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Acarbose glycosylation by AcbE for the production of acarstatins with enhanced α-amylase inhibitory activity
- Source :
- Synthetic and Systems Biotechnology, Vol 9, Iss 2, Pp 359-368 (2024)
- Publication Year :
- 2024
- Publisher :
- KeAi Communications Co., Ltd., 2024.
-
Abstract
- 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.
Details
- Language :
- English
- ISSN :
- 2405805X
- Volume :
- 9
- Issue :
- 2
- Database :
- Directory of Open Access Journals
- Journal :
- Synthetic and Systems Biotechnology
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.22356a4010b64499a611e5260f5cf45b
- Document Type :
- article
- Full Text :
- https://doi.org/10.1016/j.synbio.2024.03.006