Regio- and enantioselective O-demethylation of tetrahydroprotoberberines by cytochrome P450 enzyme system from Streptomyces griseus ATCC 13273

Tetrahydroprotoberberines (THPBs), a class of naturally occurring isoquinoline alkaloids, contain substituent methoxyl or hydroxyl groups which play a significant role in the pharmacological properties of these molecules. In this study, we report a biocatalytic strategy for selective O-demethylation...

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Bibliographic Details
Published in:Applied microbiology and biotechnology 2019-01, Vol.103 (2), p.761-776
Main Authors: Shen, Chen, Shan, Tianyue, Zhao, Wanli, Ou, Chenhui, Li, Li, Liu, Xiufeng, Liu, Jihua, Yu, Boyang
Format: Article
Language:English
Subjects:
Alkaloids
Analysis
Biomedical and Life Sciences
Biotechnologically Relevant Enzymes and Proteins
Biotechnology
Bone cancer
Chemical processes
Cytochrome
Cytochrome P-450
Cytochrome P450
Demethylation
Drug tolerance
Enantiomers
Heme
Heterocyclic aromatic compounds
Identification and classification
Iron
Life Sciences
Methods
Microbial Genetics and Genomics
Microbiology
Morphine
Pain
Pharmaceutical industry
Properties
Streptomyces
Streptomyces griseus
Structure
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Summary:Tetrahydroprotoberberines (THPBs), a class of naturally occurring isoquinoline alkaloids, contain substituent methoxyl or hydroxyl groups which play a significant role in the pharmacological properties of these molecules. In this study, we report a biocatalytic strategy for selective O-demethylation of THPBs. CYP105D1, a cytochrome P450 from Streptomyces griseus ATCC 13273, exhibited markedly regioselective demethylation of nonhydroxyl-THPBs and monohydroxyl-THPBs on the D-ring. A possible binding mode of THPBs with CYP105D1 was investigated by docking analysis, and the results revealed that the D-rings of THPBs were with the minimum distance to the heme iron. Tetrahydropalmatine was used as a model substrate and enantioselective demethylation was demonstrated. ( S )-Tetrahydropalmatine was only demethylated at C-10, while ( R )-tetrahydropalmatine was first demethylated at C-10 and then subsequently demethylated at C-9. The k cat/ K m value for demethylation of ( R )-tetrahydropalmatine by CYP105D1 was 3.7 times greater than that for demethylation of ( S )-tetrahydropalmatine. Furthermore, selective demethylation of ( S )-tetrahydropalmatine by the CYP105D1-based whole-cell system was demonstrated for the highly efficient production of ( S )-corydalmine which has distinct pharmacological applications, such as providing relief from bone cancer pain and reducing morphine tolerance. Moreover, a homologous redox partner was identified to enhance the catalytic efficiency of the CYP105D1-based whole-cell system. This is the first enzymatic characterization of a cytochrome P450 that has regio- and enantioselective demethylation activity of THPBs for application purpose. The cytochrome P450 system could be a promising strategy for selective demethylation in the pharmaceutical industry.
ISSN:0175-7598
1432-0614
DOI:10.1007/s00253-018-9416-4