Sulfatases and sulfatase modifying factors: an exclusive and promiscuous relationship
Sulfatases and sulfatase modifying factors: an exclusive and promiscuous relationship
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DOI：
10.1093/hmg/ddi351
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发表时间：
2005-11-01
影响因子：
3.5
通讯作者：
Ballabio, A
中科院分区：
文献类型：
--
作者：
Sardiello, M;Annunziata, I;Ballabio, A
硫酸酯酶催化来自多种底物的硫酸酯键的水解。几种人类遗传性疾病是由单个硫酸酯酶的缺乏引起的，而在具有多种硫酸酯酶缺乏的患者中，硫酸酯酶修饰因子1（SUMF 1）基因中的突变导致在所有硫酸酯酶的活性位点处半胱氨酸残基翻译后修饰为C-α-甲酰甘氨酸（FGly）的缺陷。这种催化活性所需的独特修饰机制在进化过程中高度保守。在这里，我们使用基因组方法来研究硫酸酯酶和它们的修饰因子在人类和几个模型系统之间的关系。首先，我们确定了人类硫酸酯酶的完整目录，其中包括17个成员（啮齿动物中为14个），包括四个新成员（ARSH，ARSI，ARSJ和ARSK）。其次，我们发现，活性位点，这是翻译后修饰的目标，是最进化的硫酸酯酶的限制区域，并显示种内序列收敛。对现有蛋白质组的详尽序列分析表明，硫酸酯酶是其修饰因子的唯一可能靶点。第三，我们发现硫酸酯酶和外核苷酸焦磷酸酶在它们的活性位点上具有显著的同源性，这表明它们具有共同的进化起源以及相似的催化机制。最重要的是，对原核生物进行的基因关联研究表明，存在至少两种额外的半胱氨酸转化为FGly的机制，这些机制不需要SUMF 1。这些结果可能对研究硫酸酯酶缺乏引起的疾病和开发治疗策略具有重要意义。
Sulfatases catalyze the hydrolysis of sulfate ester bonds from a wide variety of substrates. Several human inherited diseases are caused by the deficiency of individual sulfatases, while in patients with multiple sulfatase deficiency mutations in the Sulfatase Modifying Factor 1 (SUMF1) gene cause a defect in the post-translational modification of a cysteine residue into C-alpha-formylglycine (FGly) at the active site of all sulfatases. This unique modification mechanism, which is required for catalytic activity, has been highly conserved during evolution. Here, we used a genomic approach to investigate the relationship between sulfatases and their modifying factors in humans and several model systems. First, we determined the complete catalog of human sulfatases, which comprises 17 members (versus 14 in rodents) including four novel ones (ARSH, ARSI, ARSJ and ARSK). Secondly, we showed that the active site, which is the target of the post-translational modification, is the most evolutionarily constrained region of sulfatases and shows intraspecies sequence convergence. Exhaustive sequence analyses of available proteomes indicate that sulfatases are the only likely targets of their modifying factors. Thirdly, we showed that sulfatases and ectonucleotide pyrophosphatases share significant homology at their active sites, suggesting a common evolutionary origin as well as similar catalytic mechanisms. Most importantly, gene association studies performed on prokaryotes suggested the presence of at least two additional mechanisms of cysteine-to-FGly conversion, which do not require SUMF1. These results may have important implications in the study of diseases caused by sulfatase deficiencies and in the development of therapeutic strategies.