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Creating molecular complexity in the chemoenzymatic synthesis of chlorothricin analogues using tandem Diels-Alderases.

Chlorothricin is a polyketide-derived natural product isolated from Streptomyces antibioticus. It possesses an elaborate pentacyclic aglycon … ently relaxed substrate selectivity to facilitate access to non-natural chlorothricin analogues via biotransformations. The X-ray crystal structure of ChlE3 reveals the molecular basis of decalin formation by this enzyme. Harnessing this enzymatic cascade in biocatalysis could provide a valuable biomimetic route to both natural and non-natural spirotetronates, and …

Regulation of sterol metabolism by gut microbiota and its relevance to disease.

Sterols play an indispensable role in maintaining cell membrane stability, regulating hormone synthesis, and preserving physiological homeos … s and metabolic mechanisms of sterols, with an emphasis on the involvement of gut microbiota in the biotransformation of zoosterols, phytosterols, and mycosterols. Additionally, it explores the pathological implications of sterol metabolism disorders in diseases such as Alzheimer's disease and cancer. Finally, the review highlights the potential of dietary interven …

Site-specific impact of polyphenols on the gastrointestinal microbiome.

The gastrointestinal (GI) tract hosts a diverse microbiota composed of trillions of microorganisms that play crucial roles in maintaining human homeostasis, health, and overall well-being. Dietary polyphenols, primarily found in edible plants, exhibit intricate interactions with the GI microbiota. These polyphenols undergo biotransformation by microbial activity and can modulate the growth of microorganisms, either promoting or inhibiting their proliferation. The composition of microbes in different segments of the GI tract is highly variable and directly influences polyphenols' metabolism. Co…

Pharmacomicrobiomics in Anticancer Therapies: Why the Gut Microbiota Should Be Pointed Out.

Anticancer treatments have shown a variable therapeutic outcome that may be partly attributable to the activity of the gut microbiota on the pathology and/or therapies. In recent years, microbiota-drug interactions have been extensively investigated, but most of the underlying molecular mechanisms still remain unclear. In this review, we discuss the relationship between the gut microbiota and some of the most commonly used drugs in oncological diseases. Different strategies for manipulating the gut microbiota layout (i.e., prebiotics, probiotics, antibiotics, and fecal microbiota transplantati

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… Gut Microbial Metabolite P-Cresol Alters Biotransformation of Bisphenol A: Enzyme Competition or Gene Induction? J. Hazard. Mater. 2022 426 128093 10.1016/j.jhazmat.2021.128093 34952505 23. Clayton T.A. Baker D. Lindon J.C. Everett J.R. Nicholson J.K. …

Degradation of Xenobiotic Pollutants: An Environmentally Sustainable Approach.

The ability of microorganisms to detoxify xenobiotic compounds allows them to thrive in a toxic environment using carbon, phosphorus, sulfur, and nitrogen from the available sources. Biotransformation is the most effective and useful metabolic process to degrade xenobiotic compounds. Microorganisms have an exceptional ability due to particular genes, enzymes, and degradative mechanisms. Microorganisms such as bacteria and fungi have unique properties that enable them to partially or completely metabolize the xenobiotic substances in various ecosystems.There are many cutting-edge approaches ava…

Fate, behaviour and weathering of priority HNS in the marine environment: An online tool.

Literature data and data obtained with modelling tools were compiled to derive the physicochemical behaviour of 24 priority Hazardous and Noxious Substances (HNS), as a proxy to improve environmental, public health and political issues in relation to HNS spills. Parameters that rule the HNS behaviour in water and those that determine their distribution and persistence in the environment, such as fugacity, physicochemical degradation, biodegradation, bioaccumulation/biotransformation and aquatic toxicity, were selected. Data systematized and produced in the frame of the Arcopol Platform project…

Distribution profiles of nitroxide spin probes in human skin--a combined study using spatially resolved electron spin resonance spectroscopy and mass spectrometry.

Electron spin resonance spectroscopy and mass spectrometry are two analytical methods that are very rarely used in combination. In this paper, we will show that the methods complement one another in the example of the distribution of stable nitroxide radicals in human skin, including the spatial resolution of these distribution processes. There are many ESR investigations dealing with this subject, but unfortunately, they are all limited to the detection of paramagnetic species. The combination with MS allows the successful examination of the distribution profile of the main biotransformation …

An improved synthesis of lysosomal activated mustard prodrug for tumor-specific activation and its cytotoxic evaluation.

