RESUMO
Machine learning (ML) has increasingly been applied to predict properties of drugs. Particularly, metabolism can be predicted with ML methods, which can be exploited during drug discovery and development. The prediction of metabolism is a crucial bottleneck in the early identification of toxic metabolites or biotransformation pathways that can affect elimination of the drug and potentially hinder the development of future new drugs. Metabolism prediction can be addressed with the application of ML models trained on large and validated dataset, from early stages of lead optimization to latest stage of drug development. ML methods rely on molecular descriptors that allow to identify and learn chemical and molecular features to predict sites of metabolism (SoMs) or activity associated with mechanism of inhibition (e.g., CYP inhibition). The application of ML methods in the prediction of drug metabolism represents a powerful resource to be exploited during drug discovery and development. ML allows to improve in silico screening and safety assessments of drugs in advance, steering their path to marketing authorization. Prediction of biotransformation reactions and metabolites allows to shorten the time, save the cost, and reduce animal testing. In this context, ML methods represent a technique to fill data gaps and an opportunity to reduce animal testing, calling for the 3R principles within the Big Data era.
Assuntos
Descoberta de Drogas , Aprendizado de Máquina , Descoberta de Drogas/métodos , Humanos , Preparações Farmacêuticas/metabolismo , Biotransformação , Simulação por Computador , Animais , Desenvolvimento de Medicamentos/métodosRESUMO
The primary cause of anemia worldwide is due to poor diet and iron deficiency. Iron (Fe) enriched yeast can be the most effective way to manage anemia because of the capability for biotransformation of mineral to organic and bioavailable iron. To overcome the low richness of yeast, the use of siderophore as cellular iron carriers is a new approach. In this research, for the first time the potential of siderophore in increasing the Fe enrichment of Saccharomyces boulardii (S. boulardii), which is important because of its probiotic properties and resistance to different stresses, has been investigated to produce of potential iron supplements. For this purpose, siderophore was produced by Pseudomonas aeruginosa (P. aeruginosa). Siderophore impact, along with ten other independent process variables, has been studied on the efficiency of iron biotransformation by the Plackett-Burman design (PBD). The results showed that the highest biotransformation yield was 17.77 mg Fe/g dry cell weight (DCW) in the highest biomass weight of 9 g/l. Iron concentration is the most important variable, with contributions of 46% and 70.79% for biomass weight and biotransformation, respectively, followed by fermentation time, agitation speed, and KH2PO4 concentration. But increasing the level of siderophore and zinc led to a significant negative effect. siderophore inefficiency may be attributed to the absence of membrane receptors for pyoverdine (Pvd) and pyochelin (Pch) siderophores. Also, the steric hindrance of the cell wall mannan, the stickiness and sediment ability of the yeast, can create limitations in the absorption of elements. Such yeast can be used as a potential source of iron even for vegetarians and vegans in the form of medicinal and fortified food products to improve the treatment of anemia. It is recommended that further research be focused on increasing the iron enrichment of yeast by overcoming the structural barrier of the cell wall, investigating factors affecting membrane permeability and iron transport potential of other types of siderophores.
