Structure-function analysis of CYP719As involved in methylenedioxy bridge-formation in the biosynthesis of benzylisoquinoline alkaloids and its de novo production.
Benzylisoquinoline alkaloids (BIAs)
Corydalis yanhusuo
CyCYP719As
Methylenedioxy bridge-formation
Regiospecificity
Synthetic biology
Journal
Microbial cell factories
ISSN: 1475-2859
Titre abrégé: Microb Cell Fact
Pays: England
ID NLM: 101139812
Informations de publication
Date de publication:
03 Feb 2023
03 Feb 2023
Historique:
received:
11
12
2022
accepted:
17
01
2023
entrez:
4
2
2023
pubmed:
5
2
2023
medline:
8
2
2023
Statut:
epublish
Résumé
Benzylisoquinoline alkaloids (BIAs) are a type of secondary metabolite with clinical application value. (S)-stylopine is a special BIA which contains methylenedioxy bridge structures. CYP719As could catalyze the methylenedioxy bridge-formation on the A or D rings of protoberberine alkaloids, while displaying significant substrate regiospecificity. To explore the substrate preference of CYP719As, we cloned and identified five CyCYP719A candidates from Corydalis yanhusuo. Two CyCYP719As (CyCYP719A39 and CyCYP719A42) with high catalytic efficiency for the methylenedioxy bridge-formation on the D or A rings were characterized, respectively. The residues (Leu 294 for CyCYP719A42 and Asp 289 for CyCYP719A39) were identified as the key to controlling the regioselectivity of CYP719As affecting the methylenedioxy bridge-formation on the A or D rings by homology modeling and mutation analysis. Furthermore, for de novo production of BIAs, CyCYP719A39, CyCYP719A42, and their mutants were introduced into the (S)-scoulerine-producing yeast to produce 32 mg/L (S)-stylopine. These results lay a foundation for understanding the structure-function relationship of CYP719A-mediated methylenedioxy bridge-formation and provide yeast strains for the BIAs production by synthetic biology.
Identifiants
pubmed: 36737755
doi: 10.1186/s12934-023-02024-2
pii: 10.1186/s12934-023-02024-2
pmc: PMC9898898
doi:
Substances chimiques
Benzylisoquinolines
0
Alkaloids
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
23Subventions
Organisme : National Natural Science Foundation of China
ID : 82011530137, 31961133007, 82003904
Organisme : The ability to establish sustainable use of valuable Chinese medicine resources
ID : 2060302
Organisme : the Fundamental Research Funds of China Academy of Chinese Medical Sciences
ID : ZZXT201807 and ZZ13-YQ-083
Organisme : Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine
ID : ZYYCXTD-D-202005
Organisme : Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences
ID : CI2021B014
Informations de copyright
© 2023. The Author(s).
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