Specific Metabolites Research Articles

IMPA1-derived inositol maintains stemness in castration-resistant prostate cancer via IMPDH2 activation.

Acquisition of prostate cancer stem cells (PCSCs) manifested during androgen ablation therapy (ABT) contributes to castration-resistant prostate cancer (CRPC). However, little is known about the specific metabolites critically orchestrating this process. Here, we show that IMPA1-derived inositol enriched in PCSCs is a key metabolite crucially maintaining PCSCs for CRPC progression and ABT resistance. Notably, conditional Impa1 knockout in the prostate abrogates the pool and properties of PCSCs to orchestrate CRPC progression and prolong the survival of TRAMP mice. IMPA1-derived inositol serves as a cofactor that directly binds to and activates IMPDH2, which synthesizes guanylate nucleotides for maintaining PCSCs with ARlow/- features leading to CRPC progression and ABT resistance. IMPA1/inositol/IMPDH2 axis is upregulated in human prostate cancer, and its overexpression predicts poor survival outcomes. Genetically and pharmacologically targeting the IMPA1/inositol/IMPDH2 axis abrogates CRPC and overcomes ABT resistance in various CRPC xenografts, patient-derived xenograft (PDX) tumor models, and TRAMP mouse models. Our study identifies IMPDH2 as an inositol sensor whose activation by inositol represents a key mechanism for maintaining PCSCs for CRPC and ABT resistance.

Unraveling the key mechanisms of Gastrodia elata continuous cropping obstacles: soil bacteria Massilia, Burkholderia-Caballeronia-Paraburkholderia, and Dyella along with soil metabolites 4-hydroxy-benzenemethanol and N-(2-butyl)-N-octadecyl-, ethyl ester as crucial indicators

BackgroundTian-ma (Gastrodia elata) is a traditional medicinal herb found in China. It is used in healthy food and to treat various diseases, therefore cultivated extensively in southwest China. However, continuous cropping of this species has led to various obstacles, such as microbial disease and pest infestation, significantly affecting the production and development of valuable medicinal and food resources. As per the growth habit, soil is presumed to be the primary factor contributing to these obstacles, despite the known issues of continuous cropping obstacles in Gastrodia elata, such as microbial disease, there is a lack of comprehensive understanding of the specific soil bacterial communities and metabolites involved in these processes.MethodsWe analyzed soil samples collected during the year of Tian-ma cultivation (0 Year), after the Tian-ma harvest (1 Year), after two years (2 Year), and three years (3 Year) of fallowing post-cultivation using soil 16S rRNA metabarcoding sequencing by illumina platform and metabolomics (GC–MS/MS). Soil sample collected from the uncultivated field was used as the control (CK).ResultsMetabarcoding sequencing showed high bacterial alpha diversity during the cultivation of Tian-ma (0 Year) and the period of deterioration of soil bacterial community. (1 Year), with decreased anaerobic bacterial abundance and increased copiotrophic bacterial abundance. Bacteria associated with sulfur metabolism also showed increased abundance during the year of cropping obstacles. Further metabolomics approach identified 4-hydroxy-benzenemethanol as an indicator of Tian-ma continuous cropping obstacles. Besides, metabolites of the carbohydrate class were found to be the most abundant during the occurrence of continuous cropping obstacles of Gastrodia elata, suggesting that regulation of soil microbial diversity may be a critical factor in addressing these obstacles. Finally, the correlation analysis indicated a positive association between the abundance of some metabolite, e.g., carbamic acid, N-(2-butyl)-N-octadecyl-, ethyl ester detected after Tian-ma cultivation and the abundance of bacteria capable of degrading toxic metabolites, such as Massilia, Burkholderia-Caballeronia-Paraburkholderia, and Dyella.ConclusionThis study has revealed the specific soil bacteria and metabolic factors related to the continuous cropping obstacles of Gastrodia elata. These findings not only deepen our understanding of the continuous cropping issues but also pave the way for developing effective strategies to overcome them.

