ChemInform Abstract: STRUCTURE OF AN α‐D‐GLUCOSIDASE INHIBITOR ACARBOSE

Junge, Bodo; Heiker, F. R.; Kurz, Jürgen; Mueller, Lisa S.; Schmidt, Delf; Wuensche, C.

doi:10.1002/chin.198449305

Cited by 2 publications

(2 citation statements)

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“…One example of this compound class is Acarbose ( 1 ), an inhibitor of the GH13 enzyme human pancreatic α-amylase and a treatment for type-II diabetes mellitus (T2D), Fig. 1 15 , 16 . The inhibitory activities of 1 and related compounds has been commonly ascribed to the ability to mimic a glucopyranosyl half-chair conformation intermediate of glycosidase catalysis 12 , 15 , 17 ; further, the exocyclic nitrogen atom has been shown to form coulombic interactions in GH complexes 18 .…”

Section: Introductionmentioning

confidence: 99%

Stereoselective synthesis of a 4-⍺-glucoside of valienamine and its X-ray structure in complex with Streptomyces coelicolor GlgE1-V279S

Jayasinghe

Thanvi

et al. 2021

Sci Rep

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Glycoside hydrolases (GH) are a large family of hydrolytic enzymes found in all domains of life. As such, they control a plethora of normal and pathogenic biological functions. Thus, understanding selective inhibition of GH enzymes at the atomic level can lead to the identification of new classes of therapeutics. In these studies, we identified a 4-⍺-glucoside of valienamine (8) as an inhibitor of Streptomyces coelicolor (Sco) GlgE1-V279S which belongs to the GH13 Carbohydrate Active EnZyme family. The results obtained from the dose–response experiments show that 8 at a concentration of 1000 µM reduced the enzyme activity of Sco GlgE1-V279S by 65%. The synthetic route to 8 and a closely related 4-⍺-glucoside of validamine (7) was achieved starting from readily available D-maltose. A key step in the synthesis was a chelation-controlled addition of vinylmagnesium bromide to a maltose-derived enone intermediate. X-ray structures of both 7 and 8 in complex with Sco GlgE1-V279S were solved to resolutions of 1.75 and 1.83 Å, respectively. Structural analysis revealed the valienamine derivative 8 binds the enzyme in an E2 conformation for the cyclohexene fragment. Also, the cyclohexene fragment shows a new hydrogen-bonding contact from the pseudo-diaxial C(3)–OH to the catalytic nucleophile Asp 394 at the enzyme active site. Asp 394, in fact, forms a bidentate interaction with both the C(3)–OH and C(7)-OH of the inhibitor. In contrast, compound 7 disrupts the catalytic sidechain interaction network of Sco GlgE1-V279S via steric interactions resulting in a conformation change in Asp 394. These findings will have implications for the design other aminocarbasugar-based GH13-inhibitors and will be useful for identifying more potent and selective inhibitors.

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Section: Introductionmentioning

confidence: 99%

Stereoselective synthesis of a 4-⍺-glucoside of valienamine and its X-ray structure in complex with Streptomyces coelicolor GlgE1-V279S

Jayasinghe

Thanvi

et al. 2021

Sci Rep

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“…[10][11][12][13] 1-Aminocarbasugars are thought to mimic charge development in the TS by incorporating a basic nitrogen atom in place of C(1)-O. 14 One example of this compound class is Acarbose (1), an inhibitor of the GH13 enzyme human pancreatic αamylase and a treatment for type-II diabetes mellitus (T2D), Figure 1, 15,16 while aminocarbasugars related to validamine (2a) and valienamine (6) 17,18 show inhibitory activity against α-GHs such as α-amylase, rice α-glucosidase and yeast α-glucosidase. 19,20 IC 50 values for compounds 2 -6 against α-amylase are in the range of 10 -2 mol/L and against yeast α-glucosidase is between 10 -5 -10 -4 mol/L.…”

Section: Introductionmentioning

confidence: 99%

Stereoselective Synthesis of a 4-⍺-Glucoside of Valienamine, Inhibition, and X-Ray Structural Studies Involving a Bacterial Glycoside Hydrolase-Like Enzyme of The GH13 Family

Jayasinghe

Thanvi

et al. 2021

Preprint

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Glycoside hydrolases (GH) are a large family of hydrolytic enzymes found in all domains of life. As such, they control a plethora of normal and pathogenic biological functions. Thus, understanding selective inhibition of GH enzymes at the atomic level can lead to the identification of new classes of therapeutics. In these studies, we identified a 4-⍺-glucoside of valienamine (8) as an inhibitor (IC50 of 484 ± 51 µM) of Streptomyces coelicolor (Sco) GlgE1-V279S which belongs to the GH13 Carbohydrate Active EnZyme (CAZy) family. The synthetic route to 8 and a closely related 4-⍺-glucoside of validamine (7) was achieved starting from readily available D-maltose. A key step in the synthesis was a chelation-controlled addition of vinylmagnesium bromide to a maltose-derived enone intermediate. X-ray structures of both 7 and 8 in complex with Sco GlgE1-V279S were solved to resolutions of 1.75 and 1.78 Å, respectively. Structural analysis revealed the valienamine derivative 8 binds the enzyme in an E2 conformation for the cyclohexene fragment. Also, the cyclohexene fragment shows a new hydrogen-bonding contact from the pseudo-diaxial C(3)-OH to the catalytic nucleophile Asp 394 at the enzyme active site. Asp 394, in fact, forms a bidentate interaction with both the C(3)-OH and C(7)-OH of the inhibitor. In contrast, compound 7 disrupts the catalytic sidechain interaction network of Sco GlgE1-V279S via steric interactions resulting in a conformation change in Asp 394. These findings will have implications for the design other aminocarbasugar-based GH13-inhibitors and will be useful for identifying more potent and selective inhibitors.

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ChemInform Abstract: STRUCTURE OF AN α‐D‐GLUCOSIDASE INHIBITOR ACARBOSE

Abstract: Die Struktur des Pseudotetrasaccharids Acarbose (Ia), dessen Derivate (Ib) und (Ic) nach bekannter Methodik dargestellt werden, wird über chemische Abbaureaktionen aufgeklärt.

Cited by 2 publications

References 1 publication

Stereoselective synthesis of a 4-⍺-glucoside of valienamine and its X-ray structure in complex with Streptomyces coelicolor GlgE1-V279S

Stereoselective synthesis of a 4-⍺-glucoside of valienamine and its X-ray structure in complex with Streptomyces coelicolor GlgE1-V279S

Stereoselective Synthesis of a 4-⍺-Glucoside of Valienamine, Inhibition, and X-Ray Structural Studies Involving a Bacterial Glycoside Hydrolase-Like Enzyme of The GH13 Family

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