Cyclophosphamide, an alkylating agent widely used as anticancer agent, biotransformed in vivo to unstable phosphoramidic mustard and acrolein, where the latter metabolite has been found responsible for hemorrhagic cystitis and renal toxicity. Being one of the most popular strategies to avoid these deleterious effects, prodrug design has been attempted, which can, in addition, enable selective drug targeting. Our efforts to design, synthesize and evaluate the enzymatically activated prodrug phosphorodiamidic mustard as potential candidate for selective chemotherapy in antibody-directed enzyme p

Evaluation of the use of UPLC-TOFMS with simultaneous [14C]-radioflow detection for drug metabolite profiling: application to propranolol metabolites in rat urine.

The non-selective beta-adrenergic receptor antagonist propranolol [1-(isopropylamino)-3-(1-naphthoxy)-2-propanol] is metabolised extensively in vivo. Enumerating and identifying the many metabolites that result from multiple biotransformations provides a considerable analytical challenge, greatly aided by efficient chromatography coupled to sensitive mass spectrometric detection. Here the use of the newly introduced high-resolution technique of "ultra performance liquid chromatography" (UPLC) linked to quadrupole time-of-flight mass spectrometry (TOFMS) with simultaneous [(14)C]-radioflow dete…

Effect of hepatic insufficiency on pharmacokinetics and drug dosing.

The liver plays a central role in the pharmacokinetics of many drugs. Liver dysfunction may not only reduce the plasma clearance of a number of drugs eliminated by biotransformation and/or biliary excretion, but it can also affect plasma protein binding which in turn could influence the processes of distribution and elimination. In addition, reduced liver blood flow in patients with chronic liver disease will decrease the systemic clearance of flow limited (high extraction) drugs and portal-systemic shunting may substantially reduce their presystemic elimination (first-pass effect) following o…

Prefeeding-dependent anaerobic metabolization of xenobiotics by intestinal bacteria--methods for acarbose metabolites in an artificial colon.

The biotransformation of Acarbose (Bay g 5421) by an artificial in vitro system with viable intestinal microorganisms was investigated. The bacteria were obtained from the colon of man or from the caecum and colon of rats and were incubated anaerobically with 14C-Acarbose in a nutrient solution. The metabolites were separated and purified by chromatographic methods and identified by nuclear magnetic resonance (1H; 13C) spectrometry and by mass spectrometry. Metabolites in man and rat are component 2 (minus the terminal glucose of Acarbose), a basic disaccharide consisting of rings B and C, and…

Analysis of NADPH supply during xylitol production by engineered Escherichia coli.

Escherichia coli strain PC09 (DeltaxylB, cAMP-independent CRP (crp*) mutant) expressing an NADPH-dependent xylose reductase from Candida boi … xylitol produced per glucose consumed), and xylitol yields (Y(RPG)) were measured from resting cell biotransformations with various PC09 derivative strains. For the case of xylose-proton symport, omitting the Zwf (glucose-6-phosphate dehydrogenase) or PntAB (membrane-bound transhydrogenase) reactions or TCA cycle activity from the model reduces the theoretical maxi …

Bioconversion of selenite to selenium nanoparticles by Paenibacillus polymyxa P10: metabolic basis and potential for wastewater treatment.

Sustainable bioprocesses for selenite [Se(IV)] remediation and selenium (Se) recovery are constrained by the limited tolerance of most reported microorganisms for elevated Se(IV) concentrations. Here, we identified Paenibacillus polymyxa P10, isolated from estuarine sediment, as a highly tolerant and efficient Se(IV)-reducing bacterium. Strain P10 completely reduced 5 mM Se(IV) to Se nanoparticles (SeNPs) within 48 h and retained measurable Se(IV)-reducing activity up to 1,000 mM Se(IV). It also maintained activity over a wide range of pH (5-10), temperature (20-45°C), and salinity (1%-3.5%) c

Bacterial Autoimmune Drug Metabolism Transforms an Immunomodulator into Structurally and Functionally Divergent Antibiotics.