Preharvest salicylic acid and chitosan treatments reduce red drupelet reversion and enhance antioxidant capacity in blackberry fruit

Red drupelet reversion (RDR) is a postharvest physiological disorder affecting fresh blackberries during commercialization. The drupelets revert from fully black to red, causing detriments of the commercial value. The specific mechanism is still being investigated, some reports suggest that the occurrence of RDR is associated with pigment degradation in the fruit, and can be caused or aggravated by mechanical damage and storage conditions. Even, though studies report no significant alteration in blackberry organoleptic properties caused by RDR, the visual aspect of it affects the consumer perception of the fruit quality reducing marketability and ultimately generating economic losses. In this regard, preharvest treatments have been recently reported to have positive effects in reducing RDR in blackberries. In this study, we investigated the effects of chitosan (COS) and salicylic acid (SA) as preharvest treatments on the phenolic compound content and antioxidant capacity of blackberry fruit. The results showed that SA 3 mM and COS 0.25% treatments increased the total phenolic and flavonoid content while also enhancing the antioxidant capacity of blackberries. We also observed that the content of specialized metabolites and the activity of antioxidant enzymes have a negative correlation with the occurrence of RDR in blackberries.

Metabolomic Fingerprints: Seasonal and Farm-Specific Differences in Heterotrigona itama Bee Bread

Stingless bees’ products such as honey and bee bread are beneficial to human health. However, the metabolite composition within the products may differ according to spatial and temporal factors. This study aims to investigate the impact of spatial and temporal factors on the significant metabolite composition present in Heterotrigona itama bee bread collected from different seasons and types of bee farms. Thus, tandem mass spectrometry (LCMS/MS) based metabolomics analysis was used to achieve the said goal, focusing on H. itama bee bread samples, followed by multivariate analysis using the MetaboAnalyst platform. Our findings revealed significant metabolites that set bee bread samples apart. In terms of temporal factors, the analysis highlights specific metabolites exclusive to the wet season, such as flavones and flavonoids. However, in contrast, during the wet season, there are no significant metabolites in herbal farm samples. The results also underscore the significance of phenolic compounds in wet season samples and as vital metabolites distinguishing the groups. This study highlights a total of 24 annotated significant metabolites identified in different bee bread samples, as well as their capacity to differentiate between seasons and bee farms. Notably, these results suggest a wide variety of potential plant families as a source of bee bread. These findings shed light on the impact of seasons and diverse plant families contributing to bee bread composition, which may impact the growing meliponiculture industry greatly.

The influence of aridity on plant intraspecific chemical diversity supports adaptive differentiation and convergent evolution.

Plants synthesize a broad array of specialized chemical compounds that mediate their interactions with the surrounding environment. Some of this chemical diversity is functional and subject to natural selection, but the factors underlying chemical evolution at the intraspecific level remain largely unknown. Here, we combined chemical, environmental and genetic data to investigate the effect of aridity on the expression of chemotypes in the invasive shrub Senecio pterophorus. We studied the variation in pyrrolizidine alkaloids (PAs), a group of specialized metabolites widespread across the families Boraginaceae, Asteraceae and Fabaceae, from native populations spanning a cline of aridity and from three cross-continental introductions, under natural and common garden conditions. We examined whether the relationship between chemistry and aridity was compatible with a process of adaptive differentiation using a method that partitions the variance and covariance by controlling for the population neutral genetic structure. We found a consistent shift from retrorsine-like to seneciphylline-like compounds under increasing aridity in both natural and controlled conditions in coherence with the biosynthetic pathways. This pattern was independent of the neutral genetic structure and occurred along the environmental gradient in the native range and in a convergent manner in all nonnative regions, which suggests adaptive differentiation in response to aridity. Our findings show that the diversity of PAs in S. pterophorus has been partially shaped by aridity. Investigating how abiotic factors influence chemical evolution is key to elucidating the plant responses in future climate scenarios and the cascading effects on other trophic levels.

Study on serum metabolomics characteristics of obese patients with erectile dysfunction.

