Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme
Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme
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DOI：
10.1016/j.cell.2005.03.001
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发表时间：
2005-05-20
期刊：
影响因子：
64.5
通讯作者：
Rudolph, MG
中科院分区：
文献类型：
--
作者：
Dierks, T;Dickmanns, A;Rudolph, MG
硫酸酯酶是降解和重塑硫酸酯所必需的酶。甲酰甘氨酸（FGly）是硫酸酯酶活性中心的关键催化残基。在高等真核生物中，FGly是通过FGly生成酶（FGE）从半胱氨酸前体生成的。FGE的不活动导致多发性硫酸酯酶缺乏症（MSD），一种致命的常染色体隐性遗传综合征。基于晶体结构，我们报告说，FGE是一个单结构域的单体与一个令人惊讶的缺乏二级结构，并采取了独特的折叠。在MSD患者中发现的所有18个错义突变的影响都可以通过FGE结构来解释，从而提供了MSD的分子基础。FGly生成的催化机制是通过FGE在不同氧化还原环境中的六个高分辨率结构来阐明的。所述结构允许形成新的加氧酶机制，由此FGE利用分子氧经由半胱氨酸次磺酸中间体产生FGly。
Sulfatases are enzymes essential for degradation and remodeling of sulfate esters. Formylglycine (FGly), the key catalytic residue in the active site, is unique to sulfatases. In higher eukaryotes, FGly is generated from a cysteine precursor by the FGly-generating enzyme (FGE). Inactivity of FGE results in multiple sulfatase deficiency (MSD), a fatal autosomal recessive syndrome. Based on the crystal structure, we report that FGE is a single-domain monomer with a surprising paucity of secondary structure and adopts a unique fold. The effect of all 18 missense mutations found in MSD patients is explained by the FGE structure, providing a molecular basis of MSD. The catalytic mechanism of FGly generation was elucidated by six high-resolution structures of FGE in different redox environments. The structures allow formulation of a novel oxygenase mechanism whereby FGE utilizes molecular oxygen to generate FGly via a cysteine sulfenic acid intermediate.