Assuntos
Ferro , Saccharomyces boulardii , Sideróforos , Sideróforos/metabolismo , Ferro/metabolismo , Saccharomyces boulardii/metabolismo , Pseudomonas aeruginosa/metabolismo , Biomassa , Fermentação , BiotransformaçãoRESUMO
Aficamten, a cardiac myosin inhibitor, is being developed for the treatment of patients with symptomatic hypertrophic cardiomyopathy (HCM). The purpose of this study was to determine the absorption, metabolism, and excretion of aficamten. Eight healthy male participants received a single oral dose of 20 mg aficamten (containing approximately 100 µCi of radiocarbon). Blood, urine, and feces samples were collected up to a maximum of Day 26. The pharmacokinetics of aficamten were characterized by moderate absorption, with a median tmax of 2.0 h postdose. The median t1/2 of aficamten was 99.6 h with similar t1/2 observed for metabolites and total radioactivity in plasma and whole blood. The overall total recovery of administered total radioactivity was 89.7% with 57.7% of the dose recovered in feces and 32.0% in urine. The main circulating metabolites in plasma included monohydroxylated metabolites M1a (CK-3834282) and M1b (CK-3834283) accounting for 10.5% and 36.4% of the total radioactivity AUC both with a median tmax of 5 h. The other major plasma metabolite was M5 (an oxygen-linked glucuronide conjugate of M1a), which accounted for 10.3% of the total plasma radioactivity exposure, with a tmax of 24 h. In urine, M5 was the most abundant metabolite with 8.02% total radioactive dose (TRD), followed by M1a and M1b with 6.16% and 2.85% TRD, respectively; however, there were no metabolites in urine observed at >10% of dose. The major metabolite in feces was M18 representing 44.1% of the radioactive dose. These findings indicated that aficamten was eliminated by metabolism, and to a minor extent, by fecal excretion of unchanged aficamten with renal excretion playing a minor role. Feces were the principal route of excretion of the radioactive dose.
Assuntos
Biotransformação , Humanos , Masculino , Adulto , Fezes/química , Adulto Jovem , Miosinas Cardíacas/metabolismo , Pessoa de Meia-Idade , Administração Oral , Voluntários SaudáveisRESUMO
Alkylnaphthalene lubricating oils are synthetic Group V base oils that are utilized in wide-ranging industrial applications and which are composed of polyalkyl chain-alkylated naphthalenes. Identification of alkylnaphthalene biotransformation products and determination of their mass spectrometry (MS) fragmentation signatures provides valuable information for predicting their environmental fates and for development of analytical methods to monitor their biodegradation. In this work, laboratory-based environmental petroleomics was applied to investigate the catabolism of the alkylnaphthalene, 1-butylnaphthalene (1-BN), by liquid chromatography electrospray ionization MS data mapping and targeted collision-induced dissociation (CID) analyses. Comparative mapping revealed that numerous catabolites were produced from soil bacterium, Sphingobium barthaii KK22. Targeted CID showed unique patterns of production of even-valued deprotonated fragments that were found to originate from specific classes of bacterial catabolites. Based upon results of CID analyses of catabolites and authentic standards, MS signatures were proposed to occur through formation of distonic radical anions from bacterially-produced alkylphenol biotransformation products. Finally, spectra interpretation was guided by CID results to propose chemical structures for twenty-two 1-BN catabolites resulting in construction of 1-BN biotransformation pathways. Multiple pathways were identified that included aromatic ring-opening, alkyl chain-shortening and production of α,ß-unsaturated aldehydes from alkylated phenols. Until now, α,ß-unsaturated aldehydes have not been a class of compounds much reported from alkylated polycyclic aromatic hydrocarbon (APAH) and PAH biotransformation. This work provides a new understanding of alkylnaphthalene biotransformation and proposes MS markers applicable to monitoring APAH biotransformation in the form of alkylated phenols, and by extension, α,ß-unsaturated aldehydes, and toxic potential during spilled oil biodegradation.
Assuntos
Biodegradação Ambiental , Biotransformação , Naftalenos , Espectrometria de Massas por Ionização por Electrospray , Naftalenos/metabolismo , Naftalenos/química , Cromatografia Líquida , Espectrometria de Massas em Tandem , Lubrificantes/metabolismo , Lubrificantes/química , Bactérias/metabolismo , Sphingomonadaceae/metabolismoRESUMO
Dynamic transformation of dissolved organic matter (DOM) contributes to short-chain fatty acids (SCFAs) production during anaerobic digestion. However, the impact of refined transformation of DOM ranked by molecular weight (MW) on SCFAs has never been investigated. Results indicated that DOM conversion order was 3500-7000 Da>(MW>14000 Da) > 7000-4000 Da during hydrolysis stage, while it was independent of their MW in acidogenesis phase and followed a low to high MW order during methanogenesis stage. Proteins-like DOMs with different MW were closely related to SCFAs. Eight groups of microorganisms (e.g., Bacillus and Caldicoprobacter) responsible for the conversion of proteins-like DOMs to SCFAs. The possible routes linking environmental properties to microorganisms-proteins-like DOMs-SCFAs connections were constructed. Microbial activity modifications by regulating moisture, pH, NO3--N and NH4+-N can expedite the conversion of proteins-like DOMs to SCFAs. The study emphasizes the importance of MW-classification-based biotransformation of organic waste, offering a potential strategy to enhance anaerobic digestion performance.
