Human Enzymes for Organic Synthesis

Winkler, Margit; Geier, Martina; Hanlon, Steven P.; Nidetzky, Bernd; Glieder, Anton

doi:10.1002/anie.201800678

Cited by 46 publications

(43 citation statements)

References 150 publications

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“…Obviously, human liver P450s are in the focus of research in drug discovery because they are responsible for the degradation of drugs and xenobiotics in the body . With their broad substrate tolerance these liver P450s are attractive tools for predicting in vivo drug interactions via in vitro reactions or drug metabolite synthesis via late‐stage modifications ,…”

Section: Examplesmentioning

confidence: 99%

P450 Monooxygenases Enable Rapid Late‐Stage Diversification of Natural Products via C−H Bond Activation

Fessner

2019

ChemCatChem

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The biological potency of natural products has been exploited for decades. Their inherent structural complexity and natural diversity might hold the key to efficiently address the urgent need for the development of novel pharmaceuticals. At the same time, it is that very complexity, which impedes necessary chemical modifications such as structural diversification, to improve the effectiveness of the drug. For this purpose, Cytochrome P450 enzymes, which possess unique abilities to activate inert sp3‐hybridised C−H bonds in a late‐stage fashion, offer an attractive synthetic tool. In this review the potential of cytochrome P450 enzymes in chemoenzymatic lead diversification is illustrated discussing studies reporting late‐stage functionalisations of natural products and other high‐value compounds. These enzymes were proven to extend the synthetic toolbox significantly by adding to the flexibility and efficacy of synthetic strategies of natural product chemists, and scientists of other related disciplines.

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Section: Examplesmentioning

confidence: 99%

P450 Monooxygenases Enable Rapid Late‐Stage Diversification of Natural Products via C−H Bond Activation

Fessner

2019

ChemCatChem

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“…Total synthesis of all the metabolites is not suitable for general metabolomics‐based structure validation. Chemoenzymatic glucuronidation approaches have been reported as well; however, these show limitations for the monoglucuronidation of polyphenols, which are among the most common xenobiotics . Our enzymatic analysis design permits us to introduce an additional level of chemical structure confirmation that is not possible with standard approaches.…”

Section: Figurementioning

confidence: 99%

Coupled Enzymatic Treatment and Mass Spectrometric Analysis for Identification of Glucuronidated Metabolites in Human Samples

et al. 2019

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Glucuronidation is the most common phase II modification and plays an important role in human clearance metabolism. Glucuronidated metabolites have also been linked to disease development and microbiota–host co‐metabolism. Although many of these compounds have been identified, the total number of unknown glucuronides and their impact on the human host's physiology can only be estimated. Herein, we describe the combination of an untargeted metabolomics analysis and enzymatic metabolic conversion for the selective detection of glucuronide conjugates by using UPLC‐MS/MS in human urine samples. Our study demonstrates that this powerful strategy can be used for the selective identification of glucuronidated molecules and to discover unknown natural metabolites. In total, we identified 191 metabolites in a single sample including microbiota‐derived compounds as well as previously unidentified molecules.

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“…Generally, human drug-metabolizing P450s possess an extraordinary broad substrate spectrum and form distinct oxidation products, which are difficult to access via chemical synthesis. [5] However, application of membrane bound human P450s is somewhat limited by their low expression titers, activity and process stability. [6] For this reason, bacterial P450s with high activity and stability, easily expressible in recombinant hosts, have been subjected to rational protein design and/or directed evolution to achieve production of drug metabolites.…”

Section: Introductionmentioning

confidence: 99%

Two‐step Screening for Identification of Drug‐metabolizing Bacterial Cytochromes P450 with Diversified Selectivity

et al. 2020

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The evaluation of drug metabolites is compulsory during drug development. Since recently, bacterial cytochromes P450 and their mutated variants have attracted considerable interest as an alternative to hepatic P450s for the synthesis of human drug metabolites. Thus, straightforward screening approaches are required that enable rapid identification and evaluation of drug‐metabolizing bacterial P450s with different product selectivities. Herein, we report a two‐step screening method for discovery and characterization of new P450s from actinomycetes that enable oxidation of various drugs. In the first step, substrate profiling with three structurally different model drugs, ritonavir, testosterone, amitriptyline, allowed us to select CYP105D and CYP107Z from Streptomyces platensis DSM 40041 that accepted all model substrates and produced human‐like drug metabolites. In the second step, activity tests with an array of 25 structurally‐related molecules and derivatives of the three model compounds revealed a correlation between structural variations in the target drugs and the enzyme chemo‐ and regioselectivity.

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Human Enzymes for Organic Synthesis

Cited by 46 publications

References 150 publications

P450 Monooxygenases Enable Rapid Late‐Stage Diversification of Natural Products via C−H Bond Activation

P450 Monooxygenases Enable Rapid Late‐Stage Diversification of Natural Products via C−H Bond Activation

Coupled Enzymatic Treatment and Mass Spectrometric Analysis for Identification of Glucuronidated Metabolites in Human Samples

Two‐step Screening for Identification of Drug‐metabolizing Bacterial Cytochromes P450 with Diversified Selectivity

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