Machine Learning in Early Prediction of Metabolism of Drugs.

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.

Biotransformation of Sumatriptan by Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa and Salmonella enterica subsp. enterica.

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.

Isolation and Identification of Human Gut Bacteria Capable of Converting Curcumin to Its Hydrogenated Metabolites.

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.

[Research advances of microbial transformation of CO2 in geological sequestration].

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.

Assessment of bacterial biotransformation of alkylnaphthalene lubricating base oil component 1-butylnaphthalene by LC/ESI-MS(/MS).

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.

Microbial Biotransformation of 1-Methyl-L-tryptophan into Herbicidal Indole Alkaloids by Endophytic Fungus Nigrospora chinensis GGY-3.

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.

Effects of black soldier fly larvae on biotransformation and residues of spent mushroom substrate and wet distiller's grains.

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.

Biotransformation and Epithelial Toxicity of Prenylated Phenolics from Licorice Roots (Glycyrrhiza spp.) in 3D Apical-Out Mucus-Producing Human Enteroids.

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.

Insight into response mechanism of short-chain fatty acids to refined microbial transformation order of dissolved organic matter ranked by molecular weight during dry anaerobic digestion.

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.

Feedstock variability impacts the bioconversion of sugar and lignin streams derived from corn stover by Clostridium tyrobutyricum and engineered Pseudomonas putida.

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.

Pharmacokinetics, disposition, and biotransformation of the cardiac myosin inhibitor aficamten in humans.

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.

Sucrose as an electron source for cofactor regeneration in recombinant Escherichia coli expressing invertase and a Baeyer Villiger monooxygenase.

BACKGROUND: The large-scale biocatalytic application of oxidoreductases requires systems for a cost-effective and efficient regeneration of redox cofactors. These represent the major bottleneck for industrial bioproduction and an important cost factor. In this work, co-expression of the genes of invertase and a Baeyer-Villiger monooxygenase from Burkholderia xenovorans to E. coli W ΔcscR and E. coli BL21 (DE3) enabled efficient biotransformation of cyclohexanone to the polymer precursor, ε-caprolactone using sucrose as electron source for regeneration of redox cofactors, at rates comparable to glucose. E. coli W ΔcscR has a native csc regulon enabling sucrose utilization and is deregulated via deletion of the repressor gene (cscR), thus enabling sucrose uptake even at concentrations below 6 mM (2 g L-1). On the other hand, E. coli BL21 (DE3), which is widely used as an expression host does not contain a csc regulon. RESULTS: Herein, we show a proof of concept where the co-expression of invertase for both E. coli hosts was sufficient for efficient sucrose utilization to sustain cofactor regeneration in the Baeyer-Villiger oxidation of cyclohexanone. Using E. coli W ΔcscR, a specific activity of 37 U gDCW-1 was obtained, demonstrating the suitability of the strain for recombinant gene co-expression and subsequent whole-cell biotransformation. In addition, the same co-expression cassette was transferred and investigated with E. coli BL21 (DE3), which showed a specific activity of 17 U gDCW- 1. Finally, biotransformation using photosynthetically-derived sucrose from Synechocystis S02 with E. coli W ΔcscR expressing BVMO showed complete conversion of cyclohexanone after 3 h, especially with the strain expressing the invertase gene in the periplasm. CONCLUSIONS: Results show that sucrose can be an alternative electron source to drive whole-cell biotransformations in recombinant E. coli strains opening novel strategies for sustainable chemical production.

In vitro approach to refine bioconcentration and biotransformation predictions of organic persistent pollutants using cell lines.

The application of the 3Rs (Replacement, Reduction, and Refinement) in animal experimentation has recently concentrated its efforts on utilizing cellular systems to predict toxicity in organisms. In this context, while refining the data obtained from cell lines, this study assesses their bioaccumulation potential and various methods for extrapolating the in vitro metabolization rate constant to support modelled bioaccumulation assessments for fish and their limitations. For this purpose, the concentrations of the parent compound, phenanthrene, and its major metabolites within the cells and in the medium at various exposure times were quantified. A chemical distribution model (mass balance) was applied to calculate the concentrations of the cell-bioaccessible compounds (Cfree) based on the experimentally determined concentrations. An elevated matching was observed between the in vitro bioconcentration factor (BCF) and the in vivo BCFs reported in the literature for zebrafish liver cells (ZFL). This study demonstrates the importance of further investigating in vitro biotransformation kinetics. The results obtained with the approach developed here provide valuable information to enhance current models. Additionally, it underscores the potential of cell lines as a strategy for rapid, simple, and cost-effective predictions without the need for animal experimentation.

