Mechanisms of Biological Nitrosation from Nitric Oxide

一氧化氮的生物亚硝化机制

• 批准号: 7113122
• 负责人: Jack R Lancaster
• 金额: $ 28.32万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-10 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7113122
• 关键词: chemical kinetics; chemical reaction; electrochemistry; hydropathy; intermolecular interaction; laboratory rat; lipid bilayer membrane; mathematics; nitric oxide; nitrites; oxidation; oxygen; oxygen consumption; phospholipids; physical chemical interaction

DESCRIPTION (provided by applicant): Nitric oxide (nitrogen monoxide, NO) is subject to oxidation in vivo, which results in the production of reactive species that either form nitrogen oxide-containing adducts, oxidized cellular components, or relatively unreactive oxyanions. Among the biological actions of NO, nitrosation (the chemistry of the one-electron oxidized species nitrosonium (NO+)) has historically (and undoubtedly) received the most attention in terms of chemical pathology. Nitrosation of nucleophilic cellular targets results in both damaging (e.g., nitrosamine formation and DNA base deamination) and also possible regulatory effects (formation of nitrosothiols). However, the mechanism(s) whereby nitrosation takes place in cells is unknown. Our overall objective is to define the biochemical mechanism(s) of nitrosation from NO. To accomplish this objective, we will proceed along two lines (encompassing our four Specific Aims), based on our previous work in these two areas. In Aims I-II, we will delineate the kinetic and mechanistic characteristics of the reaction of NO with O2 within hydrophobic environments such as membranes. We have previously proposed that this is the major site biologically for this reaction that produces potent nitrosating species. We will determine the kinetic characteristics of this effect, which we have estimated accelerates the NO/O2 reaction by a factor of approximately 300-fold under biological conditions. In addition, we will examine the mechanistic effects of this partitioning, specifically, the solvation and collisional effects which the hydrophobic interior of membrane bilayers may have in influencing these reactions between small uncharged radical species (as opposed to reactions in aqueous solution). In Aims Ill-IV, we will delineate the characteristics of non-erythroid cellular O2-dependent consumption of NO, which is quantitatively the major transformation of NO that occurs outside the vascular lumen, and which we have shown results in the production of nitrite (a marker for nitrosative chemistry). This phenomenon is distinct from the membrane effect in Aims I-II, and we will identify the biochemical mechanism(s) of this reaction, including the cellular species involved and nature of the oxygen species responsible for NO oxidation (dioxygen or superoxide) as well as the involvement of transition metal ions. We will also delineate the nitrosative cellular chemistry from both exogenous and endogenous NO. These studies will provide both new insight into the basic biochemistry of NO and its derivatives, and also potentially provide new possible avenues for therapeutic development in a variety of pathological conditions, including carcinogenesis, inflammatory stimulation, and oxidative stress.

描述（由申请人提供）：一氧化氮（一氧化氮，NO）在体内发生氧化，导致产生活性物质，这些活性物质要么形成含氮氧化物的加合物、氧化的细胞成分，要么形成相对不活泼的含氧阴离子。 在 NO 的生物作用中，亚硝化（单电子氧化物质亚硝鎓 (NO+) 的​​化学反应）历来（毫无疑问）在化学病理学方面受到了最多的关注。 亲核细胞靶标的亚硝化会导致损害（例如亚硝胺形成和 DNA 碱基脱氨），也可能产生调节作用（亚硝基硫醇的形成）。 然而，细胞中发生亚硝化的机制尚不清楚。 我们的总体目标是确定 NO 亚硝化的生化机制。 为了实现这一目标，我们将根据我们之前在这两个领域的工作，沿着两条路线（包括我们的四个具体目标）前进。 在目标 I-II 中，我们将描述疏水环境（例如膜）内 NO 与 O2 反应的动力学和机械特征。 我们之前提出，这是产生强亚硝化物质的反应的主要生物学位点。 我们将确定这种效应的动力学特征，我们估计在生物条件下该效应可将 NO/O2 反应加速约 300 倍。 此外，我们将研究这种分配的机械效应，特别是膜双层的疏水内部可能具有的溶剂化和碰撞效应，以影响小的不带电自由基物种之间的这些反应（与水溶液中的反应相反）。 在目标 III-IV 中，我们将描述非红系细胞 O2 依赖性 NO 消耗的特征，这是定量地发生在血管腔外的 NO 的主要转化，并且我们已经显示了其在亚硝酸盐产生中的结果（亚硝化化学标记）。 这种现象与 Aims I-II 中的膜效应不同，我们将确定该反应的生化机制，包括涉及的细胞种类和负责 NO 氧化的氧种类（双氧或超氧化物）的性质由于过渡金属离子的参与。 我们还将描述外源性和内源性 NO 的亚硝化细胞化学。 这些研究将为NO及其衍生物的基本生物化学提供新的见解，并有可能为各种病理条件下的治疗开发提供新的可能途径，包括致癌、炎症刺激和氧化应激。

项目成果

Protein cysteine thiol nitrosation: Maker or marker of reactive nitrogen species-induced nonerythroid cellular signaling?

• DOI: 10.1016/j.niox.2008.04.028
• 发表时间: 2008-09-01
• 期刊: NITRIC OXIDE-BIOLOGY AND CHEMISTRY
• 影响因子: 3.9
• 作者: Lancaster, Jack R., Jr.

A nitric oxide releasing, self assembled peptide amphiphile matrix that mimics native endothelium for coating implantable cardiovascular devices.

• DOI: 10.1016/j.biomaterials.2009.10.051
• 发表时间: 2010-03
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Kushwaha, Meenakshi;Anderson, Joel M.;Bosworth, Charles A.;Andukuri, Adinarayana;Minor, William P.;Lancaster, Jack R., Jr.;Anderson, Peter G.;Brott, Brigitta C.;Jun, Ho-Wook
• 通讯作者: Jun, Ho-Wook