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首页> 外文期刊>The FEBS journal >Common G102S polymorphism in chitotriosidase differentially affects activity towards 4-methylumbelliferyl substrates
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Common G102S polymorphism in chitotriosidase differentially affects activity towards 4-methylumbelliferyl substrates

机译：壳三糖苷酶中常见的G102S多态性差异影响对4-甲基伞形酮底物的活性

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摘要

Chitotriosidase (CHIT1) is a chitinase that is secreted by activated macrophages. Plasma chitotriosidase activity reflects the presence of lipid-laden macrophages in patients with Gaucher disease. CHIT1 activity can be conveniently measured using fluorogenic 4-methylumbelliferyl (4MU)-chitotrioside or 4MU-chitobioside as the substrate, however, nonsaturating concentrations have to be used because of apparent substrate inhibition. Saturating substrate concentrations can, however, be used with the newly designed substrate 4MU-deoxychitobioside. We studied the impact of a known polymorphism, G102S, on the catalytic properties of CHIT1. The G102S allele was found to be common in type I Gaucher disease patients in the Netherlands ( approximately 24% of alleles). The catalytic efficiency of recombinant Ser102 CHIT1 was approximately 70% that of wild-type Gly102 CHIT1 when measured with 4MU-chitotrioside at a nonsaturating concentration. However, the activity was normal with 4MU-deoxychitobioside as the substrate at saturating concentrations, consistent with predictions from molecular dynamics simulations. In conclusion, interpretation of CHIT1 activity measurements with 4MU-chitotrioside with respect to CHIT1 protein concentrations depends on the presence of Ser102 CHIT1 in an individual, complicating estimation of the body burden of storage macrophages. Use of the superior 4MU-deoxychitobioside substrate avoids such complications because activity towards this substrate under saturating conditions is not affected by the G102S substitution.
机译：壳三糖苷酶（CHIT1）是由活化的巨噬细胞分泌的几丁质酶。血浆壳三糖苷酶活性反映了高雪氏病患者中脂质负载的巨噬细胞的存在。 CHIT1活性可以方便地使用荧光的4-甲基伞形酮（4MU）-壳三糖苷或4MU-壳二糖苷作为底物进行测量，但是，由于明显的底物抑制作用，必须使用非饱和浓度。但是，可以将饱和底物浓度与新设计的底物4MU-脱氧壳多糖苷一起使用。我们研究了已知多态性G102S对CHIT1催化性能的影响。在荷兰，我发现I型Gaucher病患者常见G102S等位基因（约占等位基因的24％）。当用4MU-壳三糖苷以非饱和浓度测量时，重组Ser102 CHIT1的催化效率约为野生型Gly102 CHIT1的70％。然而，以4MU-脱氧壳多糖作为饱和浓度的底物，该活性是正常的，这与分子动力学模拟的预测一致。综上所述，对于CHIT1蛋白浓度，用4MU-壳三糖苷对CHIT1活性的测量方法的解释取决于个体中Ser102 CHIT1的存在，从而使对储存巨噬细胞的机体负担的估计复杂化。使用优异的4MU-脱氧壳多糖苷底物可避免此类并发症，因为在饱和条件下对该底物的活性不受G102S取代的影响。

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