Tapinarof is a stilbene drug that is used to treat psoriasis and atopic dermatitis, and is thought to function through regulation of the AhR and Nrf2 signaling pathways, which have also been linked to inflammatory bowel diseases. It is produced by the gammaproteobacterial Photorhabdus genus, which thus represents a model to probe tapinarof structural and functional transformations. We show that Photorhabdus transforms tapinarof into novel drug metabolism products that kill inflammatory bacteria, and that a cupin enzyme contributes to the conversion of tapinarof and related dietary stilbenes in

LC-MS-based metabolomics: an update.

Liquid chromatography-mass spectrometry (LC-MS)-based metabolomics can have a major impact in multiple research fields, especially when combined with other technologies, such as stable isotope tracers and genetically modified mice. This review highlights recent applications of metabolomic technology in the study of xenobiotic metabolism and toxicity, and the understanding of disease pathogenesis and therapeutics. Metabolomics has been employed to study metabolism of noscapine, an aryl hydrocarbon receptor antagonist, and to determine the mechanisms of liver toxicities of rifampicin and isoniaz

Microbial degradation of the herbicide molinate by defined cultures and in the environment.

Molinate is a thiocarbamate herbicide used worldwide in rice crop protection. As with other pesticides, molinate is a recognized environmental pollutant, detected in soils, irrigation water, or rivers and bio-accumulated by some wildlife forms. For this reason, and in spite of its low toxicity to humans, environmental protection measures, which include reduction of use and/or remediation processes, are recommended. Due to its physic-chemical properties, molinate can easily disperse and react in the environment, originating diverse transformation products, some with increased toxicity. In spite

The cruciferous phytoalexins rapalexin A, brussalexin A and erucalexin: chemistry and metabolism in Leptosphaeria maculans.

The interactions of the cruciferous phytoalexins rapalexin A (1), brussalexin A (2) and erucalexin (3) with the fungal plant pathogen Leptosphaeria maculans were analyzed and their inhibitory activities against this pathogen were determined. The reaction of L. maculans to N-methyl S-(indolyl-3-methyl)carbamodithioate, an analogue of brussalexin A, was also investigated. Rapalexin A was resistant to metabolism and was the most inhibitory of all compounds tested, suggesting that increasing concentrations of rapalexin A in Brassica species would improve their disease resistance to L. maculans. By

Synthesis of short-chain diols and unsaturated alcohols from secondary alcohol substrates by the Rieske nonheme mononuclear iron oxygenase MdpJ.

The Rieske nonheme mononuclear iron oxygenase MdpJ of the fuel oxygenate-degrading bacterial strain Aquincola tertiaricarbonis L108 has been described to attack short-chain tertiary alcohols via hydroxylation and desaturation reactions. Here, we demonstrate that also short-chain secondary alcohols can be transformed by MdpJ. Wild-type cells of strain L108 converted 2-propanol and 2-butanol to 1,2-propanediol and 3-buten-2-ol, respectively, whereas an mdpJ knockout mutant did not show such activity. In addition, wild-type cells converted 3-methyl-2-butanol and 3-pentanol to the corresponding de

Biosynthesis of 2-amino-2,3-dimethylbutyramide by nitrile hydratase from a newly isolated cyanide-resistant strain of Rhodococcus qingshengii.

Cells of a new isolate of Rhodococcus qingshengii harboring nitrile hydratase converted 2-amino-2,3-dimethylbutyronitrile into 2-amino-2,3-dimethylbutyramide (ADBA). Cells also hydrated a broad range of substrates including saturated, unsaturated and cyclic aliphatic nitriles. The microorganism tolerated KCN and ADBA up to 5 mM and 40 g/l, respectively. At 10 °C, ADBA reached 33.8 g/l (yield 84.5%) which was 2.5 times that at 30 °C.

In situ production of methylmercury within a stream channel in northern California.

Natural stream ecosystems throughout the world are contaminated by methylmercury, a highly toxic compound that bioaccumulates and biomagnifies in aquatic food webs. Wetlands are widely recognized as hotspots for the production of methylmercury and are often assumed to be the main sources of this neurotoxin in downstream ecosystems. However, many streams lacking wetlands in their drainage basins (e.g., montane and semiarid regions in the western United States) have significant methylmercury contamination, and the sources of methylmercury in these streams remain largely unknown. In this study, w