Assuntos
Ácidos Graxos Voláteis , Peso Molecular , Ácidos Graxos Voláteis/metabolismo , Anaerobiose , Compostos Orgânicos/metabolismo , Bactérias/metabolismo , Biotransformação , Hidrólise , Reatores BiológicosRESUMO
Curcumin is widely recognized for its health benefits, though the role of gut microbiota in its metabolic transformation was not well studied. In this study, bacterial strains capable of metabolizing curcumin were isolated from human stool samples. Using 16S rRNA and whole-genome sequencing, two novel strains (Clostridium butyricum UMA_cur1 and Escherichia coli UMA_cur2) were identified. In addition, the metabolic products were analyzed using liquid chromatography-mass spectrometry. These strains efficiently converted curcumin into dihydro-curcumin (DHC) and tetrahydro-curcumin (THC). Notably, E. coli UMA_cur2 also produced hexahydro-curcumin (HHC) and octahydro-curcumin (OHC), marking the first identification of a strain capable of such transformations. The absence of the YncB gene (typically involved in curcumin conversion) in C. butyricum UMA_cur1 suggests an alternative metabolic pathway. Curcumin metabolism begins during the stationary growth phase, indicating that it is not crucial for primary growth functions. Furthermore, E. coli UMA_cur2 produced these metabolites sequentially, starting with DHC and THC and progressing to HHC and OHC. These findings identified two novel strains that can metabolize curcumin to hydrogenated metabolites, which enhance our understanding of the interaction between curcumin and gut microbiota.
Assuntos
Curcumina , Escherichia coli , Fezes , Microbioma Gastrointestinal , Humanos , Curcumina/metabolismo , Curcumina/química , Escherichia coli/metabolismo , Escherichia coli/genética , Fezes/microbiologia , Hidrogenação , RNA Ribossômico 16S/genética , Bactérias/metabolismo , Bactérias/genética , Bactérias/classificação , Bactérias/isolamento & purificação , BiotransformaçãoRESUMO
Alternaria alternata is a common plant pathogen that can infect crops and reduce their production. In this work, an antagonism experiment between A. alternata and the essential oil of arborvitae (Platycladus orientalis) was performed, and it was proven that A. alternata had developed resistance to this plant-derived fungicide. A. alternata facilitated the biotransformation of hinokitiol (1), the main antifungal compound in the essential oil of arborvitae, into (R)-2-hydroxy-ß-methylbenzeneethanol (2), which does not have antifungal activity against A. alternata. This biotransformation is an unusual ring-contraction reaction that was verified to be catalyzed by P450 enzyme hydroxylation and Baeyer-Villiger oxidation. In addition, the P450 enzyme inhibitors 1-aminobenzotriazole and piperonyl butoxide effectively prevented the destruction of the hinokitiol structure by A. alternata, and the combined use of these P450 enzyme inhibitors significantly increased the antifungal activity of hinokitiol. This work provides a theoretical reference for the further development of botanical fungicides.
Assuntos
Alternaria , Fungicidas Industriais , Monoterpenos , Doenças das Plantas , Tropolona , Alternaria/efeitos dos fármacos , Alternaria/metabolismo , Fungicidas Industriais/farmacologia , Fungicidas Industriais/química , Tropolona/farmacologia , Tropolona/análogos & derivados , Tropolona/química , Tropolona/metabolismo , Monoterpenos/farmacologia , Monoterpenos/metabolismo , Monoterpenos/química , Doenças das Plantas/microbiologia , Doenças das Plantas/prevenção & controle , Sistema Enzimático do Citocromo P-450/metabolismo , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/química , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Inativação Metabólica , BiotransformaçãoRESUMO
Black soldier fly larvae (BSFL) could convert a variety of organic wastes, including spent mushroom substrate (SMS) and wet distiller's grains (WDG). Nevertheless, little is known about the conversion of these wastes by BSFL. Thus, this study investigates the conversion of SMS and WDG in five different proportions by BSFL. This study demonstrates that BSFL can convert SMS, WDG, and their mixtures. It can also encourage the humification of the substrate, increasing the amount of element in the residues. It is evident that there were differences in the carbon and nitrogen element fractionation mode as well as the microbial community present in the residue. The microbial community of the substrate and the physiochemical parameters are intimately related to this. Although the mixture treated with BSFL helps to generate a residue with more humus, it might not be stable.
