ニューロンの酸化窒素合成酵素の血球調整阻害剤. 鉄-チオエーテル協調は,阻害剤の効能が増加することなく,水害性接触によって安定化されます
Jeffrey D Martell1, Huiying Li, Tzanko Doukov
1Department of Chemistry, Center for Molecular Innovation and Drug Discovery, and Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois 60208-3113, USA.
Journal of the American Chemical Society
|December 18, 2009
まとめ
この研究は,ヘムに結合するチオエーテル阻害体の最初の結晶構造を提示し,ニューロン酸化窒素合成酵素 (nNOS) 阻害に関する洞察を明らかにします. ティオエテルとヘムの相互作用は予想よりも弱く,ヘム鉄による結合が影響されている.
科学分野:
- バイオケミストリー バイオケミストリー
- 薬用化学 薬用化学について
- 構造生物学 構造生物学とは
背景:
- ヘム-チオエーテル相互作用は,メチオニンリガンドと共通しています.
- チオエーテルベースのヘム調整 (II型) 阻害剤は,Fe-S結合の不安定性のために希少です.
研究 の 目的:
- ニューロン酸化窒素合成酵素 (nNOS) の新型チオエーテルベースの阻害剤の設計と特徴付け.
- nNOSにおけるチオエテル-ヘム協調の構造的基礎を解明する.
主な方法:
- スペクトルフォトメトリとX線結晶学を用いて,阻害剤結合の特徴を明らかにした.
- 一連のチオエテル化合物 (3-8) が合成され,評価されました.
主要な成果:
- ヘム鉄 (nNOS) に複合したチオエーテル阻害体の最初の結晶構造が得られた.
- 化合物4-8は,鉄性nNOSのタイプI阻害を示し,鉄性nNOSに還元されるとタイプIIに切り替わります.
- ティオエテル-ヘム結合は,予想に反して,阻害剤の効力を高めませんでした.
結論:
- この研究は,どのヘム酵素でもチオエテル-ヘム調整の構造的証拠を初めて提供した.
- ティオエーテル-ヘム結合の強度は,特にフェリックヘムでは,これまで考えられていたよりも弱い.
- 水性相互作用は,チオエーテル-ヘム調整の安定化に不可欠であり,微妙な構造的変化が結合形態に大きく影響する.
関連する概念動画
02:34Structural Isomerism
Isomerism in Complexes
Isomers are different chemical species that have the same chemical formula. Structural isomerism of coordination compounds can be divided into two subcategories, the linkage isomers and coordination-sphere isomers.
Linkage isomers occur when the coordination compound contains a ligand that can bind to the transition metal center through two different atoms. For example, the CN− ligand can bind through the carbon atom or through the nitrogen atom. Similarly, SCN− can be...
Isomers are different chemical species that have the same chemical formula. Structural isomerism of coordination compounds can be divided into two subcategories, the linkage isomers and coordination-sphere isomers.
Linkage isomers occur when the coordination compound contains a ligand that can bind to the transition metal center through two different atoms. For example, the CN− ligand can bind through the carbon atom or through the nitrogen atom. Similarly, SCN− can be...
02:51Metal-Ligand Bonds
The hemoglobin in the blood, the chlorophyll in green plants, vitamin B-12, and the catalyst used in the manufacture of polyethylene all contain coordination compounds. Ions of the metals, especially the transition metals, are likely to form complexes.
In these complexes, transition metals form coordinate covalent bonds, a kind of Lewis acid-base interaction in which both of the electrons in the bond are contributed by a donor (Lewis base) to an electron acceptor (Lewis acid). The Lewis acid in...
In these complexes, transition metals form coordinate covalent bonds, a kind of Lewis acid-base interaction in which both of the electrons in the bond are contributed by a donor (Lewis base) to an electron acceptor (Lewis acid). The Lewis acid in...
01:29Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
Indirect-acting cholinergic agonists are agents that interact with the acetylcholinesterase enzyme in the synaptic cleft, preventing the breakdown of acetylcholine into choline and acetate. Consequently, the concentration of acetylcholine in the synaptic cleft increases. These agonists can be classified into reversible and irreversible inhibitors based on their duration of action.
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
02:42Valence Bond Theory
Coordination compounds and complexes exhibit different colors, geometries, and magnetic behavior, depending on the metal atom/ion and ligands from which they are composed. In an attempt to explain the bonding and structure of coordination complexes, Linus Pauling proposed the valence bond theory, or VBT, using the concepts of hybridization and the overlapping of the atomic orbitals. According to VBT, the central metal atom or ion (Lewis acid) hybridizes to provide empty orbitals of suitable...
01:29Drugs Affecting Neurotransmitter Synthesis
Drugs affecting neurotransmitter synthesis can impact the adrenergic neuron and the synthesis of neurotransmitters. For example, α-methyltyrosine and carbidopa target specific enzymes involved in catecholamine synthesis. α-methyltyrosine inhibits the enzyme tyrosine hydroxylase, which converts tyrosine into dopamine. By blocking this enzyme, α-methyltyrosine reduces dopamine production and other catecholamines. Carbidopa, on the other hand, inhibits the enzyme dopa decarboxylase, which converts...
01:30The Electron Transport Chain
The electron transport chain or oxidative phosphorylation is an exothermic process in which free energy released during electron transfer reactions is coupled to ATP synthesis. This process is a significant source of energy in aerobic cells, and therefore inhibitors of the electron transport chain can be detrimental to the cell's metabolic processes.
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q in...
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q in...