Kumar Tarun, Sharma Gurumayum Suraj, Singh Laishram Rajendrakumar
Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India.
PLoS One. 2014 Nov 18;9(11):e113566. doi: 10.1371/journal.pone.0113566. eCollection 2014.
Homocysteine thiolactone is a toxic metabolite produced from homocysteine by amino-acyl t-RNA synthetase in error editing reaction. The basic cause of toxicity of homocysteine thiolactone is believed to be due to the adduct formation with lysine residues (known as protein N-homocysteinylation) leading to protein aggregation and loss of enzyme function. There was no data available until now that showed the effect of homocysteine thiolactone on the native state structural changes that led to aggregate formation. In the present study we have investigated the time dependent structural changes due to homocysteine thiolactone induced modifications on three different proteins having different physico-chemical properties (cytochrome-c, lysozyme and alpha lactalbumin). We discovered that N-homocysteinylation leads to the formation of molten globule state--an important protein folding intermediate in the protein folding pathway. We also found that the formation of the molten globule state might be responsible for the appearance of aggregate formation. The study indicates the importance of protein folding intermediate state in eliciting the homocysteine thiolactone toxicity.
同型半胱氨酸硫内酯是同型半胱氨酸在错误编辑反应中由氨酰 - tRNA合成酶产生的一种有毒代谢产物。同型半胱氨酸硫内酯毒性的基本原因据信是由于与赖氨酸残基形成加合物（称为蛋白质N - 同型半胱氨酸化），导致蛋白质聚集和酶功能丧失。直到现在还没有数据表明同型半胱氨酸硫内酯对导致聚集体形成的天然状态结构变化的影响。在本研究中，我们研究了同型半胱氨酸硫内酯诱导的修饰对三种具有不同物理化学性质的不同蛋白质（细胞色素c、溶菌酶和α - 乳白蛋白）随时间的结构变化。我们发现N - 同型半胱氨酸化导致形成熔球态——蛋白质折叠途径中的一种重要蛋白质折叠中间体。我们还发现熔球态的形成可能是聚集体形成出现的原因。该研究表明蛋白质折叠中间态在引发同型半胱氨酸硫内酯毒性方面的重要性。