Assuntos
Agaricales , Biotransformação , Larva , Animais , Larva/metabolismo , Agaricales/metabolismo , Grão Comestível/metabolismo , Simuliidae/metabolismo , Dípteros/metabolismo , Carbono/metabolismo , Nitrogênio/metabolismoRESUMO
Carbon capture, utilization and storage is the vital technology for China to achieve the goals of carbon peaking and carbon neutrality. Microbial activities in situ are an indispensable part in the process of geological CO2 sequestration. Some microorganisms can convert CO2 into methane and organics as the resource for utilization or into carbonate to achieve long-term sequestration. These activities contribute to the stable storage of CO2 and even negative carbon emission. This paper focuses on the processes of bio-methanation, bio-liquefaction, and bio-precipitation that may be involved in CO2 sequestration in deep stratum and discusses the research progress in the bio-transformation pathways. Bio-methanation and bio-liquefaction can convert CO2 into methane or high-value organic compounds to realize resource reuse. The two technologies can be used alone or coupled to expand the application range of CO2 biotransformation. Bio-mineralization can convert CO2 into calcite by microorganism-induced carbonate precipitation, being a technology of great potential in fixing CO2 and limiting CO2 escape. At present, this field is still in the infancy stage, and there is an urgent need to establish and improve the theoretical and technical systems of CO2 in-situ biotransformation from transformation principle, influencing factors, conversion efficiency, economy, environmental protection, and technological conditions. Moreover, it can be combined with CCUS to establish a technical system integrating capture, transport, displace, storage, transfer, and exploit, so as to promote the value-added application of CCUS and the achievement of carbon peaking and carbon neutrality.
Assuntos
Dióxido de Carbono , Sequestro de Carbono , Metano , Dióxido de Carbono/metabolismo , Metano/metabolismo , Biotransformação , Bactérias/metabolismo , Carbonato de Cálcio/metabolismo , Carbonato de Cálcio/químicaRESUMO
Apical-out enteroids mimic the in vivo environment well due to their accessible apical surface and mucus layer, making them an ideal model for studying the impact of (bioactive) food compounds. Generated human ileal apical-out enteroids showed a fucose-containing mucus layer surrounding the apical brush border on their exposure side, indicating their physiological relevance. Effects on the mucosal epithelium of antibacterial prenylated phenolics (glabridin, licochalcone A, and glycycoumarin) from licorice roots were investigated for cytotoxicity, cell viability, barrier integrity, and biotransformation. At concentrations up to 500 µg mL-1, licochalcone A and glycycoumarin did not significantly affect apical-out enteroids, with cytotoxicities of -6 ± 2 and -2 ± 2% and cell viabilities of 77 ± 22 and 77 ± 13%, respectively (p > 0.05). Conversely, 500 µg mL-1 glabridin induced significant cytotoxicity (31 ± 25%, p < 0.05) and reduced cell viability (21 ± 14%, p < 0.01). Apical-out enteroids revealed differential sensitivities to prenylated phenolics not observed in apical-in enteroids and Caco-2 cells. Both enteroid models showed phase II biotransformation but differed in the extent of glucuronide conversion. The apical mucus layer of apical-out enteroids likely contributed to these differential interactions, potentially due to differences in electrostatic repulsion. This study underscores the relevance of 3D apical-out enteroid models and highlights the promise of prenylated phenolics for antimicrobial applications.
