代谢酶乙酰化修饰对新陈代谢的调控

蛋白质的赖氨酸乙酰化修饰可以定义为在蛋白质的赖氨酸残基上添加或移除一个乙酰基团,这个过程是由乙酰化酶和脱乙酰酶调控的.真核生物细胞核内组蛋白和转录因子的可逆乙酰化修饰对基因表达调控的机制早已研究得比较清楚.1996年以来,一些独立的研究也陆续发现,参与到其他生命活动中的蛋白质存在着乙酰化修饰情况,表明乙酰化可能在生命活动中发挥着广泛的调节作用.然而直到2009年,高通量的蛋白质质谱分析技术才使得在蛋白质组水平上研究乙酰化修饰成为可能,并发现蛋白质乙酰化普遍存在.学者们发现,乙酰化修饰是一个在细胞核或细胞质的亚细胞器内广泛存在的翻译后修饰调控机制,可能参与了染色体重塑、细胞周期调控、细胞骨架的大分子运输、新陈代谢等多种生命活动.本文详细总结代谢酶的乙酰化修饰对新陈代谢调控的关键作用,并说明代谢酶的乙酰化修饰是一个从原核生物到真核生物进化上高度保守的调控机制.     

Reversible acetylation of metabolic enzymes celebration: SIRT2 and p300 join the party

Compelling evidence suggests that metabolic pathways are coordinated through reversible acetylation of metabolic enzymes in response to nutrient availability. In this issue of Molecular Cell, Jiang et al. (2011) show that the rate-limiting enzyme in gluconeogenesis, phosphoenolpyruvate carboxykinase 1, is regulated through reversible acetylation by SIRT2 and p300.     

Histone acetylation and chromatin pattern in cancer. A review

Chromatin phenotype is known to be significantly disrupted in cancer. This has been demonstrated in many morphologic studies on cancer and in recent years by the application of digital texture analysis for quantitative evaluation of chromatin phenotype in neoplasia. Studies have consistently demonstrated the role of chromatin phenotype as a biomarker of diagnosis and prognosis. The underlying molecular mechanisms for chromatin reorganization and its role as a biomarker are largely unknown, but epigenetic processes are likely to be a main factor that not only modify chromatin arrangement but in doing so alter gene expression profiles in a reversible fashion. Of the range of epigenetic modifications that might control chromatin phenotype, histone acetylation is a strong candidate because of its role in the direct modification of chromatin, both through local relaxation of nucleosomal structure and recruitment of chromatin remodeling complexes. The reversible nature of histone acetylation is therapeutically attractive for treatment of aberrant histone acetylation; however, it still remains to be seen whether histone deacetylase inhibitors are clinically applicable or for use primarily as valuable research tools. This review explores the role of histone acetylation in cancer development, as a potential therapeutic candidate and a potential biomarker in tissue pathology.     

Lysine acetylation sites prediction using an ensemble of support vector machine classifiers

Lysine acetylation is an essentially reversible and high regulated post-translational modification which regulates diverse protein properties. Experimental identification of acetylation sites is laborious and expensive. Hence, there is significant interest in the development of computational methods for reliable prediction of acetylation sites from amino acid sequences. In this paper we use an ensemble of support vector machine classifiers to perform this work. The experimentally determined acetylation lysine sites are extracted from Swiss-Prot database and scientific literatures. Experiment results show that an ensemble of support vector machine classifiers outperforms single support vector machine classifier and other computational methods such as PAIL and LysAcet on the problem of predicting acetylation lysine sites. The resulting method has been implemented in EnsemblePail, a web server for lysine acetylation sites prediction available at http://www.aporc.org/EnsemblePail/.     

Alkylating agent methyl methanesulfonate (MMS) induces a wave of global protein hyperacetylation: implications in cancer cell death

Protein acetylation modification has been implicated in many cellular processes but the direct evidence for the involvement of protein acetylation in signal transduction is very limited. In the present study, we found that an alkylating agent methyl methanesulfonate (MMS) induces a robust and reversible hyperacetylation of both cytoplasmic and nuclear proteins during the early phase of the cellular response to MMS. Notably, the acetylation level upon MMS treatment was strongly correlated with the susceptibility of cancer cells, and the enhancement of MMS-induced acetylation by histone deacetylase (HDAC) inhibitors was shown to increase the cellular susceptibility. These results suggest protein acetylation is important for the cell death signal transduction pathway and indicate that the use of HDAC inhibitors for the treatment of cancer is relevant.     

Acetylation of Lysine 201 Inhibits the DNA-Binding Ability of PhoP to Regulate Salmonella Virulence

The two-component system PhoP-PhoQ is highly conserved in bacteria and regulates virulence in response to various signals for bacteria within the mammalian host. Here, we demonstrate that PhoP could be acetylated by Pat and deacetylated by deacetylase CobB enzymatically in vitro and in vivo in Salmonella Typhimurium. Specifically, the conserved lysine residue 201(K201) in winged helix–turn–helix motif at C-terminal DNA-binding domain of PhoP could be acetylated, and its acetylation level decreases dramatically when bacteria encounter low magnesium, acid stress or phagocytosis of macrophages. PhoP has a decreased acetylation and increased DNA-binding ability in the deletion mutant of pat. However, acetylation of K201 does not counteract PhoP phosphorylation, which is essential for PhoP activity. In addition, acetylation of K201 (mimicked by glutamine substitute) in S. Typhimurium causes significantly attenuated intestinal inflammation as well as systemic infection in mouse model, suggesting that deacetylation of PhoP K201 is essential for Salmonella pathogenesis. Therefore, we propose that the reversible acetylation of PhoP K201 may ensure Salmonella promptly respond to different stresses in host cells. These findings suggest that reversible lysine acetylation in the DNA-binding domain, as a novel regulatory mechanism of gene expression, is involved in bacterial virulence across microorganisms.     

An integrated perspective and functional impact of the mitochondrial acetylome

Growing evidence suggests that a range of reversible protein post-translational modifications such as acetylation regulates mitochondria signalling, impacting cellular homeostasis. However, the extent of this type of regulation in the control of mitochondria functionality is just beginning to be discovered, aided by the availability of high-resolution mass spectrometers and bioinformatic tools. Data mining from literature on protein acetylation profiling focused on mitochondria isolated from tissues retrieved more than 1395 distinct proteins, corresponding to more than 4858 acetylation sites. ClueGo analysis of identified proteins highlighted oxidative phosphorylation, tricarboxylic acid cycle, fatty acid oxidation and amino acid metabolism as the biological processes more prone to regulation through acetylation. This review also examines the physiological relevance of protein acetylation on the molecular pathways harbored in mitochondria under distinct pathophysiological conditions as caloric restriction and alcohol-induced liver damage. This integrative perspective will certainly help to envisage future studies targeting the regulation of mitochondrial functionality.