四氢生物蝶呤的4-氨基类似物作为二氢蝶啶还原酶抑制剂和大鼠神经元型一氧化氮合酶的强效蝶呤拮抗剂的鉴定。
Identification of the 4-amino analogue of tetrahydrobiopterin as a dihydropteridine reductase inhibitor and a potent pteridine antagonist of rat neuronal nitric oxide synthase.
作者信息
Werner E R, Pitters E, Schmidt K, Wachter H, Werner-Felmayer G, Mayer B
机构信息
Institut für Medizinische Chemie und Biochemie, Universität Innsbruck, Austria.
出版信息
Biochem J. 1996 Nov 15;320 ( Pt 1)(Pt 1):193-6. doi: 10.1042/bj3200193.
Abstract
The binding of tetrahydropteridines with 6-di- and trihydroxypropyl side chains to recombinant rat neuronal nitric oxide (NO) synthase (EC 1.14.13.39) was determined by competition with 6R-[3'-3H]-5,6,7,8-tetrahydro-L-erythro-biopterin (6R-[3'-3H]H4biopterin). Although all but one of the derivatives exhibited only poor affinities (Ki 50 microM), the 4-amino analogue of 6R-H4 biopterin was a potent antagonist of 6R-H4 biopterin binding (Ki 13.2 nM). The 4-amino analogue of 6R-H4 biopterin inhibited NO synthase stimulation by the natural cofactor 6R-H4 biopterin with an IC50 of 1 microM without affecting the basal activity observed in the absence of added 6R-H4 biopterin. Because the 4-amino analogue of 6R-H4biopterin also inhibited dihydropteridine reductase (EC 1.6.99.7; IC50 20 microM), our results support the hypothesis that redox cycling of H4 biopterin might be required for the NO synthase reaction.
摘要
通过与6R-[3'-3H]-5,6,7,8-四氢-L-赤藓糖型生物蝶呤（6R-[3'-3H]H4生物蝶呤）竞争，测定了带有6-二羟基丙基和三羟基丙基侧链的四氢蝶啶与重组大鼠神经元型一氧化氮合酶（EC 1.14.13.39）的结合情况。尽管除一种衍生物外其他所有衍生物仅表现出较弱的亲和力（Ki>50 μM），但6R-H4生物蝶呤的4-氨基类似物是6R-H4生物蝶呤结合的强效拮抗剂（Ki 13.2 nM）。6R-H4生物蝶呤的4-氨基类似物抑制天然辅因子6R-H4生物蝶呤对一氧化氮合酶的刺激作用，IC50为1 μM，且不影响在未添加6R-H4生物蝶呤时观察到的基础活性。由于6R-H4生物蝶呤的4-氨基类似物也抑制二氢蝶呤还原酶（EC 1.6.99.7；IC50 20 μM），我们的结果支持以下假设，即一氧化氮合酶反应可能需要H4生物蝶呤的氧化还原循环。
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本文引用的文献
1
Large-scale purification of rat brain nitric oxide synthase from baculovirus overexpression system.从杆状病毒过表达系统中大规模纯化大鼠脑一氧化氮合酶
Methods Enzymol. 1996;268:420-7. doi: 10.1016/s0076-6879(96)68044-6.
2
Characterization of heme-deficient neuronal nitric-oxide synthase reveals a role for heme in subunit dimerization and binding of the amino acid substrate and tetrahydrobiopterin.血红素缺乏型神经元型一氧化氮合酶的特性揭示了血红素在亚基二聚化以及氨基酸底物和四氢生物蝶呤结合中的作用。
J Biol Chem. 1996 Mar 29;271(13):7336-42. doi: 10.1074/jbc.271.13.7336.
3
Reduction of quinonoid dihydrobiopterin to tetrahydrobiopterin by nitric oxide synthase.一氧化氮合酶将醌型二氢生物蝶呤还原为四氢生物蝶呤。
J Biol Chem. 1996 Feb 23;271(8):4143-7. doi: 10.1074/jbc.271.8.4143.
4
Biosynthesis of nitric oxide: dependence on pteridine metabolism.一氧化氮的生物合成：对蝶啶代谢的依赖性。
Rev Physiol Biochem Pharmacol. 1996;127:97-135. doi: 10.1007/BFb0048266.
5
6
In search of a function for tetrahydrobiopterin in the biosynthesis of nitric oxide.寻找四氢生物蝶呤在一氧化氮生物合成中的作用。
Naunyn Schmiedebergs Arch Pharmacol. 1995 May;351(5):453-63. doi: 10.1007/BF00171035.
7
Structural analysis of porcine brain nitric oxide synthase reveals a role for tetrahydrobiopterin and L-arginine in the formation of an SDS-resistant dimer.
EMBO J. 1995 Aug 1;14(15):3687-95. doi: 10.1002/j.1460-2075.1995.tb00038.x.
8
Nitric oxide synthases: properties and catalytic mechanism.
Annu Rev Physiol. 1995;57:707-36. doi: 10.1146/annurev.ph.57.030195.003423.
9
Molecular mechanisms of inhibition of porcine brain nitric oxide synthase by the antinociceptive drug 7-nitro-indazole.抗痛觉过敏药物7-硝基吲唑对猪脑一氧化氮合酶的抑制作用的分子机制
Neuropharmacology. 1994 Nov;33(11):1253-9. doi: 10.1016/0028-3908(94)90024-8.
10
Expression of rat brain nitric oxide synthase in baculovirus-infected insect cells and characterization of the purified enzyme.大鼠脑一氧化氮合酶在杆状病毒感染昆虫细胞中的表达及纯化酶的特性研究
Biochem J. 1994 Dec 15;304 ( Pt 3)(Pt 3):683-6. doi: 10.1042/bj3040683.
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