Abstract
The α-glucosidase inhibitor acarbose, produced by Actinoplanes sp. SE50/110, is a well-known drug for the treatment of type 2 diabetes mellitus. However, the largely unexplored biosynthetic mechanism of this compound has impeded further titer improvement. Herein, we uncover that 1-epi-valienol and valienol, accumulated in the fermentation broth at a strikingly high molar ratio to acarbose, are shunt products that are not directly involved in acarbose biosynthesis. Additionally, we find that inefficient biosynthesis of the amino-deoxyhexose moiety plays a role in the formation of these shunt products. Therefore, strategies to minimize the flux to the shunt products and to maximize the supply of the amino-deoxyhexose moiety are implemented, which increase the acarbose titer by 1.2-fold to 7.4 g L−1. This work provides insights into the biosynthesis of the C7-cyclitol moiety and highlights the importance of assessing shunt product accumulation when seeking to improve the titer of microbial pharmaceutical products.
Highlights
The α-glucosidase inhibitor acarbose, produced by Actinoplanes sp
The biosynthesis of the C7-cyclitol moiety has been demonstrated to be initiated by the cyclization of sedo-heptulose-7-phosphate by AcbC to give 2-epi-5-epi-valiolone (3), which is subsequently phosphorylated by AcbM and isomerized by AcbO to give intermediate 5-epi-valiolone-7-P (4)[19,20,21]
The amino-deoxyhexose moiety has been shown to derive from glucose-1-P (5) catalyzed by D-glucose-1-P thymidylyltransferase (AcbA, abbreviated as G-1-PT) and dTDP-Dglucose 4,6-dehydratase (AcbB, 4,6-DH) to give dTDP-4-keto-6deoxy-D-glucose (6), followed by transamination catalyzed by AcbV to give dTDP-4-amino-4,6-dideoxy-D-glucose (7)[1,22]
Summary
The α-glucosidase inhibitor acarbose, produced by Actinoplanes sp. SE50/110, is a well-known drug for the treatment of type 2 diabetes mellitus. 1234567890():,; The α-glucosidase inhibitor acarbose (1) is one of the prominent representatives of C7N-aminocyclitol-containing natural products and has been used for the clinical treatment of type 2 diabetes mellitus since it was introduced to the market in 19901,2. This pseudosugar-containing oligosaccharide has competitive inhibitory activities toward intestinal maltase, sucrase, dextrinase, and glucoamylase, and thereby delays carbohydrate absorption and controls postprandial hyperglycemia[1,3]. We employ multiple metabolic engineering strategies to modulate the flux between the C7-cyclitol and the aminodeoxyhexose moieties and are able to substantially increase the titer of 1 and decrease the accumulations of the shunt products
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
