Introduction of C-alkyl branches to l-iminosugars changes their active site binding orientation

Atsushi Kato, Izumi Nakagome, Kozue Yoshimura, Uta Kanekiyo, Mana Kishida, Kenta Shinzawa, Tian-Tian Lu, Yi-Xian Li, Robert J. Nash, George W. J. Fleet, Nobuhiko Tanaka, Chu-Yi Yu

Allbwn ymchwil: Cyfraniad at gyfnodolynErthygladolygiad gan gymheiriaid

2 Dyfyniadau (Scopus)
1 Wedi eu Llwytho i Lawr (Pure)

Crynodeb

l-ido-Deoxynojirimycin (l-ido-DNJ) itself showed no affinity for human lysosomal acid α-glucosidase (GAA), whereas 5-C-methyl-l-ido-DNJ showed a strong affinity for GAA, comparable to the glucose analog DNJ, with a K i value of 0.060 μM. This excellent affinity for GAA and enzyme stabilization was observed only when methyl and ethyl groups were introduced. Docking simulation analysis revealed that the alkyl chains of 5-C-alkyl-l-ido-DNJs were stored in three different pockets, depending on their length, thereby the molecular orientation was changed. Comparison of the binding poses of DNJ and 5-C-methyl-l-ido-DNJ showed that they formed a common ionic interaction with Asp404, Asp518, and Asp616, but both the binding orientation and the distance between the ligand and each amino acid residue were different. 5-C-Methyl-l-ido-DNJ dose-dependently increased intracellular GAA activity in Pompe patient fibroblasts with the M519V mutation and also promoted enzyme transport to lysosomes. This study provides the first example of a strategy to design high-affinity ligands by introducing alkyl branches into rare sugars and l-sugar-type iminosugars to change the orientation of binding.

Iaith wreiddiolSaesneg
Tudalennau (o-i)7250-7260
Nifer y tudalennau11
CyfnodolynOrganic and Biomolecular Chemistry
Cyfrol20
Rhif cyhoeddi36
Dyddiad ar-lein cynnar08 Gorff 2022
Dynodwyr Gwrthrych Digidol (DOIs)
StatwsCyhoeddwyd - 28 Medi 2022

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