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Max J Cryle - One of the best experts on this subject based on the ideXlab platform.
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Chlorinated Glycopeptide Antibiotic Peptide Precursors Improve Cytochrome P450-Catalyzed Cyclization Cascade Efficiency
Biochemistry, 2017Co-Authors: Madeleine Peschke, Clara Brieke, Ralf B. Schittenhelm, Robert J.a. Goode, Max J CryleAbstract:The activity of glycopeptide antibiotics (GPAs) depends upon important structural modifications to their precursor heptapeptide backbone: specifically, the cytochrome P450-catalyzed oxidative cross-linking of aromatic side chains as well as the Halogenation of specific residues within the peptide. The timing of Halogenation and its effect on the cyclization of the peptide are currently unclear. Our results show that chlorination of peptide precursors improves their processing by P450 enzymes in vitro, which provides support for GPA Halogenation occurring prior to peptide cyclization during nonribosomal peptide synthesis. We could also determine that the activity of the second enzyme in the oxidative cyclization cascade, OxyA, remains higher for chlorinated peptide substrates even when the biosynthetic GPA product possesses an altered chlorination pattern, which supports the role of the chlorine atoms in orienting the peptide substrate in the active site of these enzymes.
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Chlorinated Glycopeptide Antibiotic Peptide Precursors Improve Cytochrome P450-Catalyzed Cyclization Cascade Efficiency
2017Co-Authors: Madeleine Peschke, Clara Brieke, Ralf B. Schittenhelm, Robert J.a. Goode, Max J CryleAbstract:The activity of glycopeptide antibiotics (GPAs) depends upon important structural modifications to their precursor heptapeptide backbone: specifically, the cytochrome P450-catalyzed oxidative cross-linking of aromatic side chains as well as the Halogenation of specific residues within the peptide. The timing of Halogenation and its effect on the cyclization of the peptide are currently unclear. Our results show that chlorination of peptide precursors improves their processing by P450 enzymes in vitro, which provides support for GPA Halogenation occurring prior to peptide cyclization during nonribosomal peptide synthesis. We could also determine that the activity of the second enzyme in the oxidative cyclization cascade, OxyA, remains higher for chlorinated peptide substrates even when the biosynthetic GPA product possesses an altered chlorination pattern, which supports the role of the chlorine atoms in orienting the peptide substrate in the active site of these enzymes
Madeleine Peschke - One of the best experts on this subject based on the ideXlab platform.
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Chlorinated Glycopeptide Antibiotic Peptide Precursors Improve Cytochrome P450-Catalyzed Cyclization Cascade Efficiency
Biochemistry, 2017Co-Authors: Madeleine Peschke, Clara Brieke, Ralf B. Schittenhelm, Robert J.a. Goode, Max J CryleAbstract:The activity of glycopeptide antibiotics (GPAs) depends upon important structural modifications to their precursor heptapeptide backbone: specifically, the cytochrome P450-catalyzed oxidative cross-linking of aromatic side chains as well as the Halogenation of specific residues within the peptide. The timing of Halogenation and its effect on the cyclization of the peptide are currently unclear. Our results show that chlorination of peptide precursors improves their processing by P450 enzymes in vitro, which provides support for GPA Halogenation occurring prior to peptide cyclization during nonribosomal peptide synthesis. We could also determine that the activity of the second enzyme in the oxidative cyclization cascade, OxyA, remains higher for chlorinated peptide substrates even when the biosynthetic GPA product possesses an altered chlorination pattern, which supports the role of the chlorine atoms in orienting the peptide substrate in the active site of these enzymes.