Erectile dysfunction (ED) is a common male sexual health problem that can be associated with obesity. This study aimed to identify serum metabolic differences and pathways related to ED in obese men using non-targeted metabolomics techniques. We included 54 obese male patients with (n = 27) and without (n = 27) ED. We collected 5 mL of fasting elbow vein blood and analyzed serum metabolites using ultra-high-performance liquid chromatography-mass spectrometry. Multivariate statistical methods (principal component analysis and orthogonal partial least squares discriminant analysis) were used to identify differential metabolites between the groups. Finally, pathway analysis using the Kyoto encyclopedia of genes and genomes database identified 4 differential metabolic pathways in obese men with ED compared to obese men without ED. A total of 77 differential metabolites were identified in obese men with ED compared to the control group (obese men without ED) using a threshold of variable importance in the projection > 1 and P < .05. Pathway analysis revealed 4 main differences: glycine, serine and threonine metabolism, glycerophospholipid metabolism, aminoacyl-tRNA biosynthesis, and D-glutamine and D-glutamate metabolism. Specific metabolites associated with these pathways included betaine aldehyde, choline, L-threonine, phosphatidylcholine, L-serine, and D-glutamine. Our findings suggest abnormalities in fatty acid metabolism, phospholipid metabolism, and amino acid metabolism between obese men with and without ED. Metabolites such as betaine aldehyde, choline, L-threonine, phosphatidylcholine, L-serine, and D-glutamine may be potential biomarkers for distinguishing obese men with ED.

Reinventing gut health: leveraging dietary bioactive compounds for the prevention and treatment of diseases

The human gut harbors a complex and diverse microbiota essential for maintaining health. Diet is the most significant modifiable factor influencing gut microbiota composition and function, particularly through bioactive compounds like polyphenols, dietary fibers, and carotenoids found in vegetables, fruits, seafood, coffee, and green tea. These compounds regulate the gut microbiota by promoting beneficial bacteria and suppressing harmful ones, leading to the production of key microbiota-derived metabolites such as short-chain fatty acids, bile acid derivatives, and tryptophan metabolites. These metabolites are crucial for gut homeostasis, influencing gut barrier function, immune responses, energy metabolism, anti-inflammatory processes, lipid digestion, and modulation of gut inflammation. This review outlines the regulatory impact of typical bioactive compounds on the gut microbiota and explores the connection between specific microbiota-derived metabolites and overall health. We discuss how dietary interventions can affect disease development and progression through mechanisms involving these metabolites. We examine the roles of bioactive compounds and their metabolites in the prevention and treatment of diseases including inflammatory bowel disease, colorectal cancer, cardiovascular diseases, obesity, and type 2 diabetes mellitus. This study provides new insights into disease prevention and underscores the potential of dietary modulation of the gut microbiota as a strategy for improving health.

Gut bacteria facilitate leaf beetles in adapting to dietary specialization by enhancing larval fitness

Dietary specialization between insect stages can reduce intraspecific food competition. The involvement of gut bacteria and the mechanisms underlying this phenomenon received limited attention. Plagiodera versicolora is a pest harming Salicaceae trees. Here, we confirmed dietary specialization in P. versicolora, wherein adults prefer new leaves, while larvae predominantly consume mature leaves when both types are available. We demonstrated the larval preference for mature leaves confers ecological advantages by promoting growth, development and immunity and this advantage is contingent upon the presence of gut bacteria. Gut microbiota in larvae revealed a significant enrichment of Pantoea when feeding new leaves, with P. anthophila exhibiting the most pronounced inhibitory effect on larval development. Further exploration identified specific metabolites, such as Tyrosyl-valine, with higher content in new leaves, which serve as substrates for the entomopathogenic gut bacterium to facilitate its proliferation. This study provides a fresh perspective on the ecological role of gut bacteria.

Maternal gastrointestinal microbiome shapes gut microbial function and resistome of newborns in a cow-to-calf model

BackgroundThe maternal gut microbiome is the direct and important source of early colonization and development of the neonatal gut microbiome. However, differences in unique and shared features between mothers with different physiological phenotypes and their newborns still lack exhaustive investigation. Here, using a cow-to-calf model, a comprehensive investigation was conducted to elucidate the pattern and characterization of microbial transfer from the maternal source to the offspring.ResultsThe microbiota in the rumen and feces of dairy cows were divided into two clusters via enterotype analysis. The cows from the enterotype distinguished by Prevotella in the rumen had better production performance, whereas no difference was observed in the cows classified by feces enterotype. Furthermore, through a pairwise combination of fecal and ruminal enterotypes, we screened a group of dairy cows with excellent phenotypes. The gastrointestinal microbiomes of cows with different phenotypes and their offspring differed significantly. The rumen was a more important microbial source for meconium than feces. Transmission of beneficial bacteria from mother to offspring was observed. Additionally, the meconium inherits advantageous metabolic functions of the rumen. The resistome features of the rumen, feces, and meconium were consistent, and resistome abundance from cows to calves showed an expanding trend. The interaction between antibiotic-resistance genes and mobile genetic elements from the rumen to meconium was the most remarkable. The diversity of core metabolites from cows to calves was stable and not affected by differences in phenotypes. However, the abundance of specific metabolites varied greatly.ConclusionsOur study demonstrates the microbial taxa, metabolic function, and resistome characteristics of maternal and neonatal microbiomes, and reveals the potential vertical transmission of the microbiome from a cow-to-calf model. These findings provide new insights into the transgenerational transmission pattern of the microbiome.2cueHjjtpyRzwmAWUdZ5oAVideo