Assuntos
Biotransformação , Glycyrrhiza , Fenóis , Extratos Vegetais , Raízes de Plantas , Humanos , Glycyrrhiza/química , Glycyrrhiza/metabolismo , Fenóis/metabolismo , Fenóis/química , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Extratos Vegetais/metabolismo , Extratos Vegetais/química , Sobrevivência Celular/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Prenilação , Muco/metabolismo , Muco/química , Células CACO-2 , IsoflavonasRESUMO
Indole alkaloids are privileged secondary metabolites, and their production may be achieved by the microbial biotransformation of tryptophan analogues. By feeding 1-methyl-L-tryptophan (1-MT) into the culture of endophytic Nigrospora chinensis GGY-3, six novel (1-6) and seven known indole alkaloids (7-13) were generated. Their structures were elucidated by means of NMR spectroscopy, experimental electronic circular dichroism (ECD) spectra, and X-ray crystallography analysis. A Friedel-Crafts reaction was proposed as the key reaction responsible for the formation of the new compounds. Racemates 4 and 6 were separated into isomers by chiral HPLC, with their absolute configurations determined by X-ray and ECD calculation. Compounds 3, 4, and 8 display good herbicidal activity against dicotyledon weed Eclipta prostrata, of which 4 and 8 exhibited 88.50% and 100% inhibition rates on the radicle at 200 µg/mL, respectively, a similar effect compared to the positive control penoxsulam.
Assuntos
Biotransformação , Herbicidas , Alcaloides Indólicos , Triptofano , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Alcaloides Indólicos/metabolismo , Alcaloides Indólicos/isolamento & purificação , Triptofano/química , Triptofano/metabolismo , Herbicidas/química , Herbicidas/farmacologia , Herbicidas/metabolismo , Ascomicetos/química , Ascomicetos/metabolismo , Estrutura Molecular , Cristalografia por Raios X , Modelos Moleculares , Conformação MolecularRESUMO
Feedstock variability represents a challenge in lignocellulosic biorefineries, as it can influence both lignocellulose deconstruction and microbial conversion processes for biofuels and biochemicals production. The impact of feedstock variability on microbial performance remains underexplored, and predictive tools for microbial behaviour are needed to mitigate risks in biorefinery scale-up. Here, twelve batches of corn stover were deconstructed via deacetylation, mechanical refining, and enzymatic hydrolysis to generate lignin-rich and sugar streams. These batches and their derived streams were characterised to identify their chemical components, and the streams were used as substrates for producing muconate and butyrate by engineered Pseudomonas putida and wildtype Clostridium tyrobutyricum, respectively. Bacterial performance (growth, product titers, yields, and productivities) differed among the batches, but no strong correlations were identified between feedstock composition and performance. To provide metabolic insights into the origin of these differences, we evaluated the effect of twenty-three isolated chemical components on these microbes, including three components in relevant bioprocess settings in bioreactors, and we found that growth-inhibitory concentrations were outside the ranges observed in the streams. Overall, this study generates a foundational dataset on P. putida and C. tyrobutyricum performance to enable future predictive models and underscores their resilience in effectively converting fluctuating lignocellulose-derived streams into bioproducts.
