Production of metabolites of the anti-cancer drug noscapine using a P450BM3 mutant library

Richards, Luke; Lutz, Adrian; Chalmers, David K.; Jarrold, Ailsa; Bowser, Tim; Stevens, Geoffrey W.; Gras, Sally L.

doi:10.1016/j.btre.2019.e00372

Cited by 16 publications

(16 citation statements)

References 58 publications

(81 reference statements)

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“…B. Chlorzoxazon, Te stosteron (14), Amitriptylin, Lidocain, Diclofenac,N aproxen und Noscapin, welches somit die Bedeutung P450-katalysierter Hydroxylie-rungen fürd ie Synthese mutmaßlicher Wirkstoffmetabolite hervorhebt. [53,54] Die Entwicklung von P450-Enzymen fürd ie Produktion nützlicher oxygenierter Terpenintermediate fürd ie weitere Funktionalisierung erçffnet einen Ausganspunkt fürw ertvolle Carotenoide und Vitamine. [55] Zum Beispiel erleichtern P450cam und P450-BM3 eine Verschiebung der Hydroxylierungsselektivitätd er Monoterpene 1,4-(16)u nd 1,8-Cineol (17), wodurch zwei Stereozentren aufgebaut werden (Abbildung 6).…”

Section: Hydroxylierungunclassified

Enzymkatalysierte späte Modifizierungen: Besser spät als nie

Romero

Jones²,

Hogg³

et al. 2021

Angewandte Chemie

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Section: Hydroxylierungunclassified

Enzymkatalysierte späte Modifizierungen: Besser spät als nie

Romero

Jones²,

Hogg³

et al. 2021

Angewandte Chemie

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“…The biosynthesis of noscapine ( 5 ) starts from l ‐tyrosine ( 6 ) and proceeds via the intermediate reticuline ( 7 ). Residues that were successfully modified in reticuline and noscapine by biotechnological or semisynthetic methods are highlighted [90–102,105,106,108] …”

Section: Engineering Anti‐inflammatory Natural Productsmentioning

confidence: 99%

“…The respective platform strain will certainly facilitate further endeavors for the biotechnological preparation of noscapine analogues. Another noteworthy development in this field was the use of a library of cytochrome P450 monooxygenases to selectively introduce modifications into the noscapine scaffold [108] . A directed evolution of these enzymes enhanced their activity on 5 , which then enabled the production of N ‐demethylated and different hydroxylated noscapine derivatives under in vitro conditions [108] …”

Section: Engineering Anti‐inflammatory Natural Productsmentioning

confidence: 99%

“…Residues that were successfully modified in reticuline and noscapine by biotechnological or semisynthetic methods are highlighted. [90][91][92][93][94][95][96][97][98][99][100][101][102]105,106,108] The biotechnological production of noscapine analogues became possible following the discovery and characterization of its biosynthesis gene cluster in the opium poppy. [103,104] The natural assembly of 5 is extremely complex.…”

Section: Noscapinementioning

confidence: 99%

“…[108] A directed evolution of these enzymes enhanced their activity on 5, which then enabled the production of N-demethylated and different hydroxylated noscapine derivatives under in vitro conditions. [108]…”

Section: Noscapinementioning

confidence: 99%

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Inflammatory processes occur as a generic response of the immune system and can be triggered by various factors, such as infection with pathogenic microorganisms or damaged tissue. Due to the complexity of the inflammation process and its role in common diseases like asthma, cancer, skin disorders or Alzheimer's disease, anti‐inflammatory drugs are of high pharmaceutical interest. Nature is a rich source for compounds with anti‐inflammatory properties. Several studies have focused on the structural optimization of natural products to improve their pharmacological properties. As derivatization through total synthesis is often laborious with low yields and limited stereoselectivity, the use of biosynthetic, enzyme‐driven reactions is an attractive alternative for synthesizing and modifying complex bioactive molecules. In this minireview, we present an outline of the biotechnological methods used to derivatize anti‐inflammatory natural products, including precursor‐directed biosynthesis, mutasynthesis, combinatorial biosynthesis, as well as whole‐cell and in vitro biotransformation.

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Enzyme catalysis is gaining increasing importance in synthetic chemistry. Nowadays, the growing number of biocatalysts accessible by means of bioinformatics and enzyme engineering opens up an immense variety of selective reactions. Biocatalysis especially provides excellent opportunities for late‐stage modification often superior to conventional de novo synthesis. Enzymes have proven to be useful for direct introduction of functional groups into complex scaffolds, as well as for rapid diversification of compound libraries. Particularly important and highly topical are enzyme‐catalysed oxyfunctionalisations, halogenations, methylations, reductions, and amide bond formations due to the high prevalence of these motifs in pharmaceuticals. This Review gives an overview of the strengths and limitations of enzymatic late‐stage modifications using native and engineered enzymes in synthesis while focusing on important examples in drug development.

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Production of metabolites of the anti-cancer drug noscapine using a P450BM3 mutant library

Abstract: Highlights Mutants of P450 BM3 can metabolise noscapine. Noscapine is N -demethylated with high selectivity. The metabolites produced are of interest for drug development. The profile of metabolites generated resembles that of mammalian CYP3A4.

Cited by 16 publications

References 58 publications

Enzymkatalysierte späte Modifizierungen: Besser spät als nie

Enzymkatalysierte späte Modifizierungen: Besser spät als nie

Bioengineering of Anti‐Inflammatory Natural Products

Enzymatic Late‐Stage Modifications: Better Late Than Never

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