Complete biosynthetic pathway to the antidiabetic drug acarbose

The market demand for acarbose, a drug used for treatment of patients affected by type-2 diabetes, has increased. In this article, the authors report the acarbose complete biosynthetic pathway, clarifying previously unknown steps and identifying a pseudoglycosyltransferase enzyme, AcbS, a homologue of AcbI that catalyzes the formation of a non-glycosidic C-N bond. Acarbose is a bacterial-derived alpha-glucosidase inhibitor clinically used to treat patients with type 2 diabetes. As type 2 diabetes is on the rise worldwide, the market demand for acarbose has also increased. Despite its significant therapeutic importance, how it is made in nature is not completely understood. Here, we report the complete biosynthetic pathway to acarbose and its structural components, GDP-valienol and O-4-amino-(4,6-dideoxy-alpha-D-glucopyranosyl)-(1 -> 4)-O-alpha-D-glucopyranosyl-(1 -> 4)-D-glucopyranose. GDP-valienol is derived from valienol 7-phosphate, catalyzed by three cyclitol modifying enzymes, whereas O-4-amino-(4,6-dideoxy-alpha-D-glucopyranosyl)-(1 -> 4)-O-alpha-D-glucopyranosyl-(1 -> 4)-D-glucopyranose is produced from dTDP-4-amino-4,6-dideoxy-D-glucose and maltose by the glycosyltransferase AcbI. The final assembly process is catalyzed by a pseudoglycosyltransferase enzyme, AcbS, which is a homologue of AcbI but catalyzes the formation of a non-glycosidic C-N bond. This study clarifies all previously unknown steps in acarbose biosynthesis and establishes a complete pathway to this high value pharmaceutical.

Automated summary

This article reports the complete biosynthetic pathway of acarbose, a drug used for treating type-2 diabetes, and identifies a pseudoglycosyltransferase enzyme. The market demand for acarbose has increased as the number of type-2 diabetes patients worldwide rises.