Acarbose glycosylation by AcbE for the production of acarstatins with enhanced α-amylase inhibitory activity

Acarbose is a potent glycosidase inhibitor widely used in the clinical treatment of type 2 diabetes mellitus (T2DM). Various acarbose analogs have been identified while exploring compounds with improved pharmacological properties. In this study, we found that AcbE from Actinoplanes sp. SE50/110 cata...

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Bibliographic Details
Published in:Synthetic and systems biotechnology 2024-06, Vol.9 (2), p.359-368
Main Authors: Zhang, Xin, Huang, Qungang, Guo, Ziyue, Cai, Feifei, Kang, Qianjin, Bai, Linquan
Format: Article
Language:English
Subjects:
Acarbose
Acarbose analogs
Actinoplanes sp
Amylases
Analogs
Catalysis
Chromatography
Diabetes
Diabetes mellitus
Diabetes mellitus (non-insulin dependent)
Fermentation
Glucosidase
Glycosidases
Glycosylation
Hydrolysis
Kinases
Mass spectrometry
Mass spectroscopy
Microbiomes
Microbiota
NMR
Nuclear magnetic resonance
Peptides
Pharmacology
Phosphorylation
Scientific imaging
Substrates
Transglycosylase
α-Amylase
α-amylase inhibitory activity
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Summary:Acarbose is a potent glycosidase inhibitor widely used in the clinical treatment of type 2 diabetes mellitus (T2DM). Various acarbose analogs have been identified while exploring compounds with improved pharmacological properties. In this study, we found that AcbE from Actinoplanes sp. SE50/110 catalyzes the production of acarbose analogs that exhibit significantly improved inhibitory activity towards α-amylase than acarbose. Recombinant AcbE mainly catalyzed the formation of two new compounds, namely acarstatins A and B, using acarbose as substrate. Using high-resolution mass spectrometry, nuclear magnetic resonance, and glycosidase hydrolysis, we elucidated their chemical structures as O-α-d-maltosyl-(1 → 4)-acarbose and O-α-d-maltotriosyl-(1 → 4)-acarbose, respectively. Acarstatins A and B exhibited 1584- and 1478-fold greater inhibitory activity towards human salivary α-amylase than acarbose. Furthermore, both acarstatins A and B exhibited complete resistance to microbiome-derived acarbose kinase 1-mediated phosphorylation and partial resistance to acarbose-preferred glucosidase-mediated hydrolysis. Therefore, acarstatins A and B have great potential as candidate therapeutic agents for T2DM.
ISSN:2405-805X
2405-805X
DOI:10.1016/j.synbio.2024.03.006