Pyridoxine non-responsive p.R336C mutation alters the molecular properties of cystathionine beta-synthase leading to severe homocystinuria phenotype
Author | Al-Sadeq, Duaa W. |
Author | Thanassoulas, Angelos |
Author | Islam, Zeyaul |
Author | Kolatkar, Prasanna |
Author | Al-Dewik, Nader |
Author | Safieh-Garabedian, Bared |
Author | Nasrallah, Gheyath K. |
Author | Nomikos, Michail |
Available date | 2022-04-24T08:28:09Z |
Publication Date | 2022-07-01 |
Publication Name | Biochimica et Biophysica Acta - General Subjects |
Identifier | http://dx.doi.org/10.1016/j.bbagen.2022.130148 |
Citation | Al-Sadeq, D. W., Thanassoulas, A., Islam, Z., Kolatkar, P., Al-Dewik, N., Safieh-Garabedian, B., ... & Nomikos, M. (2022). Pyridoxine non-responsive R336C mutation alters the molecular properties of cystathionine beta-synthase leading to severe homocystinuria phenotype. Biochimica et Biophysica Acta (BBA)-General Subjects, 130148. |
ISSN | 03044165 |
Abstract | The prevalence of homocystinuria in Qatar is 1:1800, mainly due to a founder missense mutation p.R336C. • The cystathionine beta-synthase (CBS) R336C mutant was bacterially expressed, purified and its molecular properties were compared to CBS wild type (WT) recombinant protein. • Our data revealed that p.R336C mutation results in a dramatic reduction (∼86%) of CBS enzymatic activity. • Circular Dichroism experiments suggested that the p.R336C mutation does not significantly alter the secondary structure of the CBS protein. • CD spectra also revealed distinct differences in the thermal unfolding mechanisms of CBS WT and R336C mutant protein species. • Chemical denaturation experiments indicated that the WT CBS protein is thermodynamically more stable than the R336C mutant, suggesting a destabilizing effect of the p.R336C mutation. • This study provides mechanistic insight into the pathogenicity of the p.R336C mutation that leads to a severe homocystinuria phenotype. |
Sponsor | This publication was made possible by GSRA grant, GSRA6-1-0413-19013, from the Qatar National Research Fund (a member of Qatar Foundation). In addition, NA would like to thank fund from The Medical Research Center at Hamad Medical Corporation for IRGC-06-SI-19-167 grant. The statements made herein are solely the responsibility of the authors. Open Access funding provided by the Qatar National Library. |
Language | en |
Publisher | Elsevier |
Subject | Biochemical characterization Biophysical characterization Cystathionine beta-synthase Homocystinuria R336C mutation |
Type | Article |
Issue Number | 7 |
Volume Number | 1866 |
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