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首页> 外文期刊>Biochemistry >Dominant Intermediate Charcot-Marie-Tooth Disorder Is Not Due to a Catalytic Defect in Tyrosyl-tRNA Synthetase
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Dominant Intermediate Charcot-Marie-Tooth Disorder Is Not Due to a Catalytic Defect in Tyrosyl-tRNA Synthetase

机译：中等水平的夏科特-玛丽齿病不是由于酪氨酸-tRNA合成酶的催化缺陷引起的

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Charcot-Marie-Tooth disorder (CMT) is the most common inherited peripheral neuropathy, afflicting 1 in every 2500 Americans. One form of this disease, Dominant Intermediate Charcot-Marie-Tooth disorder type C (DI-CMTC), is due to mutation of the gene encoding the cytoplasmic tyrosyltRNA synthetase (TyrRS). Three different TyrRS variants have been found to give rise to DI-CMTC: replacing glycine at position 41 by arginine (G41R), replacing glutamic acid at position 196 by lysine (E196K), and deleting amino acids 153?156 (Δ(153?156)). To test the hypothesis that DI-CMTC is due to a defect in the ability of tyrosyl-tRNA synthetase to catalyze the aminoacylation of tRNATyr, we have expressed each of these variants as recombinant proteins and used single turnover kinetics to characterize their abilities to catalyze the activation of tyrosine and its subsequent transfer to the 3′ end of tRNATyr. Two of the variants, G41R and Δ(153?156), display a substantial decrease in their ability to bind tyrosine (>100-fold). In contrast, the E196K substitution does not significantly affect the kinetics for formation of the tyrosyl-adenylate intermediate and actually increases the rate at which the tyrosyl moiety is transferred to tRNATyr. The observation that the E196K substitution does not decrease the rate of catalysis indicates that DI-CMTC is not due to a catalytic defect in tyrosyl-tRNA synthetase. a
机译：Charcot-Marie-Tooth病（CMT）是最常见的遗传性周围神经病，每2500名美国人中就有1名患此病。这种疾病的一种形式，即显性中度夏洛特-玛丽-牙齿紊乱C型（DI-CMTC），是由于编码胞质酪氨酰tRNA合成酶（TyrRS）的基因突变所致。已发现三种不同的TyrRS变体产生DI-CMTC：用精氨酸（G41R）取代41位的甘氨酸，用赖氨酸（E196K）取代196位的谷氨酸，并缺失153-156（Δ（153？ 156））。为了检验DI-CMTC是酪氨酸-tRNA合成酶催化tRNATyr的氨酰化能力缺陷的假说，我们已经将这些变体中的每一个表达为重组蛋白，并使用单周转动力学来表征它们催化TRNATyr的能力。酪氨酸的活化及其随后转移至tRNATyr的3'端。 G41R和Δ（153？156）这两个变体显示其结合酪氨酸的能力大大降低（> 100倍）。相比之下，E196K取代不会显着影响形成酪氨酰-腺苷酸中间体的动力学，并实际上提高了酪氨酰部分转移至tRNATyr的速率。 E196K取代不会降低催化速率的观察结果表明，DI-CMTC不是由于酪氨酰-tRNA合成酶的催化缺陷引起的。一个

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