摘要
oseltamivir 的使用，广泛地是的 stockpiled 为在可能的鸟的流行性感冒的使用的药之一流行，被报导了与 neuropsychiatricdisorders 和严重皮肤反应被联系，首先在日本。这里，我们在 dbSNP 数据库识别了非同义的 SNP (单个核苷酸多型性) ， R41Q 在 humancytosolic sialidase 的酶的活跃地点附近，是 oseltamivir 的目标的病毒 neuraminidase 的一个相当或相同事物。在欧洲、非洲的美国人口的 9.29% 亚洲人口和没有的这 SNPoccurred。Ourstructural 分析和 Ki 大小使用试管内 sialidase 试金显示这 SNPcould 增加人的 sialidase 的非计划中的有约束力的亲密关系到 oseltamivir 羧化物， oseltamivir 的活跃形式，因此减少 sialidase 活动。另外，这 SNP 自己与一项内在地更低的 sialidase 活动导致酶，由它的增加的 Km 证明 Vmax 珍视并且减少。理论上，到有这 SNP 的人的 oseltamivir 的管理可能进一步减少他们的 sialidase 活动。我们注意 oseltamivir 的 reportedneuropsychiatric 副酌和人的 sialidase-relateddisorders 的已知的症状的类似。我们建议这个充实亚洲人的 sialidase 变化由 SNP 引起了，在同型结合的形式可能，可以与对 oseltamivir 的某些严重不利反应被联系。
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 ofoseltamivir 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.
