Abstract

The aminotransferase from Bacillus circulans (BtrR), which is involved in the biosynthesis of butirosin, catalyzes the pyridoxal phosphate (PLP)-dependent transamination reaction to convert valienone to β-valienamine (a new β-glycosidase inhibitor for the treatment of lysosomal storage diseases) with an optical purity enantiomeric excess value. To explore the stereoselective mechanism of valienamine generated by BtrR, multiple molecular dynamics (MD) simulations were performed for the BtrR/PLP/valienamine and BtrR/PLP/β-valienamine complexes. The theoretical results showed that β-valienamine could make BtrR more stable and dense than valienamine. β-valienamine could increase the hydrogen bond probability and decrease the binding free energy between coenzyme PLP and BtrR by regulating the protein structure of BtrR, which was conducive to the catalytic reaction. β-valienamine maintained the formation of cation-p interactions between basic and aromatic amino acids in BtrR, thus enhancing its stability and catalytic activity. In addition, CAVER 3.0 analysis revealed that β-valienamine could make the tunnel of BtrR wider and straight, which was propitious to the removal of products from BtrR. Steered MD simulation results showed that valienamine interacted with more residues in the tunnel during dissociation compared with β-valienamine, resulting in the need for a stronger force to be acquired from BtrR. Taken together, BtrR was more inclined to catalyze the substrates to form β-valienamine, either from the point of view of the catalytic reaction or product removal.

Highlights

  • Valienamine is an unsaturated cyclic alcohol pseudo-aminosaccharide with side chains and has been developed as a novel glucosidase inhibitor because of its similar chemical structure with D-glucose [1]

  • The results showed that β-valienamine could enhance the interaction between pyridoxal phosphate (PLP) and Bacillus used a heterogeneous aminotransferase (BtrR)

  • molecular dynamics (MD) results showed that β-valienamine could enhance the hydrogen bond interaction between BtrR

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Summary

Introduction

Valienamine is an unsaturated cyclic alcohol pseudo-aminosaccharide with side chains and has been developed as a novel glucosidase inhibitor because of its similar chemical structure with D-glucose [1]. It can control blood glucose elevation, and various diseases caused by hyperglycemia, such as diabetes. It can effectively treat sclerosis, obesity, diabetes, and hyperlipidemia [2,3]. The derivative (N-octyl-β-valienamine) of β-valienamine is an effective therapeutic agent for lysosomal storage diseases caused by the disorder of β-glycosidase [4,5,6].

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