Pyridoxine non-responsive p.R336C mutation alters the molecular properties of cystathionine beta-synthase leading to severe homocystinuria phenotype
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Date
2022-07-01Author
Al-Sadeq, Duaa W.Thanassoulas, Angelos
Islam, Zeyaul
Kolatkar, Prasanna
Al-Dewik, Nader
Safieh-Garabedian, Bared
Nasrallah, Gheyath K.
Nomikos, Michail
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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.
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