目的:药学上有吸引力的肿瘤启动子/抑制子SIRT5的赖氨酸脱甲醛化底物的特异性尚未全面阐明。本研究重新分析了公开可用的数据,并通过使用生物信息学突出了潜在的药学上有趣的结果。
方法:使用GeneMania(3.5.2)应用程序在Cytoscape(3.9.1)环境下运行,对来自野生型和ob/ob(肥胖糖尿病前期)小鼠的SIRT5丙二糖的相互作用网络进行途径富集和基因功能预测分析。
结果:在野生型小鼠中的分析显示SIRT5malonylome参与了真核翻译延伸(ETE;节点EF1A1,EEF2,EEF1D,和EEF1G),氨基酸和衍生物代谢(AADM),和硒氨基酸代谢(SAM)。SIRT5的肿瘤启动子/抑制活性是通过AADM中包含的肿瘤启动子底物(GLUD1,SHMT1,ACAT1)介导的,和参与AADM和SAM的肿瘤抑制底物(ALDH9A1,BHMT,GNMT)。Selen刺激SIRT5和其他沉默调节蛋白的表达。SIRT5反过来调节硒代半胱氨酸的合成,这就形成了一个监管循环。SIRT5malonylome在糖尿病前期ob/ob小鼠中的分析确定mTORC1通路是一种机制,这有助于SIRT5功能。SIRT5丙二糖的结果比较,琥珀酰,和戊二酶体分析揭示了几个差异。
结论:分析显示,除了控制葡萄糖代谢外,SIRT5丙二糖的其他方面的功能。它定义了几种独特的底物和途径,与SIRT5的其他酶活性相比,它显示出差异,可用于药物益处。
OBJECTIVE: The specificity of the lysine demalonylation substrates of the pharmaceutically attractive tumor promoter/suppressor SIRT5 is not comprehensively clarified. The present study re-analyses publicly available data and highlights potentially pharmaceutically interesting outcomes by the use of bioinformatics.
METHODS: The interaction networks of SIRT5 malonylome from the wild-type and ob/ob (obese pre-diabetic type) mice were subjected to the pathway enrichment and gene function prediction analysis using GeneMania (3.5.2) application run under Cytoscape (3.9.1) environment.
RESULTS: The analysis in the wild-type mice revealed the involvement of SIRT5 malonylome in Eukaryotic translation elongation (ETE; the nodes EF1A1, EEF2, EEF1D, and EEF1G), Amino acid and derivative metabolism (AADM), and Selenoamino acid metabolism (SAM). The tumor promoter/suppressor activity of SIRT5 is mediated through the tumor promoter substrates included in AADM (GLUD1, SHMT1, ACAT1), and the tumor suppressor substrates involved in AADM and SAM (ALDH9A1, BHMT, GNMT). Selen stimulates the expression of SIRT5 and other sirtuins. SIRT5 in turn regulates the selenocysteine synthesis, which creates a regulatory loop. The analysis of SIRT5 malonylome in pre-diabetic ob/ob mice identifies the mTORC1 pathway as a mechanism, which facilitates SIRT5 functions. The comparison of the outcomes of SIRT5 malonylome, succinylome, and glutarylome analysis disclosed several differences.
CONCLUSIONS: The analysis showed additional aspects of SIRT5 malonylome functions besides the control of glucose metabolism. It defined several unique substrates and pathways, and it showed differences compared to other enzymatic activities of SIRT5, which could be used for pharmaceutical benefits.