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  

作　　者：Chuan-Yun Li Quan Yu Zhi-Qiang Ye Ying Sun Quanyuan He Xiao-Mo Li Wuxue Zhang Jingchu Luo Xiaocheng Gu Xiaofeng Zheng Liping Wei 

机构地区：[1]Center for Bioinformatics [2]Department of Biochemistry and Molecular Biology, National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing 100871, China [3]Laboratory of Biochemistry, College of Life Sciences, Hunan Normal University, Changsha 410081, China

出　　处：《Cell Research》2007年第4期357-362,共6页细胞研究（英文版）

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 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.

关 键 词：Asia SNP neuraminidase inhibitor OSELTAMIVIR SIALIDASE BIOINFORMATICS 

分 类 号：R978.7[医药卫生—药品] R511.7[医药卫生—药学]