Journal article
Novel substrates for nitric oxide synthases
Bioorganic & medicinal chemistry, Vol.10(9), pp.3049-3055
2002
Handle:
https://hdl.handle.net/2376/116387
PMID: 12110328
Abstract
Enzymatic generation of nitric oxide (NO) by nitric oxide synthase (NOS) consists of two oxidation steps. The first step converts
l-arginine to
N
G-hydroxy-
l-arginine (NOHA), a key intermediate, and the second step converts NOHA to NO and
l-citrulline. To fully probe the substrate specificity of the second enzymatic step, an extensive structural screening was carried out using a series of
N-alkyl (and
N-aryl) substituted-
N′-hydroxyguanidines (
1–
14). Among the eleven
N-alkyl-
N′-hydroxyguanidines evaluated,
N-
n-propyl (
2),
N-
iso-propyl (
3),
N-
n-butyl (
4),
N-
s-butyl (
5),
N-
iso-butyl (
6),
N-pentyl (
8) and
N-
iso-pentyl (
9) derivatives were efficiently oxidized by the three isoenzymes of NOS (nNOS, iNOS and eNOS) to generate NO.
N-Butyl-
N′-hydroxyguanidine (
4) was the best substrate for iNOS (
K
m=33
μM) and
N-
iso-propyl-
N′-hydroxyguanidine (
3) was the best substrate for nNOS (
K
m=56
μM). When the alkyl substituents were too small (such as ethyl
1) or too large (such as hexyl
10 and cyclohexyl
11), the activity decreased significantly. This suggests that the van der Waals interaction between the alkyl group and the hydrophobic cavity in the NOS active site contributes significantly to the relative reactivity of compounds
3–
11. Moreover, five
N-aryl-
N′-hydroxyguanidines were found to be good substrates for iNOS, but not substrates for eNOS and nNOS.
N-phenyl-
N′-hydroxyguanidine was the best substrate among them (
K
m=243
μM). This work demonstrates that
N-alkyl substituted hydroxyguanidine compounds are novel NOS substrates which ‘short-circuit’ the first oxidation step of NOS, and
N-aryl substituted hydroxyguanidine compounds are isoform selective NOS substrate.
A series of
N-hydroxyguanidine derivatives was synthesized and evaluated as NOS substrate. Some of them were shown to be good substrates for NOS.
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Details
- Title
- Novel substrates for nitric oxide synthases
- Creators
- Ming Xian - Department of Chemistry, Wayne State University, Detroit, MI 48202, USANoriko Fujiwara - Department of Biochemistry, Osaka University Medical School, Osaka 565-0871, JapanZhong Wen - Department of Chemistry, Wayne State University, Detroit, MI 48202, USATingwei Cai - Department of Chemistry, Wayne State University, Detroit, MI 48202, USASatoshi Kazuma - Department of Biochemistry, Osaka University Medical School, Osaka 565-0871, JapanAdam J Janczuk - Department of Chemistry, Wayne State University, Detroit, MI 48202, USAXiaoping Tang - Department of Chemistry, Wayne State University, Detroit, MI 48202, USAVladislav V Telyatnikov - Department of Biochemistry, Osaka University Medical School, Osaka 565-0871, JapanYingxin Zhang - Department of Chemistry, Wayne State University, Detroit, MI 48202, USAXinchao Chen - Department of Chemistry, Wayne State University, Detroit, MI 48202, USAYasuhide Miyamoto - Department of Biochemistry, Osaka University Medical School, Osaka 565-0871, JapanNaoyuki Taniguchi - Department of Biochemistry, Osaka University Medical School, Osaka 565-0871, JapanPeng George Wang - Department of Chemistry, Wayne State University, Detroit, MI 48202, USA
- Publication Details
- Bioorganic & medicinal chemistry, Vol.10(9), pp.3049-3055
- Academic Unit
- Chemistry, Department of
- Publisher
- Elsevier Ltd
- Identifiers
- 99900548209801842
- Language
- English
- Resource Type
- Journal article