The Novel Binding Mode of N-Alkyl-N'-hydroxyguanidine to Neuronal Nitric Oxide Synthase Provides Mechanistic Insights into NO Biosynthesis
详细信息 查看全文
- 作者：Huiying Li ; Hideaki Shimizu ; Mack Flinspach ; Joumana Jamal ; Weiping Yang ; Ming Xian ; Tingwei Cai ; Edward Zhong Wen ; Qiang Jia ; Peng George Wang ; and Thomas L. Poulos
- 刊名：Biochemistry
- 出版年：2002
- 出版时间：November 26, 2002
- 年：2002
- 卷：41
- 期：47
- 页码：13868 - 13875
- 全文大小：313K
- 年卷期：v.41,no.47(November 26, 2002)
- ISSN：1520-4995
文摘
A series of N-alkyl-N'-hydroxyguanidine compounds have recently been characterized as non-amino acid substrates for all three nitric oxide synthase (NOS) isoforms which mimic NO formation fromN
-hydroxy-L-arginine. Crystal structures of the nNOS heme domain complexed with either N-isopropyl-N'-hydroxyguanidine or N-butyl-N'-hydroxyguanidine reveal two different binding modes in the substratebinding pocket. The binding mode of the latter is consistent with that observed for the substrate N-hydroxy-L-arginine bound in the nNOS active site. However, the former binds to nNOS in an unexpectedfashion, thus providing new insights into the mechanism on how the hydroxyguanidine moiety leads toNO formation. Structural features of substrate binding support the view that the OH-substituted guanidinenitrogen, instead of the hydroxyl oxygen, is the source of hydrogen supplied to the active ferric-superoxyspecies for the second step of the NOS catalytic reaction.
-hydroxy-L-arginine. Crystal structures of the nNOS heme domain complexed with either N-isopropyl-N'-hydroxyguanidine or N-butyl-N'-hydroxyguanidine reveal two different binding modes in the substratebinding pocket. The binding mode of the latter is consistent with that observed for the substrate N-hydroxy-L-arginine bound in the nNOS active site. However, the former binds to nNOS in an unexpectedfashion, thus providing new insights into the mechanism on how the hydroxyguanidine moiety leads toNO formation. Structural features of substrate binding support the view that the OH-substituted guanidinenitrogen, instead of the hydroxyl oxygen, is the source of hydrogen supplied to the active ferric-superoxyspecies for the second step of the NOS catalytic reaction.