Organic Nitrogen Nutrition Does Not Increase Glucosinolate Concentrations in Broccoli (Brassica oleracea L. var. italica)

Concentrations of specific secondary metabolites can be higher in organically grown crops. This may be linked to organic nitrogen (N) nutrition that provides a gradual supply of N to crops over the growing season. This study examined whether organic N nutrition influenced the concentration of glucosinolates in broccoli crops. Nitrogen release patterns were determined from three synthetic (Rustica, 12% N; calcium nitrate, 15.5% N; urea, 46% N) and two organic fertilizers in an incubation experiment. Broccoli seedlings were then grown in two N dose response pot trials with different N source or application timing treatments to investigate growth and glucosinolate responses. Synthetic fertilizers released 84 to 89% of total N after 28 days, while chicken manure pellets and composted cow manure had only released 52% and 13% of total N, respectively, after 91 days. Broccoli yield and N content were generally higher in synthetic fertilizer treatments. Glucosinolate concentrations were generally higher in the synthetic fertilizer treatments, and only sinigrin and glucoiberin concentrations in the 800 kg ha−1 N application rate of organic fertilizer matched those in the corresponding synthetic fertilizer treatment. Broccoli head weight was reduced when N was applied fortnightly compared to basal and weekly N applications, but glucosinolate concentrations were not significantly different. Overall, there was no evidence that organic (chicken manure) N nutrition, or the rate of N supply to broccoli plants, affect glucosinolate concentrations.

Pyrrolizwilline, a unique bacterial alkaloid assembled by a nonribosomal peptide synthetase and non-enzymatic dimerization.

Pyrrolizidine alkaloids (PAs) are a structurally diverse group of heterocyclic specialized metabolites characterized by a core structure comprising a hexahydro-1H-pyrrolizine. PAs are synthesized through two main pathways. In plants, assembly occurs via a homospermidine synthase, and in bacteria, through combined action of a nonribosomal peptide synthetase and a Baeyer-Villiger monooxygenase. While the toxic properties of plant-derived PAs and their prevalence in animal and human foods have been extensively studied, the biological roles and biosynthesis of more complex bacterial PAs are not well understood. Here, we report the identification and characterization of a bacterial biosynthetic gene cluster fromXenorhabdus hominickii,xhpA-G, which is responsible for producing the PA pseudo-dimer pyrrolizwilline. Analysis ofX. hominickiipromoter exchange mutants together with heterologous expression ofxhpA-GinE. coli, revealed a set of pathway intermediates, two of which were chemically synthesized, as well as multiple derivatives. This information was leveraged to propose a detailed biosynthetic pathway to pyrrolizwilline. Furthermore, we have characterized the hydrolase XhpG, the key enzyme in the conversion of the pathway intermediate pyrrolizixenamide to pyrrolizwilline, using X-ray crystallography and small-angle X-ray scattering (SAXS).

