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Pyridoxine non-responsive p.R336C mutation alters the molecular properties of cystathionine beta-synthase leading to severe homocystinuria phenotype

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submitted on 2023-12-06, 10:34 and posted on 2023-12-07, 08:59 authored by Duaa W. Al-Sadeq, Angelos Thanassoulas, Zeyaul Islam, Prasanna Kolatkar, Nader Al-Dewik, Bared Safieh-Garabedian, Gheyath K. Nasrallah, Michail Nomikos
  • 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.

Other Information

Published in: Biochimica et Biophysica Acta (BBA) - General Subjects
License: http://creativecommons.org/licenses/by/4.0/
See article on publisher's website: https://dx.doi.org/10.1016/j.bbagen.2022.130148

Additional institutions affiliated with: Hamad Medical Corporation, Hamad General Hospital - HMC, Women's Wellness and Research Center - HMC, Interim Translational Research Institute - HMC

Funding

Open Access funding provided by the Qatar National Library.

History

Language

  • English

Publisher

Elsevier

Publication Year

  • 2022

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License.

Institution affiliated with

  • Qatar University Health - QU
  • College of Medicine - QU HEALTH
  • College of Health Sciences - QU HEALTH
  • Qatar University
  • Biomedical Research Center - QU
  • Hamad Bin Khalifa University
  • Qatar Biomedical Research Institute - HBKU
  • Diabetes Research Center - QBRI
  • College of Health and Life Sciences - HBKU