Molecular mechanisms of 4-hydroxy-2-nonenal and acrolein toxicity: nucleophilic targets and adduct formation.
Molecular mechanisms of 4-hydroxy-2-nonenal and acrolein toxicity: nucleophilic targets and adduct formation.
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DOI：
10.1021/tx900147g
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发表时间：
2009-09
影响因子：
4.1
通讯作者：
Barber, David S.
中科院分区：
文献类型：
--
作者：
LoPachin, Richard M.;Gavin, Terrence;Petersen, Dennis R.;Barber, David S.
丙烯醛和 4-羟基-2-壬烯醛 (HNE) 是脂质过氧化的副产物，被认为在涉及细胞氧化应激的各种创伤性损伤和疾病状态中发挥着核心作用；例如，脊髓损伤、糖尿病、阿尔茨海默病。在本评论中，我们将讨论决定其毒性的丙烯醛和 HNE 的化学属性。具体来说，这些醛被归类为2型烯烃，其特征在于具有α,β-不饱和羰基结构。该结构是包含移动π电子的共轭体系。羰基氧原子呈负电性，可促进移动电子密度从β碳原子撤出，导致区域电子缺乏。基于这种电子极化性，丙烯醛和 HNE 都被认为是软亲电子试剂，优先与软亲核试剂形成 1,4-Michael 型加合物。蛋白质组学、量子力学和动力学数据表明半胱氨酸巯基是丙烯醛和 HNE 的主要软亲核靶标。这与较硬的生物亲核体（例如赖氨酸或组氨酸残基）上的氮基团相反。加合物形成的毒理学结果不仅取决于残基选择性，还取决于目标氨基酸在蛋白质功能或结构中的重要性。在试图辨别给定加合物的毒理学意义时，我们将考虑蛋白质中半胱氨酸、赖氨酸和组氨酸残基的正常作用以及相应加合物在疾病或毒性状态表现中的相对优点。了解丙烯醛和 HNE 的分子作用可以深入了解许多涉及初始细胞氧化应激的致病条件，从而提供新的有效的药理学防御途径。
Acrolein and 4-hydroxy-2-nonenal (HNE) are by-products of lipid peroxidation and are thought to play central roles in various traumatic injuries and disease states that involve cellular oxidative stress; e.g., spinal cord trauma, diabetes, Alzheimer's disease. In this Commentary, we will discuss the chemical attributes of acrolein and HNE that determine their toxicities. Specifically, these aldehydes are classified as type-2 alkenes and are characterized by an α,β-unsaturated carbonyl structure. This structure is a conjugated system that contains mobile pi electrons. The carbonyl oxygen atom is electronegative and can promote the withdrawal of mobile electron density from the β carbon atom causing regional electron deficiency. Based on this type of electron polarizability, both acrolein and HNE are considered to be soft electrophiles that preferentially form 1,4-Michael type adducts with soft nucleophiles. Proteomic, quantum mechanical and kinetic data will be presented indicating that cysteine sulfhydryl groups are the primary soft nucleophilic targets of acrolein and HNE. This is in contrast to nitrogen groups on harder biological nucleophiles such as lysine or histidine residues. The toxicological outcome of adduct formation is not only dependent upon residue selectivity, but also the importance of the targeted amino acid in protein function or structure. In attempting to discern the toxicological significance of a given adduct, we will consider the normal roles of cysteine, lysine and histidine residues in proteins and the relative merits of corresponding adducts in the manifestations of diseases or toxic states. Understanding the molecular actions of acrolein and HNE could provide insight into many pathogenic conditions that involve initial cellular oxidative stress and could, thereby, offer new efficacious avenues of pharmacological defense.
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影响因子：
4.1
作者：
Cai, Jian;Bhatnagar, Aruni;Pierce, William M., Jr.
通讯作者：
Pierce, William M., Jr.
影响因子：
4.8
作者：
Britto, PJ;Knipling, L;Wolff, J
通讯作者：
Wolff, J
DOI：
10.1074/mcp.m800070-mcp200
发表时间：
2009-04
期刊：
Molecular & cellular proteomics : MCP
影响因子：
--
作者：
Codreanu SG;Zhang B;Sobecki SM;Billheimer DD;Liebler DC
通讯作者：
Liebler DC
影响因子：
2.5
作者：
Castellani, RJ;Perry, G;Smith, MA
通讯作者：
Smith, MA
影响因子：
2.3
作者：
Aldini, Giancarlo;Gamberoni, Luca;Carini, Marina
通讯作者：
Carini, Marina