Chaperone therapy for homocystinuria: the rescue of CBS mutations by heme arginate
Language English Country United States Media print-electronic
Document type Case Reports, Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Arginine pharmacology MeSH
- CHO Cells MeSH
- Cricetulus MeSH
- Cystathionine beta-Synthase genetics metabolism MeSH
- Phenotype MeSH
- Fibroblasts drug effects enzymology MeSH
- Genetic Predisposition to Disease MeSH
- Heme pharmacology MeSH
- Homocystinuria diagnosis drug therapy enzymology genetics MeSH
- Homozygote MeSH
- Catalytic Domain MeSH
- Protein Conformation MeSH
- Humans MeSH
- Molecular Chaperones pharmacology MeSH
- Models, Molecular MeSH
- Mutation * MeSH
- Proteostasis Deficiencies diagnosis drug therapy enzymology genetics MeSH
- Protein Folding MeSH
- Substrate Specificity MeSH
- Transfection MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Arginine MeSH
- Cystathionine beta-Synthase MeSH
- Heme MeSH
- heme arginate MeSH Browser
- Molecular Chaperones MeSH
Classical homocystinuria is caused by mutations in the cystathionine β-synthase (CBS) gene. Previous experiments in bacterial and yeast cells showed that many mutant CBS enzymes misfold and that chemical chaperones enable proper folding of a number of mutations. In the present study, we tested the extent of misfolding of 27 CBS mutations previously tested in E. coli under the more folding-permissive conditions of mammalian CHO-K1 cells and the ability of chaperones to rescue the conformation of these mutations. Expression of mutations in mammalian cells increased the median activity 16-fold and the amount of tetramers 3.2-fold compared with expression in bacteria. Subsequently, we tested the responses of seven selected mutations to three compounds with chaperone-like activity. Aminooxyacetic acid and 4-phenylbutyric acid exhibited only a weak effect. In contrast, heme arginate substantially increased the formation of mutant CBS protein tetramers (up to sixfold) and rescued catalytic activity (up to ninefold) of five out of seven mutations (p.A114V, p.K102N, p.R125Q, p.R266K, and p.R369C). The greatest effect of heme arginate was observed for the mutation p.R125Q, which is non-responsive to in vivo treatment with vitamin B(6). Moreover, the heme responsiveness of the p.R125Q mutation was confirmed in fibroblasts derived from a patient homozygous for this genetic variant. Based on these data, we propose that a distinct group of heme-responsive CBS mutations may exist and that the heme pocket of CBS may become an important target for designing novel therapies for homocystinuria.
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