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Chlorinated Glycopeptide Antibiotic Peptide Precursors Improve Cytochrome P450-Catalyzed Cyclization Cascade Efficiency
2017Co-Authors: Madeleine Peschke, Clara Brieke, Ralf B. Schittenhelm, Robert J.a. Goode, Max J CryleAbstract:The activity of glycopeptide antibiotics (GPAs) depends upon important structural modifications to their precursor heptapeptide backbone: specifically, the cytochrome P450-catalyzed oxidative cross-linking of aromatic side chains as well as the Halogenation of specific residues within the peptide. The timing of Halogenation and its effect on the cyclization of the peptide are currently unclear. Our results show that chlorination of peptide precursors improves their processing by P450 enzymes in vitro, which provides support for GPA Halogenation occurring prior to peptide cyclization during nonribosomal peptide synthesis. We could also determine that the activity of the second enzyme in the oxidative cyclization cascade, OxyA, remains higher for chlorinated peptide substrates even when the biosynthetic GPA product possesses an altered chlorination pattern, which supports the role of the chlorine atoms in orienting the peptide substrate in the active site of these enzymes
Gunda I Georg - One of the best experts on this subject based on the ideXlab platform.
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preparation and three carbon two carbon cycloaddition of cyclopropenone 1 3 propanediol ketal 5 5 dicyano 4 phenyl 2 cyclopenten 1 one 1 3 propanediol ketal
Organic Syntheses, 2003Co-Authors: Dale L Boger, Christine E Brotherton, Gunda I GeorgAbstract:Preparation and three-carbon + two-carbon cycloaddition of cyclopropenone 1,3-propanediol ketal: 5,5-Dicyano-4-phenyl-2-cyclopenten-1-one 1,3-propanediol ketal intermediate: 2-(bromomethyl)-2-(chloromethyl)-1,3-dioxane intermediate: Cyclopropenone 1,3-propanediol ketal product: 5,5-dicyano-4-phenyl-2-cyclopenten-1-one 1,3-propanediol ketal Keywords: acetal (and thioacetal) formation; alkylation, C-alkylation; annulation, carbocyclic-[3]; annulation, carbocyclic-[5]; cyclization, condensation; cyclization, cycloaddition; Halogenation, bromination; Halogenation, bromination; ring expansion reactions; potassium amide, preparation of; pressure reactions, use of resealable glass tubes
Norbert Sewald - One of the best experts on this subject based on the ideXlab platform.
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Straightforward Regeneration of Reduced Flavin Adenine Dinucleotide Required for Enzymatic Tryptophan Halogenation.
ACS catalysis, 2019Co-Authors: Mohamed F. Ismail, Lea Schroeder, Marcel Frese, Tilman Kottke, Frank Hollmann, Caroline E. Paul, Norbert SewaldAbstract:Flavin-dependent halogenases are known to regioselectively introduce halide substituents into aromatic moieties, for example, the indole ring of tryptophan. The process requires halide salts and oxygen instead of molecular halogen in the chemical Halogenation. However, the reduced cofactor flavin adenine dinucleotide (FADH2) has to be regenerated using a flavin reductase. Consequently, coupled biocatalytic steps are usually applied for cofactor regeneration. Nicotinamide adenine dinucleotide (NADH) mimics can be employed stoichiometrically to replace enzymatic cofactor regeneration in biocatalytic Halogenation. Chlorination of l-tryptophan is successfully performed using such NADH mimics. The efficiency of this approach has been compared to the previously established enzymatic regeneration system using the two auxiliary enzymes flavin reductase (PrnF) and alcohol dehydrogenase (ADH). The reaction rates of some of the tested mimics were found to exceed that of the enzymatic system. Continuous enzymatic Halogenation reaction for reaction scale-up is also possible.
