AI Article Synopsis

  • Retaining glycoside hydrolases use acid/base catalysis to facilitate glycosidic bond cleavage through a covalent intermediate, typically with the catalytic components being in close proximity (4.5-6.5 Å) for effective reaction.
  • In glycoside hydrolase family 116, including human acid β-glucosidase 2 (GBA2), the distance between the catalytic acid/base and nucleophile is greater (8 Å), leading to differences in the enzyme's catalytic behavior compared to others in this family.
  • New structures of the GBA2 mutant with cellobiose and laminaribiose reveal a unique perpendicular orientation of amide hydrogen bonding to glycosidic oxygen, suggesting distinct protonation

Article Abstract

Retaining glycoside hydrolases use acid/base catalysis with an enzymatic acid/base protonating the glycosidic bond oxygen to facilitate leaving-group departure alongside attack by a catalytic nucleophile to form a covalent intermediate. Generally, this acid/base protonates the oxygen laterally with respect to the sugar ring, which places the catalytic acid/base and nucleophile carboxylates within about 4.5-6.5 Å of each other. However, in glycoside hydrolase (GH) family 116, including disease-related human acid β-glucosidase 2 (GBA2), the distance between the catalytic acid/base and the nucleophile is around 8 Å (PDB: 5BVU) and the catalytic acid/base appears to be above the plane of the pyranose ring, rather than being lateral to that plane, which could have catalytic consequences. However, no structure of an enzyme-substrate complex is available for this GH family. Here, we report the structures of β-glucosidase (GH116) D593N acid/base mutant in complexes with cellobiose and laminaribiose and its catalytic mechanism. We confirm that the amide hydrogen bonding to the glycosidic oxygen is in a perpendicular rather than lateral orientation. Quantum mechanics/molecular mechanics (QM/MM) simulations of the glycosylation half-reaction in wild-type GH116 indicate that the substrate binds with the nonreducing glucose residue in an unusual relaxed chair at the subsite. Nevertheless, the reaction can still proceed through a half-chair transition state, as in classical retaining β-glucosidases, as the catalytic acid D593 protonates the perpendicular electron pair. The glucose C6OH is locked in a , orientation with respect to the C5-O5 and C4-C5 bonds to facilitate perpendicular protonation. These data imply a unique protonation trajectory in Clan-O glycoside hydrolases, which has strong implications for the design of inhibitors specific to either lateral protonators, such as human GBA1, or perpendicular protonators, such as human GBA2.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10167657PMC
http://dx.doi.org/10.1021/acscatal.3c00620DOI Listing

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