Accessing the Biocatalytic Potential for C−H‐Activation by Targeted Genome Mining and Screening

Cytochrome P450 monooxygenases (P450s) are ubiquitous hemeproteins that insert oxygen specifically into substrates leading to diverse chemical transformations. Utilizing their capabilities, microbial whole‐cell biocatalysts are applied in pharmaceutical and fine chemical industry to produce biomolec...

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Bibliographic Details
Published in:ChemCatChem 2019-12, Vol.11 (23), p.5766-5777
Main Authors: Schmitz, Lisa Marie, Schäper, Jonas, Rosenthal, Katrin, Lütz, Stephan
Format: Article
Language:English
Subjects:
Actinosynnema mirum
Biocatalysts
Biomolecules
Biotransformation
biotransformations
Chemical industry
Conversion
cytochrome P450 monooxygenases (P450s)
Cytochromes P450
Fine chemicals
Genomes
genomic data mining
hydroxylation
Metabolites
Microorganisms
NMR
Nuclear magnetic resonance
Organic chemistry
Screening
Substrates
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Summary:Cytochrome P450 monooxygenases (P450s) are ubiquitous hemeproteins that insert oxygen specifically into substrates leading to diverse chemical transformations. Utilizing their capabilities, microbial whole‐cell biocatalysts are applied in pharmaceutical and fine chemical industry to produce biomolecules and drug metabolites. In order to synthesize novel bioactive compounds there is a great demand to identify P450s with new reaction and substrate scope. In this study, genome mining and an activity screening were successfully combined to discover so far underutilized biocatalysts. The screening revealed the expected broad range of reactions, such as hydroxylations, dealkylations, reductions and desaturations. For Actinosynnema mirum and ritonavir the biotransformation was transferred to a preparative scale resulting in a ritonavir conversion of 90 % after 48 h and 13 different metabolites analyzed by LC‐MS2 and NMR. These results clearly demonstrate the potential of the underlying approach to identify promising whole cell biocatalysts with good conversion and product scopes. Finding the P450 in the haystack! Genome data mining within sequenced strains finds novel microbial P450 monooxygenases. In combination with an activity screening this approach revealed several microbial candidates showing broad substrate scopes and a diverse formation of hydroxylation products. These strains harbor huge potential for further biotechnological applications.
ISSN:1867-3880
1867-3899
DOI:10.1002/cctc.201901273