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首页> 外文期刊>Biochemistry >Influence of UDP-GlcNAc 2-epimerase/ManNAc kinase mutant proteins on hereditary inclusion body myopathy
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Influence of UDP-GlcNAc 2-epimerase/ManNAc kinase mutant proteins on hereditary inclusion body myopathy

机译：UDP-GlcNAc 2-表异构酶/ ManNAc激酶突变蛋白对遗传性包涵体肌病的影响

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摘要

Hereditary inclusion body myopathy (HIBM), a neuromuscular disorder, is caused by mutations in UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), the key enzyme of sialic acid biosynthesis. To date, more than 40 different mutations in the GNE gene have been reported to cause the disease. Ten of them, representing mutations in both functional domains of GNE, were recombinantly expressed in insect cells (Sf9). Each of the mutants that was analyzed displayed a reduction in the two known GNE activities, thus revealing that mutations may also influence the function of the domain not harboring them. The extent of reduction strongly differs among the point mutants, ranging from only 20% reduction found for A631T and A631V to almost 80% reduction of at least one activity in D378Y and N519S mutants and more than 80% reduction of both activities of G576E, underlined by structural changes of N519S and G576E, as observed in CD spectroscopy and gel filtration analysis, respectively. We therefore generated models of the three-dimensional structures of the epimerase and the kinase domains of GNE, based on Escherichia coli UDP-N-acetylglucosamine 2-epimerase and glucokinase, respectively, and determined the localization of the HIBM mutations within these proteins. Whereas in the kinase domain most of the mutations are localized inside the enzyme, mutations in the epimerase domain are mostly located at the protein surface. Otherwise, the different mutations result in different enzymatic activities but not in different disease phenotypes and, therefore, do not suggest a direct role of the enzymatic function of GNE in the disease mechanism.
机译：遗传性包涵体肌病（HIBM）是一种神经肌肉疾病，是由唾液酸生物合成的关键酶UDP-N-乙酰氨基葡萄糖2-表异构酶/ N-乙酰甘露糖胺激酶（GNE）突变引起的。迄今为止，已经报道了GNE基因中40多种不同的突变导致该疾病。其中十个代表GNE两个功能域中的突变，在昆虫细胞（Sf9）中重组表达。所分析的每个突变体均显示出两种已知的GNE活性降低，因此表明突变也可能影响不携带它们的域的功能。点突变体的还原程度差异很大，范围从A631T和A631V降低仅20％到D378Y和N519S突变体至少一种活性降低近80％，G576E两种活性均降低80％以上。分别在CD光谱法和凝胶过滤分析中观察到的N519S和G576E的结构变化。因此，我们分别基于大肠杆菌UDP-N-乙酰氨基葡萄糖2-表异构酶和葡萄糖激酶，生成了差向异构酶和GNE激酶结构域的三维结构模型，并确定了这些蛋白中HIBM突变的定位。而在激酶结构域中，大多数突变位于酶内部，而差向异构酶结构域中的突变大部分位于蛋白质表面。否则，不同的突变会导致不同的酶活性，但不会导致不同的疾病表型，因此，并不表明GNE的酶功能在疾病机制中具有直接作用。

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