Assuntos
Clostridium tyrobutyricum , Lignina , Engenharia Metabólica , Pseudomonas putida , Zea mays , Pseudomonas putida/genética , Pseudomonas putida/metabolismo , Lignina/metabolismo , Zea mays/microbiologia , Clostridium tyrobutyricum/metabolismo , Clostridium tyrobutyricum/genética , Biotransformação , Reatores Biológicos/microbiologia , Açúcares/metabolismo , Butiratos/metabolismoRESUMO
This study aimed at the biotransformation of sumatriptan by Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa and Salmonella enterica subsp. enterica and the identification of the drug metabolites by liquid chromatography-mass spectrometry. The drug was incubated with the organisms in tryptic soya broth at 37 °C. The broth was filtered and subjected to liquid chromatography-mass spectrometry. The metabolites identified by the use of mass spectral (+ve ion mode) fragmentation patterns were (3-methylphenyl)methanethiol (Bacillus subtilis), 1-(4-amino-3-ethylphenyl)-N-methylmethanesulfonamide (Salmonella enterica subsp. enterica) and 1-{4-amino-3-[(1E)-3-(dimethylamino)prop-1-en-1-yl]phenyl}methanesulfinamide (Salmonella enterica subsp. enterica, Bacillus subtilis, Pseudomonas aeruginosa, Staphylococcus aureus). These metabolites exhibit high gastrointestinal absorption, no blood-brain barrier permeability (except (3-methylphenyl)methanethiol), a bioavailability score of 0.55 and no inhibitory effect on CYP2C19, CYP2C9, CYP2D6, CYP3A4 or cytochrome P450 1A2 (except (3-methylphenyl)methanethiol), as determined by SwissADME software ver. 2024. The metabolites appear to be more toxic than the parent drug, as suggested by their calculated median lethal dose values. All four organisms under investigation transformed sumatriptan to different chemical substances that were more toxic than the parent drug.
Assuntos
Bacillus subtilis , Biotransformação , Pseudomonas aeruginosa , Salmonella enterica , Staphylococcus aureus , Sumatriptana , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/metabolismo , Bacillus subtilis/metabolismo , Bacillus subtilis/efeitos dos fármacos , Sumatriptana/metabolismo , Sumatriptana/farmacologia , Salmonella enterica/metabolismo , Salmonella enterica/efeitos dos fármacos , Humanos , Sistema Enzimático do Citocromo P-450/metabolismoRESUMO
Microorganisms are the only entities in the biosphere with an incomparable ability to employ diverse organic and inorganic compounds for growth and convert it to simple form that is no longer harmful to human health and environment. Food grade microorganisms such as lactic acid bacteria, bifidobacteria, propionibacteria as well as several yeast species are associated with food fermentation processes as well as have gained probiotic status owing to their noteworthy offerings in health stimulation as a natural gut microbiota in animals and humans. However, as biological agents little is known about their application for bioremediation and biotransformation aptitude. In context to this, aflatoxin M1 is a class of mycotoxins often associated with milk through consumption of fungus contaminated feed & fodders by cattle and well documented for their adverse health effects. Therefore, current review summarizes significance of aflatoxins present in milk and dairy products in human life, their source, types & health implications; food grade bacteria including probiotic strains and their mechanism of action involved in the removal of aflatoxin; and last section discusses the outcome of major studies showing aflatoxin reduction potential of food grade bacteria in milk and milk based products.
Assuntos
Leite , Animais , Leite/microbiologia , Leite/química , Biotransformação , Humanos , Aflatoxinas , Probióticos , Contaminação de Alimentos , Laticínios/microbiologia , Bovinos , Bactérias/metabolismo , Microbiologia de AlimentosRESUMO
Phytochemicals, plant-derived compounds, are the major components of traditional medicinal plants. Some phytochemicals have restricted applications, due to low bioavailability and less efficacy. However, their medicinal properties can be enhanced by converting them into value-added products for different bioactivities like anti-oxidant, neuroprotective, anti-obesity, anti-neuroinflammatory, anti-microbial, anti-cancer and anti-inflammatory. Microbial transformation is one such process that is generally more specific and makes it possible to modify a compound without making any unwanted alterations in the molecule. This has led to the efficient production of value-added products with important pharmacological properties and the discovery of new active compounds. The present review assimilates the existing knowledge of the microbial transformation of some phytochemicals like eugenol, curcumin, ursolic acid, cinnamaldehyde, piperine, ß-carotene, ß-sitosterol, and quercetin to value-added products for their application in food, fragrances, and pharmaceutical industries.
