title: 2,5-Dideoxy-2,5-imino-d-altritol as a new class of pharmacological chaperone for Fabry disease.
abstract: Chromatographic separation of the extract from roots of Adenophora triphylla resulted in the isolation of two pyrrolidines, six piperidines, and two piperidine glycosides. The structures of new iminosugars were elucidated by spectroscopic methods as 2,5-dideoxy-2,5-imino-d-altritol (DIA) (2), beta-1-C-butenyl-1-deoxygalactonojirimycin (8), 2,3-dideoxy-beta-1-C-ethyl-1-deoxygalactonojirimycin (9), and 6-O-beta-d-glucopyranosyl-2,3-dideoxy-beta-1-C-ethyl-1-deoxygalactonojirimycin (10). beta-1-C-Butyl-1-deoxygalactonojirimycin (7) and compound 8 were found to be better inhibitors of alpha-galactosidase than N-butyl-1-deoxygalactonojirimycin. The present work elucidated that DIA was a powerful competitive inhibitor of human lysosome alpha-galactosidase A (alpha-Gal A) with a K(i) value of 0.5muM. Furthermore, DIA improved the thermostability of alpha-Gal A in vitro and increased intracellular alpha-Gal A activity by 9.6-fold in Fabry R301Q lymphoblasts after incubation for 3days. These experimental results suggested that DIA would act as a specific pharmacological chaperone to promote the smooth escape from the endoplasmic reticulum (ER) quality control system and to accelerate transport and maturation of the mutant enzyme.
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan. kato@med.u-toyama.ac.jp
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kato
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Shinpei
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Koike
authors.forename: Isao
authors.initials: I
authors.lastname: Adachi
authors.forename: Jackie
authors.initials: J
authors.lastname: Hollinshead
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Nash
authors.forename: Kyoko
authors.initials: K
authors.lastname: Ikeda
authors.forename: Naoki
authors.initials: N
authors.lastname: Asano
mesh_terms: D029422:Campanulaceae / Q000737:chemistry; D000795:Fabry Disease / Q000188:drug therapy*; D006801:Humans; D050111:Imino Sugars / Q000302:isolation & purification; D018832:Molecular Chaperones / Q000737:chemistry*; D050505:Mutant Proteins / Q000378:metabolism; D008517:Phytotherapy / Q000379:methods*; D010880:Piperidines / Q000302:isolation & purification; D010936:Plant Extracts / Q000737:chemistry; D021381:Protein Transport; D011759:Pyrrolidines / Q000302:isolation & purification; D013402:Sugar Alcohols / Q000302:isolation & purification / Q000627:therapeutic use*; D000519:alpha-Galactosidase / Q000037:antagonists & inhibitors
chemical_list: D050111:Imino Sugars; D018832:Molecular Chaperones; D050505:Mutant Proteins; D010880:Piperidines; D010936:Plant Extracts; D011759:Pyrrolidines; D013402:Sugar Alcohols; C042890:altritol; D000519:alpha-Galactosidase