Pyrrolizwilline, a unique bacterial alkaloid assembled by a nonribosomal peptide synthetase and non‐enzymatic dimerization

Pyrrolizidine alkaloids (PAs) are a structurally diverse group of heterocyclic specialized metabolites characterized by a core structure comprising a hexahydro‐1H‐pyrrolizine. PAs are synthesized through two main pathways. In plants, assembly occurs via a homospermidine synthase, and in bacteria, through combined action of a nonribosomal peptide synthetase and a Baeyer‐Villiger monooxygenase. While the toxic properties of plant‐derived PAs and their prevalence in animal and human foods have been extensively studied, the biological roles and biosynthesis of more complex bacterial PAs are not well understood. Here, we report the identification and characterization of a bacterial biosynthetic gene cluster from Xenorhabdus hominickii, xhpA‐G, which is responsible for producing the PA pseudo‐dimer pyrrolizwilline. Analysis of X. hominickii promoter exchange mutants together with heterologous expression of xhpA‐G in E. coli, revealed a set of pathway intermediates, two of which were chemically synthesized, as well as multiple derivatives. This information was leveraged to propose a detailed biosynthetic pathway to pyrrolizwilline. Furthermore, we have characterized the hydrolase XhpG, the key enzyme in the conversion of the pathway intermediate pyrrolizixenamide to pyrrolizwilline, using X‐ray crystallography and small‐angle X‐ray scattering (SAXS).

Self-DNA in Caenorhabditis elegans Affects the Production of Specific Metabolites: Evidence from LC-MS and Chemometric Studies

The worm Caenorhabditis elegans, with its short lifecycle and well-known genetic and metabolic pathways, stands as an exemplary model organism for biological research. Its simplicity and genetic tractability make it an ideal system for investigating the effects of different conditions on its metabolism. The chemical analysis of this nematode was performed to identify specific metabolites produced by the worms when fed with either self- or nonself-DNA. A standard diet with OP50 feeding was used as a control. Different development stages were sampled, and their chemical composition was assessed by liquid chromatography–mass spectrometry combined with chemometrics, including both principal component analysis and orthogonal partial least squares discriminant analysis tools. The obtained data demonstrated that self-DNA-treated larvae, when arrested in their cycle, showed significant decreases in dynorphin, an appetite regulator of the nematode, and in N-formyl glycine, a known longevity promoter in C. elegans. Moreover, a substantial decrease was also recorded in the self-DNA-fed adults for the FMRF amide neuropeptide, an embryogenesis regulator, and for a dopamine derivative modulating nematode locomotion. In conclusion, this study allowed for the identification of key metabolites affected by the self-DNA diet, providing interesting hints on the main molecular pathways involved in its biological inhibitory effects.

Discovery and Biosynthesis of Sulfenicin and Its New-to-Nature Acylsulfenic Acid Functional Group.

Life's organic molecules are built with diverse functional groups that enable biology by fine tuning intimate connections through time and space. As such, the discovery of new-to-nature functional groups can expand our understanding of the natural world and motivate new applications in biotechnology and biomedicine. Herein we report the genome-aided discovery of sulfenicin, a novel polyketide-nonribosomal peptide hybrid natural product from a marine Streptomyces bacterium bearing a unique acylsulfenic acid functionality. Through a series of heterologous biosynthesis, functional genetics, and enzymatic reconstitution experiments, we show that this previously described synthetic functional group is biologically assembled by a set of enzymes from both primary and secondary metabolism, including a novel flavin-dependent S -hydroxylase that hydroxylates a thiocarboxylic acid's sulfur atom. While the sulfenicin biosynthetic gene cluster is presently without parallel in public databases, acylsulfenic acid-encoding enzymes are widely distributed in bacterial genomes, implying that this labile functional group may similarly have a broad distribution among specialized metabolites.

Genetic Insights into Sepsis: Mendelian Randomization Analysis of Cerebrospinal Fluid Metabolites.

Sepsis, a life-threatening response to infection leading to systemic inflammation and organ dysfunction, has been hypothesized to be influenced by metabolic alterations in cerebrospinal fluid (CSF). Despite extensive research, the specific metabolic pathways contributing to sepsis remain unclear. This study aims to elucidate the causal relationships between CSF metabolites and sepsis risk using Mendelian Randomization (MR), offering insights that could lead to novel therapeutic strategies. We conducted a two-sample MR analysis using genetic variants as instrumental variables (IVs) to investigate 338 CSF metabolites identified through a genome-wide association study. Data on sepsis-related outcomes were extracted from the genome-wide association study (GWAS) catalog encompassing 486,484 individuals of European descent. IVs were rigorously selected based on stringent genetic association and linkage disequilibrium criteria. Statistical analyses, including inverse variance weighting (IVW) and weighted median methods, were performed using the 'TwoSampleMR' package in R software, supplemented by comprehensive sensitivity analyses to ensure the robustness of our findings. Our analysis identified 19 CSF metabolites causally associated with sepsis risk. Notably, metabolites such as 1-palmitoyl-2-stearoyl-gpc (16:0/18:0) and 2-hydroxyglutarate showed significant negative correlations with sepsis risk. The reverse MR analysis further revealed that sepsis could negatively impact certain CSF metabolite levels, particularly Ribonate, suggesting a bidirectional relationship. These relationships were substantiated by rigorous statistical testing and sensitivity analyses confirming the absence of horizontal pleiotropy and the stability of our results across various MR methods. This study demonstrates significant causal associations between specific CSF metabolites and the risk of developing sepsis, highlighting the potential for these metabolites to serve as biomarkers or therapeutic targets. The bidirectional nature of these findings also suggests that sepsis itself may alter metabolic profiles, offering further avenues for intervention.