Assuntos
Compostos Fitoquímicos , Plantas Medicinais , Compostos Fitoquímicos/farmacologia , Plantas Medicinais/química , Eugenol/farmacologia , Ácido Ursólico , Alcaloides/farmacologia , Triterpenos/química , Acroleína/análogos & derivados , Curcumina/química , Curcumina/farmacologia , Biotransformação , Quercetina/química , Alcamidas Poli-Insaturadas , Sitosteroides , Piperidinas , BenzodioxóisRESUMO
Tebuconazole (TEB), a prominent chiral triazole fungicide, has been extensively utilized for plant pathogen control globally. Despite experimental evidence of TEB metabolism in mammals, the enantioselectivity in the biotransformation of R- and S-TEB enantiomers by specific CYP450s remains elusive. In this work, integrated in silico simulations were employed to unveil the binding interactions and enantioselective metabolic fate of TEB enantiomers within human CYP1A2, 2B6, 2E1, and 3A4. Molecular dynamics (MD) simulations clearly delineated the binding specificity of R- and S-TEB to the four CYP450s, crucially determining their differences in metabolic activity and enantioselectivity. The primary driving force for robust ligand binding was identified as van der Waals interactions with CYP450s, particularly involving the hydrophobic residues. Mechanistic insights derived from quantum mechanics/molecular mechanics (QM/MM) calculations established C2-methyl hydroxylation as the predominant route of R-/S-TEB metabolism, while C6-hydroxylation and triazol epoxidation were deemed kinetically infeasible pathways. Specifically, the resulting hydroxy-R-TEB metabolite primarily originates from R-TEB biotransformation by 1A2, 2E1 and 3A4, whereas hydroxy-S-TEB is preferentially produced by 2B6. These findings significantly contribute to our comprehension of the binding specificity and enantioselective metabolic fate of chiral TEB by CYP450s, potentially informing further research on human health risk assessment associated with TEB exposure.
Assuntos
Sistema Enzimático do Citocromo P-450 , Fungicidas Industriais , Simulação de Dinâmica Molecular , Triazóis , Triazóis/química , Triazóis/metabolismo , Fungicidas Industriais/química , Fungicidas Industriais/metabolismo , Humanos , Sistema Enzimático do Citocromo P-450/metabolismo , Estereoisomerismo , Simulação por Computador , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP1A2/química , Citocromo P-450 CYP2B6/metabolismo , Citocromo P-450 CYP2B6/química , Biotransformação , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP2E1/química , Citocromo P-450 CYP3A/metabolismoRESUMO
This comprehensive review elucidates the pivotal role of microbes in drug metabolism, synthesizing insights from an exhaustive analysis of over two hundred papers. Employing a structural classification system grounded in drug atom involvement, the review categorizes the microbiome-mediated drug-metabolizing capabilities of over 80 drugs. Additionally, it compiles pharmacodynamic and enzymatic details related to these reactions, striving to include information on encoding genes and specific involved microorganisms. Bridging biochemistry, pharmacology, genetics, and microbiology, this review not only serves to consolidate diverse research fields but also highlights the potential impact of microbial drug metabolism on future drug design and in silico studies. With a visionary outlook, it also lays the groundwork for personalized medicine interventions, emphasizing the importance of interdisciplinary collaboration for advancing drug development and enhancing therapeutic strategies.
Assuntos
Bactérias , Microbioma Gastrointestinal , Humanos , Bactérias/metabolismo , Bactérias/genética , Bactérias/classificação , Preparações Farmacêuticas/metabolismo , Animais , BiotransformaçãoRESUMO
Phenol-pyranoanthocyanins, a structurally modified type of anthocyanin, has higher stability than anthocyanins. However, their conversion occurs slowly. Therefore, it is crucial to improve the conversion efficiency and production of pyranoanthocyanins. In this study, cranberry anthocyanin (CRAN) was fermented using two Lactobacillus strains along with caffeic acid to form cranberry-derived pyranoanthocyanins (PY-CRAN). PY-CRAN was characterized and identified. The physicochemical properties, antioxidant activity, and tyrosinase inhibitory capacity of PY-CRAN were assessed. The results showed that phenol-pyranoanthocyanins can be rapidly produced through fermentative transformation using Lactiplantibacillus plantarum and Lacticaseibacillus paracasei. Lacticaseibacillus paracasei exhibits a higher propensity for producing phenol-pyranoanthocyanins. PY-CRAN exhibits high stability under light and various pH conditions. Moreover, they possess excellent antioxidant properties and the ability to inhibit tyrosinase. These results suggest that fermentative biotransformation conducted by Lactobacillus is an ideal method for producing cranberry pyranoanthocyanins. The resulting anthocyanins have potential as antioxidant and whitening agents, making them promising bioactive ingredients.
