title: Gaucher disease-associated glucocerebrosidases show mutation-dependent chemical chaperoning profiles.
abstract: Gaucher disease is a lysosomal storage disorder caused by deficient glucocerebrosidase activity. We have previously shown that the cellular activity of the most common Gaucher disease-associated glucocerebrosidase variant, N370S, is increased when patient-derived cells are cultured with the chemical chaperone N-nonyl-deoxynojirimycin. Chemical chaperones stabilize proteins against misfolding, enabling their trafficking from the endoplasmic reticulum. Herein, the generality of this therapeutic strategy is evaluated with other glucocerebrosidase variants and with additional candidate chemical chaperones. Improved chemical chaperones are identified for N370S glucocerebrosidase. Moreover, we demonstrate that G202R, a glucocerebrosidase variant that is known to be retained in the endoplasmic reticulum, is also amenable to chemical chaperoning. The L444P variant is not chaperoned by any of the active site-directed molecules tested, likely because this mutation destabilizes a domain distinct from the catalytic domain.
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Anu R
authors.initials: AR
authors.lastname: Sawkar
authors.forename: Sara L
authors.initials: SL
authors.lastname: Adamski-Werner
authors.forename: Wei-Chieh
authors.initials: WC
authors.lastname: Cheng
authors.forename: Chi-Huey
authors.initials: CH
authors.lastname: Wong
authors.forename: Ernest
authors.initials: E
authors.lastname: Beutler
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Zimmer
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
mesh_terms: D000478:Alkylation; D002478:Cells, Cultured; D005776:Gaucher Disease / Q000201:enzymology* / Q000235:genetics*; D020869:Gene Expression Profiling; D005947:Glucose / Q000031:analogs & derivatives / Q000378:metabolism*; D005960:Glucosides / Q000737:chemistry / Q000378:metabolism*; D005962:Glucosylceramidase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D007700:Kinetics; D008247:Lysosomes / Q000201:enzymology; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics*; D017510:Protein Folding
chemical_list: D005960:Glucosides; D005962:Glucosylceramidase; D005947:Glucose