FMT intervention decreases urine 5-HIAA levels: a randomized double-blind controlled study

BackgroundAutism spectrum disorder (ASD) is often linked to gastrointestinal issues and altered serotonin metabolism. Emerging evidence suggests gut microbiota influence both, with fecal microbiota transplantation (FMT) offering a potential therapeutic approach. However, its impact on serotonin metabolism and ASD symptoms is not well understood. In this study, we aimed to evaluate the clinical effects of FMT and examine changes in specific urinary metabolites in children with ASD.MethodsA randomized double-blind controlled trial was performed to evaluate the clinical effects of FMT on GI and ASD-related symptoms. Gastrointestinal symptoms were assessed using the Gastrointestinal Symptom Rating Scale (GSRS), and the ASD-related symptoms were assessed using the Childhood Autism Rating Scale (CARS), Aberrant Behavior Checklist (ABC), and Social Responsiveness Scale (SRS) scores. Urinary metabolites were analyzed by homogeneous enzyme immunoassay using commercially available kits.ResultsSignificant improvements in GI and core ASD symptoms were observed following FMT intervention. The average GSRS scores decreased from 30.17 (before) to 19 (after; p &amp;lt; 0.0001), CARS scores decreased from 36.22 to 33.33 (p &amp;lt; 0.0001), SRS scores decreased from 151.17 to 137.5 (p = 0.0002), and the ABC scores decreased 76.39 to 53.17 (p &amp;lt; 0.0001) in the FMT group. However, in the placebo group, GSRS, CARS, and SRS scores showed no significant changes, while ABC scores decreased from 72 to 58.75 (p = 0.034). The FMT group also showed a significant reduction in urinary 5-hydroxyindoleacetic acid (5-HIAA) levels from 8.6 to 7.32 mg/L (p = 0.022), while other metabolites showed no significant changes.ConclusionFMT is a safe and effective treatment for improving GI and core symptoms in children with ASD, with 5-HIAA showing potential as a urinary biomarker for treatment response.

Catechol acetylglucose: a newly identified benzoxazinoid-regulated defensive metabolite in maize.

An enormous diversity of specialized metabolites is produced in the plant kingdom, with each individual plant synthesizing thousands of these compounds. Previous research showed that benzoxazinoids, the most abundant class of specialized metabolites in maize, also function as signaling molecules by regulating the production callose as a defense response. We searched for additional benzoxazinoid-regulated specialized metabolites, characterized them, examined whether they too function in herbivore protection, and determined how Spodoptera frugiperda (fall armyworm), a prominent maize pest, copes with these metabolites. We identified catechol acetylglucose (CAG) as a benzoxazinoid-regulated metabolite that is produced from salicylic acid via catechol and catechol glucoside. Genome-wide association studies of CAG abundance identified a gene encoding a predicted acetyltransferase. Knockout of this gene resulted in maize plants that lack CAG and over-accumulate catechol glucoside. Upon tissue disruption, maize plants accumulate catechol, which inhibits S. frugiperda growth. Analysis of caterpillar frass showed that S. frugiperda detoxifies catechol by glycosylation, and the efficiency of catechol glycosylation was correlated with S. frugiperda growth on a catechol-containing diet. Thus, the success of S. frugiperda as an agricultural pest may depend partly on its ability to detoxify catechol, which is produced as a defensive metabolite by maize.