Assuntos
Antocianinas , Antioxidantes , Biotransformação , Fermentação , Vaccinium macrocarpon , Antocianinas/química , Antocianinas/metabolismo , Antioxidantes/química , Antioxidantes/metabolismo , Vaccinium macrocarpon/química , Vaccinium macrocarpon/metabolismo , Lactobacillus/metabolismo , Lactobacillus/química , Monofenol Mono-Oxigenase/metabolismo , Monofenol Mono-Oxigenase/química , Monofenol Mono-Oxigenase/antagonistas & inibidores , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Fenóis/metabolismo , Fenóis/químicaRESUMO
This study investigated the uptake pathways, acropetal translocation, subcellular distribution, and biotransformation of OPEs by rice (Oryza sativa L.) after Cu exposure. The symplastic pathway was noted as the major pathway for the uptake of organophosphate triesters (tri-OPEs) and diesters (di-OPEs) by rice roots. Cu exposure enhanced the accumulation of tri-OPEs in rice roots, and such enhancement was positively correlated with Cu concentrations, attributing to the Cu-induced root damage. The hydrophilic Cl-OPEs in the cell-soluble fraction of rice tissues were enhanced after Cu exposure, while the subcellular distributions of alkyl- and aryl-OPEs were not affected by Cu exposure. Significantly higher biotransformation rates of tri-OPEs to di-OPEs occurred in leaves, followed by those in stems and roots. Our study reveals the mechanisms associated with the uptake, translocation, and biotransformation of various OPEs in rice after Cu exposure, which provides new insights regarding the phytoremediation of soils cocontaminated with heavy metal and OPEs.
Assuntos
Biodegradação Ambiental , Biotransformação , Cobre , Organofosfatos , Oryza , Raízes de Plantas , Poluentes do Solo , Oryza/metabolismo , Oryza/química , Oryza/efeitos dos fármacos , Cobre/metabolismo , Poluentes do Solo/metabolismo , Raízes de Plantas/metabolismo , Raízes de Plantas/química , Raízes de Plantas/efeitos dos fármacos , Organofosfatos/metabolismo , Transporte Biológico , Folhas de Planta/metabolismo , Folhas de Planta/química , Folhas de Planta/efeitos dos fármacos , Ésteres/metabolismo , Ésteres/químicaRESUMO
α-Terpineol, an alcoholic monoterpene with lilac-like aroma, possesses diverse biological activities and has found applications in the food, pharmaceutical, cosmetic, and agricultural industries. Our previous studies indicated that gene PdTP1 was highly expressed in Penicillium digitatum DSM 62840 during the biotransformation of limonene to α-terpineol, while its actual biological functions are not fully understood. Here, PdTP1 was functionally characterized with bioinformatics analysis, subcellular localization, transcriptional activation activity, overexpression, and RNA interference (RNAi) silencing and RNA-seq analysis. Results showed that PdTP1 protein contained a GAL4-like Zn2Cys6 DNA-binding domain and a fungal_trans domain, was located in the nucleus and cell membrane and presented transcriptional activation effect, suggesting that PdTP1 encoded a Zn2Cys6 type transcription factor. Overexpression of PdTP1 in P. digitatum promoted limonene biotransformation and increased α-terpineol production, and opposite results were observed after the silencing of PdTP1. Moreover, transcription factor PdTP1 was found to affect the growth of P. digitatum and participate in ionic stress and oxidative stress responses. RNA-seq data revealed that altering the PdTP1 expression influenced the expression of some genes related to terpene metabolism or biosynthesis, fungal growth, and stress responses. In summary, PdTP1, which encoded a Zn2Cys6 transcription factor, played important roles in improving the production of α-terpineol from limonene and regulating fungal growth and environmental stress responses.