrest at the R3 stage, significantly contributing to the anemia phenotype observed in the models. This study elucidates the critical role of Shmt2 in erythroid development within the hematopoietic system, highlighting the underlying mechanisms of erythroid developmental arrest associated with Shmt2 loss. Full article