Microbiome research in autoimmune and immune-mediated inflammatory diseases: lessons, advances and unmet needs

The increasing prevalence of autoimmune and immune-mediated diseases (AIMDs) underscores the need to understand environmental factors that contribute to their pathogenesis, with the microbiome emerging as a key player. Despite...

Understanding the biosynthesis, metabolic regulation, and anti-phytopathogen activity of 3,7-dihydroxytropolone in Pseudomonas spp.

The genus Pseudomonas is a prolific source of specialized metabolites with significant biological activities, including siderophores, antibiotics, and plant hormones. These molecules play pivotal roles in environmental interactions, influencing pathogenicity, inhibiting microorganisms, responding to nutrient limitation and abiotic challenges, and regulating plant growth. These properties mean that pseudomonads are suitable candidates as biological control agents against plant pathogens. Multiple transposon-based screens have identified a Pseudomonas biosynthetic gene cluster (BGC) associated with potent antibacterial and antifungal activities, which produces 7-hydroxytropolone (7-HT). In this study, we show that this BGC also makes 3,7-dihydroxytropolone (3,7-dHT), which has strong antimicrobial activity toward Streptomyces scabies, a potato pathogen. Through metabolomics and reporter assays, we unveil the involvement of cluster-situated genes in generating phenylacetyl-coenzyme A, a key precursor for tropolone biosynthesis via the phenylacetic acid catabolon. The clustering of these phenylacetic acid genes within tropolone BGCs is unusual in other Gram-negative bacteria. Our findings support the interception of phenylacetic acid catabolism via an enoyl-CoA dehydratase encoded in the BGC, as well as highlighting an essential role for a conserved thioesterase in biosynthesis. Biochemical assays were used to show that this thioesterase functions after a dehydrogenation-epoxidation step catalyzed by a flavoprotein. We use this information to identify diverse uncharacterized BGCs that encode proteins with homology to flavoproteins and thioesterases involved in tropolone biosynthesis. This study provides insights into tropolone biosynthesis in Pseudomonas, laying the foundation for further investigations into the ecological role of tropolone production.IMPORTANCEPseudomonas bacteria produce various potent chemicals that influence interactions in nature, such as metal-binding molecules, antibiotics, or plant hormones. This ability to synthesize bioactive molecules means that Pseudomonas bacteria may be useful as biological control agents to protect plants from agricultural pathogens, as well as a source of antibiotic candidates. We have identified a plant-associated Pseudomonas strain that can produce 3,7-dihydroxytropolone, which has broad biological activity and can inhibit the growth of Streptomyces scabies, a bacterium that causes potato scab. Following the identification of this molecule, we used a combination of genetic, chemical, and biochemical experiments to identify key steps in the production of tropolones in Pseudomonas species. Understanding this biosynthetic process led to the discovery of an array of diverse pathways that we predict will produce new tropolone-like molecules. This work should also help us shed light on the natural function of antibiotics in nature.

The roles of GLUT5 in cancer progression, metastasis, and drug resistance

Emerging evidence has suggested that high fructose intake, particularly from added sugars and processed foods, is associated with increased cancer risk and progression. The fructose intake is believed to be mediated by the abnormal expression of glucose transporter 5 (GLUT5), the specific fructose transporter in cancer cells. The GLUT5-regulated fructose metabolism has shown to greatly affect cancer progression, metastasis, and drug resistance. This review aims to synchronize the current knowledge to highlight the underlying mechanisms of those impacts and understand the therapeutic potential of GULT5. First, we review the fructose metabolism and its alteration in cancer cells by comparing with glucose metabolism. Subsequently, the key contributors or biological pathways involved in GLUT5-asosociated tumor growth, cancer metastasis, and drug resistance are discussed. The contributions of specific pathways, metabolites, and key enzymes from the fructose metabolism process are also covered, such as enhanced glycolysis for tumor growth, epithelial-mesenchymal transition and angiogenesis for cancer metastasis, and efflux pump expression and activation of survival pathways for cancer drug resistance. The detailed analysis of these mechanisms will allow further understanding of the therapeutic potential of GLUT 5-mediated fructose metabolism in cancer therapy. In particular, targeting GLUT 5 and its-associated processes in fructose metabolism may offer promising strategies for improving cancer treatment outcomes through dietary interventions, specific GLUT5 inhibitors, or in combination.