ArticleJournal of inherited metabolic disease2015
Chaperone therapy for homocystinuria: the rescue of CBS mutations by heme arginate.
Article in Journal of inherited metabolic disease, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 42 citations in OpenAlex.
- Association of Cystathionine β-Synthase Gene Polymorphisms With Preeclampsia.Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis · 2018Trial
- Homocystinuria: Advances in metabolic and molecular therapies targeting homocysteine pathways (Review).Molecular medicine reports · 2026Review
- Cellular turnover and degradation of the most common missense cystathionine beta-synthase variants causing homocystinuria.Protein science : a publication of the Protein Society · 2024Article
- Architecture and regulation of filamentous human cystathionine beta-synthase.Nature communications · 2024Article
- Recent therapeutic approaches to cystathionine beta-synthase-deficient homocystinuria.British journal of pharmacology · 2023Review
- Genetic and Pharmacological Modulation of Cellular Proteostasis Leads to Partial Functional Rescue of Homocystinuria-Causing Cystathionine-Beta Synthase Variants.Molecular and cellular biology · 2023Article
- How to fix a broken protein: restoring function to mutant human cystathionine β-synthase.Human genetics · 2022Review
- Chemical Chaperones Modulate the Formation of Metabolite Assemblies.International journal of molecular sciences · 2021Article
- Hyperhomocysteinemia and dyslipidemia in point mutation G307S of cystathionine β-synthase-deficient rabbit generated using CRISPR/Cas9.Lipids in health and disease · 2020Article
- A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase.Genome medicine · 2020Article
- Mouse modeling and structural analysis of the p.G307S mutation in human cystathionine β-synthase (The Journal of biological chemistry · 2018Article
- Tuning protein folding in lysosomal storage diseases: the chemistry behind pharmacological chaperones.Chemical science · 2018Review
- Hydrogen Sulfide Biochemistry and Interplay with Other Gaseous Mediators in Mammalian Physiology.Oxidative medicine and cellular longevity · 2018Review
- The c.797 G>A (p.R266K) cystathionine β-synthase mutation causes homocystinuria by affecting protein stability.Human mutation · 2017Article
- Functional characterization of missense mutations in severe methylenetetrahydrofolate reductase deficiency using a human expression system.Journal of inherited metabolic disease · 2017Article
- A Clinically Relevant Variant of the Human Hydrogen Sulfide-Synthesizing Enzyme CystathionineOxidative medicine and cellular longevity · 2017Article
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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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