Modulation of homocysteine toxicity by S-nitrosothiol formation: a mechanistic approach.
Modulation of homocysteine toxicity by S-nitrosothiol formation: a mechanistic approach.
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通过 S-亚硝基硫醇形成调节同型半胱氨酸毒性：一种机械方法。
DOI：
10.1021/jp103679v
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Simoyi,ReubenH
中科院分区：
文献类型：
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作者：
Morakinyo,MoshoodK;Strongin,RobertM;Simoyi,ReubenH
同型半胱氨酸（HCYSH）代谢转化为同型半胱氨酸硫内酯（HTL）已被报道为HCYSH发病机制的主要原因。假设通过S-亚硝化抑制HCYSH的巯基将阻止其代谢转化为HTL。本文研究了HCYSH与亚硝酸在弱酸性和强酸性条件下反应生成S-亚硝基高半胱氨酸（HCYSNO）的动力学、反应动力学和反应机理。在生理pH 7.4的磷酸盐缓冲液中，还研究了S-亚硝基谷胱甘肽（GSNO）对这种非蛋白质形成氨基酸的转亚硝化作用。在这两种情况下，HCYSNO定量形成。发现铜离子起双重作用，催化HCYSNO的形成速率以及其分解速率。在过渡金属离子螯合剂的存在下，HCYSNO是非常稳定的，在pH 7.4的半衰期为198小时。亚硝酸的亚硝化作用通过形成更强大的亚硝化剂亚硝阳离子（NO+）和三氧化二氮（N2 O3）而发生。在高酸性环境中，NO+被认为是最有效的亚硝化剂与一级依赖于亚硝酸。N2 O3是最相关的亚硝化剂在温和的酸性环境中，与亚硝酸的二阶依赖。HCYSH与亚硝酸、N2 O3和NO+直接反应的双分子速率常数分别为9.0 × 10−2、9.50 × 103和6.57 × 1010 M − 1 s −1。这些速率常数值与这些亚硝化试剂的亲电顺序一致：HNO_2 <N_2O_3 < NO ~+。通过GSNO的HCYSH的转亚硝化产生HCYSNO和其他产物，包括谷胱甘肽（还原型和氧化型）和同型半胱氨酸-谷胱甘肽混合二硫化物。计算机模拟涉及八个反应给出了一个很好的适合所观察到的HCYSNO的形成动力学。这项研究表明，它是可能的，以调节同型半胱氨酸的毒性，防止其转化为毒性更大的HTL的S-亚硝化。
The metabolic conversion of homocysteine (HCYSH) to homocysteine thiolactone (HTL) has been reported as the major cause of HCYSH pathogenesis. It was hypothesized that inhibition of the thiol group of HCYSH by S-nitrosation will prevent its metabolic conversion to HTL. The kinetics, reaction dynamics, and mechanism of reaction of HCYSH and nitrous acid to produceS-nitrosohomocysteine (HCYSNO) was studied in mildly to highly acidic pHs. Transnitrosation of this non-protein-forming amino acid byS-nitrosoglutathione (GSNO) was also studied at physiological pH 7.4 in phosphate buffer. In both cases, HCYSNO formed quantitatively. Copper ions were found to play dual roles, catalyzing the rate of formation of HCYSNO as well as its rate of decomposition. In the presence of a transition-metal ions chelator, HCYSNO was very stable with a half-life of 198 h at pH 7.4. Nitrosation by nitrous acid occurred via the formation of more powerful nitrosating agents, nitrosonium cation (NO+) and dinitrogen trioxide (N2O3). In highly acidic environments, NO+was found to be the most effective nitrosating agent with a first-order dependence on nitrous acid. N2O3was the most relevant nitrosating agent in a mildly acidic environment with a second-order dependence on nitrous acid. The bimolecular rate constants for the direct reactions of HCYSH and nitrous acid, N2O3, and NO+were 9.0 × 10−2, 9.50 × 103, and 6.57 × 1010M−1s−1, respectively. These rate constant values agreed with the electrophilic order of these nitrosating agents: HNO2< N2O3< NO+. Transnitrosation of HCYSH by GSNO produced HCYSNO and other products including glutathione (reduced and oxidized) and homocysteine-glutathione mixed disulfide. A computer modeling involving eight reactions gave a good fit to the observed formation kinetics of HCYSNO. This study has shown that it is possible to modulate homocysteine toxicity by preventing its conversion to a more toxic HTL by S-nitrosation.