Human glutathione transferase A4-4:: an Alpha class enzyme with high catalytic efficiency in the conjugation of 4-hydroxynonenal and other genotoxic products of lipid peroxidation
Human glutathione transferase A4-4:: an Alpha class enzyme with high catalytic efficiency in the conjugation of 4-hydroxynonenal and other genotoxic products of lipid peroxidation
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DOI：
10.1042/bj3300175
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发表时间：
1998-02-15
影响因子：
4.1
通讯作者：
Mannervik, B
中科院分区：
文献类型：
--
作者：
Hubatsch, I;Ridderström, M;Mannervik, B
在人胎脑cDNA文库中发现了一个新的谷胱甘肽转移酶GSTA 4 -4的编码序列。在优化密码子使用以进行高水平异源表达后，已在大肠杆菌中产生该蛋白。基于推导的氨基酸组成，二聚体蛋白具有25704 Da的亚基分子量。人GST A4-4是α类的成员，但与主要肝酶GST A1-1仅显示53%的氨基酸序列同一性。对4-羟基烯醛和自由基反应和脂质过氧化的其他细胞毒性和致突变产物的高催化效率是GST A4-4的显著特征。4-羟基壬烯醛和4-羟基癸烯醛的k（cat）/K-m值> 3 x 10（6）M-1.s（-1），比传统GST底物的值高几个数量级。4-由氧化代谢产生的羟基壬烯醛和其他反应性亲电体与衰老、动脉粥样硬化、白内障形成、帕金森病和阿尔茨海默病以及其他退行性人类病症有关，表明人GST A4-4发挥重要的保护作用，并且其表达的变化可能具有显著的病理生理学后果。
A sequence encoding a novel glutathione transferase, GST A4-4, has been identified in a human fetal brain cDNA library. The protein has been produced in Escherichia coli after optimization of the codon usage for high-level heterologous expression. The dimeric protein has a subunit molecular mass of 25704 Da based on the deduced amino acid composition. Human GST A4-4 is a member of the Alpha class but shows only 53 % amino acid sequence identity with the major liver enzyme GST A1-1. High catalytic efficiency with 4-hydroxyalkenals and other cytotoxic and mutagenic products of radical reactions and lipid peroxidation is a significant feature of GST A4-4. The k(cat)/K-m values for 4-hydroxynonenal and 4-hydroxydecenal are > 3 x 10(6) M-1.s(-1), several orders of magnitude higher than the values for conventional GST substrates. 4-Hydroxynonenal and other reactive electrophiles produced by oxidative metabolism have been linked to aging, atherosclerosis, cataract formation, Parkinson's disease and Alzheimer's disease, as well as other degenerative human conditions, suggesting that human GST A4-4 fulfills an important protective role and that variations in its expression may have significant pathophysiological consequences.