Microbial transformation of some phytochemicals into value-added products: A review.

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.

Lactobacillus fermentation accelerated biotransformation of cranberry anthocyanins towards phenol-pyranoanthocyanins and their stability and antioxidant property.

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.

Computational simulations uncover enantioselective metabolism of chiral triazole fungicides by human CYP450 enzymes: A case study of tebuconazole.

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.

Biotransformation pathways of pharmaceuticals and personal care products (PPCPs) during acidogenesis and methanogenesis of anaerobic digestion.

Pharmaceuticals and personal care products (PPCPs) exhibit varying biodegradability during the acidogenic and methanogenic phases of anaerobic digestion. However, there is limited information regarding the end products generated during these processes. This work investigates the biotransformation products (BTPs) generated in a two-phase (TP) acidogenic-methanogenic (Ac-Mt) bioreactor using advanced suspect and nontarget strategies. Fourteen BTPs were confidently identified from ten parent PPCPs including carbamazepine (CBZ), naproxen (NPX), diclofenac (DCF), ibuprofen (IBU), acetaminophen (ACT), metoprolol (MTP), sulfamethoxazole (SMX), ciprofloxacin (CIP), methylparaben (MPB) and propylparaben (PPB). These BTPs were linked with oxidation reactions such as hydroxylation, demethylation and epoxidation. Their generation was related to organic acid production, since all metabolites were detected during acidogenesis, with some being subsequently consumed during methanogenesis, e.g., aminothiophenol and kynurenic acid. Another group of BTPs showed increased concentrations under methanogenic conditions, e.g., hydroxy-diclofenac and epoxy-carbamazepine. The most PPCPs showed high removal efficiencies (> 90 %) - SMX, CIP, NPX, MTP, ACT, MPB, PPB, while DCF, CBZ and IBU demonstrated higher persistence - DCF (42 %); CBZ (40 %), IBU (47 %). The phase separation of anaerobic digestion provided a deeper understanding of the biotransformation pathways of PPCPs, in addition to enhancing the biodegradability of the most persistent compounds, i.e., DCF, CBZ and IBU.

Combination of biotransformation and metabolomics reveals tolfenpyrad-induced hepatocytotoxicity.

Tolfenpyrad (TFP) is an extensively used pesticide that inevitably leads to human exposure to both TFP and its transformation product residues. However, the biotransformation of TFP in humans has not been elucidated, and the toxicity of TFP along with its biotransformation products remains largely unknown. In this study, the biotransformation process of TFP was investigated using human liver microsomes and human hepatic cells. Endogenous metabolic changes in the cells were studied to investigate the hepatocytotoxicity of TFP at environmentally relevant concentrations. Fourteen phase I biotransformation products and four phase II TFP products were characterized, among which twelve products were identified for the first time. The oxidative product tolfenpyrad-benzoic acid (PT-CA) was particularly abundant and stable. Further hepatotoxicity assessments and metabolic studies demonstrated comparable metabolic profiles for TFP and PT-CA in HepG2 cells, with both significantly disrupting purine and glutathione metabolism. These processes are closely associated with oxidative stress, mitochondrial damage, and cell death. Our results provide novel perspectives on the biotransformation, metabolism, and hepatotoxicity of TFP, thereby highlighting the non-negligible toxicity of its crucial biotransformation product PT-CA in environmental risk assessments.

Microbial metabolism marvels: a comprehensive review of microbial drug transformation capabilities.

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.

[Progress and perspectives of natural cell factories for chemical production from methanol].

Methanol has been considered one of the most important alternative carbon sources for the next-generation biomanufacturing due to its low price, mature production processes, and potential sustainability. Constructing microbial cell factories for methanol to chemical biotransformation has become a research hotspot in the green biomanufacturing industry. Focusing on the microorganisms that can naturally use methanol, we compare them with non-natural cell factories for chemical production from methanol. We discuss the key issues and challenges associated with natural cell factories for chemical production from methanol, summarize recent research progress surrounding these issues, and propose possible solutions to these challenges. This review helps to generate feasible guidelines and research strategies for the modification of natural cell factories for efficient methanol to chemical production in the future.