Biochemical and structural impact of two novel missense mutations in cystathionine β-synthase gene associated with homocystinuria,Biochemical Journal

当前位置： X-MOL 学术 › Biochem. J. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Biochemical and structural impact of two novel missense mutations in cystathionine β-synthase gene associated with homocystinuria
Biochemical Journal ( IF 4.1 ) Pub Date : 2024-04-24 , DOI: 10.1042/bcj20240012
Duaa Al-Sadeq ₁ , Carolina Conter ₂ , Angelos Thanassoulas ₁ , Nader Al-Dewik ₃ , Bared Safieh-Garabedian ₁ , Luis Alfonso Luis Alfonso Martínez-Cruz ₄ , Gheyath Nasrallah ₁ , Alessandra Astegno ₅ , Michail Nomikos ₁

Affiliation

Homocystinuria 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 5′-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.

更新日期：2024-04-22

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南

全部期刊列表>>