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Straightforward Regeneration of Reduced Flavin Adenine Dinucleotide Required for Enzymatic Tryptophan Halogenation
2019Co-Authors: Mohamed Ismail, Lea Schroeder, Marcel Frese, Tilman Kottke, Frank Hollmann, Caroline E. Paul, Norbert SewaldAbstract:Flavin-dependent halogenases are known to regioselectively introduce halide substituents into aromatic moieties, for example, the indole ring of tryptophan. The process requires halide salts and oxygen instead of molecular halogen in the chemical Halogenation. However, the reduced cofactor flavin adenine dinucleotide (FADH2) has to be regenerated using a flavin reductase. Consequently, coupled biocatalytic steps are usually applied for cofactor regeneration. Nicotinamide adenine dinucleotide (NADH) mimics can be employed stoichiometrically to replace enzymatic cofactor regeneration in biocatalytic Halogenation. Chlorination of l-tryptophan is successfully performed using such NADH mimics. The efficiency of this approach has been compared to the previously established enzymatic regeneration system using the two auxiliary enzymes flavin reductase (PrnF) and alcohol dehydrogenase (ADH). The reaction rates of some of the tested mimics were found to exceed that of the enzymatic system. Continuous enzymatic Halogenation reaction for reaction scale-up is also possible
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modular combination of enzymatic Halogenation of tryptophan with suzuki miyaura cross coupling reactions
Chemcatchem, 2016Co-Authors: Marcel Frese, Christian Schnepel, Hannah Minges, Hauke Vos, Rebecca C Feiner, Norbert SewaldAbstract:The combination of the biocatalytic Halogenation of l-tryptophan with subsequent chemocatalytic Suzuki-Miyaura crosscoupling reactions leads to the modular synthesis of an array of C5, C6, or C7 aryl-substituted tryptophan derivatives. In a three-step one-pot reaction, the bromo substituent is initially incorporated regioselectively by immobilized tryptophan 5-, 6-, or 7-halogenases, respectively, with concomitant cofactor regeneration. The Halogenation proceeds in aqueous media at room temperature in the presence of NaBr and O-2. After the separation of the biocatalyst by filtration, a Pd catalyst, base, and boronic acid are added to the aryl halide formed in situ to effect direct Suzuki-Miyaura cross-coupling reactions followed by tert-butoxycarbonyl (Boc) protection. After a single purification step, different Boc-protected aryl tryptophan derivatives are obtained that can, for example, be used for peptide or peptidomimetic synthesis.
Clara Brieke - One of the best experts on this subject based on the ideXlab platform.
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Chlorinated Glycopeptide Antibiotic Peptide Precursors Improve Cytochrome P450-Catalyzed Cyclization Cascade Efficiency
Biochemistry, 2017Co-Authors: Madeleine Peschke, Clara Brieke, Ralf B. Schittenhelm, Robert J.a. Goode, Max J CryleAbstract:The activity of glycopeptide antibiotics (GPAs) depends upon important structural modifications to their precursor heptapeptide backbone: specifically, the cytochrome P450-catalyzed oxidative cross-linking of aromatic side chains as well as the Halogenation of specific residues within the peptide. The timing of Halogenation and its effect on the cyclization of the peptide are currently unclear. Our results show that chlorination of peptide precursors improves their processing by P450 enzymes in vitro, which provides support for GPA Halogenation occurring prior to peptide cyclization during nonribosomal peptide synthesis. We could also determine that the activity of the second enzyme in the oxidative cyclization cascade, OxyA, remains higher for chlorinated peptide substrates even when the biosynthetic GPA product possesses an altered chlorination pattern, which supports the role of the chlorine atoms in orienting the peptide substrate in the active site of these enzymes.
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Chlorinated Glycopeptide Antibiotic Peptide Precursors Improve Cytochrome P450-Catalyzed Cyclization Cascade Efficiency
2017Co-Authors: Madeleine Peschke, Clara Brieke, Ralf B. Schittenhelm, Robert J.a. Goode, Max J CryleAbstract:The activity of glycopeptide antibiotics (GPAs) depends upon important structural modifications to their precursor heptapeptide backbone: specifically, the cytochrome P450-catalyzed oxidative cross-linking of aromatic side chains as well as the Halogenation of specific residues within the peptide. The timing of Halogenation and its effect on the cyclization of the peptide are currently unclear. Our results show that chlorination of peptide precursors improves their processing by P450 enzymes in vitro, which provides support for GPA Halogenation occurring prior to peptide cyclization during nonribosomal peptide synthesis. We could also determine that the activity of the second enzyme in the oxidative cyclization cascade, OxyA, remains higher for chlorinated peptide substrates even when the biosynthetic GPA product possesses an altered chlorination pattern, which supports the role of the chlorine atoms in orienting the peptide substrate in the active site of these enzymes
