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AuthorAl-Sadeq, Duaa W.
AuthorConter, Carolina
AuthorThanassoulas, Angelos
AuthorAl-Dewik, Nader
AuthorSafieh-Garabedian, Bared
AuthorMartínez-Cruz, Luis Alfonso
AuthorNasrallah, Gheyath K.
AuthorAstegno, Alessandra
AuthorNomikos, Michail
Available date2024-05-21T07:55:38Z
Publication Date2024-04-22
Publication NameBiochemical Journal
CitationAl-Sadeq, D. W., Conter, C., Thanassoulas, A., Al-Dewik, N., Safieh-Garabedian, B., Martínez-Cruz, L. A., ... & Nomikos, M. (2024). Biochemical and structural impact of two novel missense mutations in cystathionine β-synthase gene associated with homocystinuria. Biochemical Journal, 481(8), 569-585.
AbstractHomocystinuria is a rare disease caused by mutations in the CBS gene that results in a deficiency of cystathionine β-synthase (CBS). CBS is an essential pyridoxal 50-phosphate (PLP)-dependent enzyme in the transsulfuration pathway, responsible for combining serine with homocysteine to produce cystathionine, whose activity is enhanced by the allosteric regulator S-adenosylmethionine (SAM). CBS also plays a role in generating hydrogen sulfide (H2S), a gaseous signaling molecule with diverse regulatory functions within the vascular, nervous, and immune systems. In this study, we present the clinical and biochemical characterization of two novel CBS missense mutations that do not respond to pyridoxine treatment, namely c.689T > A (L230Q) and 215A > T (K72I), identified in a Chinese patient. We observed that the disease-associated K72I genetic variant had no apparent effects on the spectroscopic and catalytic properties of the full-length enzyme. In contrast, the L230Q variant expressed in Escherichia coli did not fully retain heme and when compared with the wild-type enzyme, it exhibited more significant impairments in both the canonical cystathionine-synthesis and the alternative H2S-producing reactions. This reduced activity is consistent with both in vitro and in silico evidence, which indicates that the L230Q mutation significantly decreases the overall protein’s stability, which in turn, may represent the underlying cause of its pathogenicity.
SponsorThis publication was made possible by QNRF GSRA grant no. GSRA6-1-0413-19013, from the Qatar National Research Fund (a member of Qatar Foundation). Also, the authors would like to acknowledge the fund from MRC-HMC, grant number QUEX-CHS-HMC-20/21. This research was also supported by the MUR-PRIN 2022 grant No. 20224BYR59 to A.A., and by Spanish Ministry of Economy and Competitiveness Grant BFU2016-77408-R and by Spanish Ministerio de Ciencia e Innovaci\u00F3n (MICINN), Grants No PID2019-109055RB-I00 and PID2022-141748OB-I00, to L.A.M.-C.
PublisherPortland Press Ltd
Subjectcystathionine β-synthase (CBS)
protein subunit
TitleBiochemical and structural impact of two novel missense mutations in cystathionine β-synthase gene associated with homocystinuria
Issue Number8
Volume Number481

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