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首页> 外文期刊>Cell Research >A nonsynonymous SNP in human cytosolic sialidase in a small Asian population results in reduced enzyme activity: potential link with severe adverse reactions to oseltamivir
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A nonsynonymous SNP in human cytosolic sialidase in a small Asian population results in reduced enzyme activity: potential link with severe adverse reactions to oseltamivir

机译：在亚洲少数人群中人胞浆唾液酸酶中的一个非同义SNP会导致酶活性降低：可能与奥司他韦的严重不良反应相关

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摘要

The use of oseltamivir, widely stockpiled as one of the drugs for use in a possible avian influenza pandemic, has been reported to be associated with neuropsychiatric disorders and severe skin reactions, primarily in Japan. Here we identified a nonsynonymous SNP (single nucleotide polymorphism) in dbSNP database, R41Q, near the enzymatic active site of human cytosolic sialidase, a homologue of virus neuraminidase that is the target of oseltamivir. This SNP occurred in 9.29% of Asian population and none of European and African American population. Our structural analyses and Ki measurements using in vitro sialidase assays indicated that this SNP could increase the unintended binding affinity of human sialidase to oseltamivir carboxylate, the active form of oseltamivir, thus reducing sialidase activity. In addition, this SNP itself results in an enzyme with an intrinsically lower sialidase activity, as shown by its increased Km and decreased Vmax values. Theoretically administration of oseltamivir to people with this SNP might further reduce their sialidase activity. We note the similarity between the reported neuropsychiatric side effects of oseltamivir and the known symptoms of human sialidase-related disorders. We propose that this Asian-enriched sialidase variation caused by the SNP, likely in homozygous form, may be associated with certain severe adverse reactions to oseltamivir.
机译：据报道，广泛储存的奥司他韦作为可能的禽流感大流行中使用的药物之一，主要在日本与神经精神疾病和严重的皮肤反应有关。在这里，我们在人胞浆唾液酸酶的酶活性位点附近发现了dbSNP数据库R41Q中的一个非同义SNP（单核苷酸多态性），后者是奥司他韦的目标，是病毒神经氨酸酶的同源物。该SNP发生在亚洲人口的9.29％，欧洲和非裔美国人中均没有。我们的结构分析和使用体外唾液酸酶测定的Ki测定表明，该SNP可以增加人唾液酸酶与oseltamivir羧酸盐（一种活性形式的oseltamivir）的意外结合亲和力，从而降低了唾液酸酶的活性。此外，此SNP本身会产生一种本质上较低的唾液酸酶活性的酶，如其Km增大和Vmax值减小所表明。从理论上讲，对具有该SNP的人服用奥司他韦可能会进一步降低其唾液酸酶活性。我们注意到奥司他韦报道的神经精神副作用与人类唾液酸酶相关疾病的已知症状之间的相似性。我们建议这种由SNP引起的亚洲丰富的唾液酸酶变异可能是纯合子形式，可能与奥司他韦的某些严重不良反应有关。

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