Acarbose degradation mechanism guides design of next-generation antidiabetic drug

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder marked by hyperglycemia. Acarbose is a potent glycosidase inhibitor widely used in the clinical treatment of T2DM. However, acarbose-preferred glucosidase (Apg) in K. grimontii TD1 degrades acarbose to acarviosine-glucose (M1) and acarviosine (M2), affecting its efficiency.

In a study published in Nature Communications, a research team led by GU Yang from the Shenzhen Institutes of Advanced Technology (SIAT) of the Chinese Academy of Sciences, along with collaborators, revealed the detailed molecular mechanism of Apg hydrolyzing acarbose.

Molecular docking simulations in previous research suggest that acarbose is hydrolyzed by orienting the nucleophile D336 towards at the linkage between the third and the fourth rings, yielding the three-ring product M1, or at the linkage between the second and the third rings, yielding the two-ring product M2.

In this study, through high-resolution structural analysis, biochemical experiments, and multiscale computational simulations, researchers identified D448 as the key nucleophile, rather than D336, and found that both E373 and R334 could function as substrate donors. 

Besides, they revealed that the two-step acarbose degradation mechanism involves an M1 intermediate, with the second-step hydrolysis being the rate-limiting step.

Moreover, researchers conducted comprehensive computational evaluations of acarbose analogs acarstatins A and B based on crystallographic structures, and demonstrated their resistance to Apg. 

These findings provide clear targets for designing novel anti-degradation diabetes therapeutics, specifically, by interfering with the nucleophilic attack of D448 through the extension of the sugar chain or the modification of the -1 subsite. 

This study paves the way for developing more efficient and degradation-resistant hypoglycemic drugs.