更新于：2024-05-01
SIRT4
NAD依赖性脱乙酰酶sirtuin-4
更新于：2024-05-01
基本信息
别名 NAD-dependent ADP-ribosyltransferase sirtuin-4、NAD-dependent protein biotinylase sirtuin-4、NAD-dependent protein lipoamidase sirtuin-4, mitochondrial + [7] |
简介 Acts as NAD-dependent protein lipoamidase, biotinylase, deacetylase and ADP-ribosyl transferase (PubMed:16959573, PubMed:17715127, PubMed:24052263, PubMed:25525879). Catalyzes more efficiently removal of lipoyl- and biotinyl- than acetyl-lysine modifications (PubMed:24052263, PubMed:25525879). Inhibits the pyruvate dehydrogenase complex (PDH) activity via the enzymatic hydrolysis of the lipoamide cofactor from the E2 component, DLAT, in a phosphorylation-independent manner (PubMed:25525879). Catalyzes the transfer of ADP-ribosyl groups onto target proteins, including mitochondrial GLUD1, inhibiting GLUD1 enzyme activity (PubMed:16959573, PubMed:17715127). Acts as a negative regulator of mitochondrial glutamine metabolism by mediating mono ADP-ribosylation of GLUD1: expressed in response to DNA damage and negatively regulates anaplerosis by inhibiting GLUD1, leading to block metabolism of glutamine into tricarboxylic acid cycle and promoting cell cycle arrest (PubMed:16959573, PubMed:17715127). In response to mTORC1 signal, SIRT4 expression is repressed, promoting anaplerosis and cell proliferation (PubMed:23663782). Acts as a tumor suppressor (PubMed:23562301, PubMed:23663782). Also acts as a NAD-dependent protein deacetylase: mediates deacetylation of 'Lys-471' of MLYCD, inhibiting its activity, thereby acting as a regulator of lipid homeostasis (By similarity). Does not seem to deacetylate PC (PubMed:23438705). Controls fatty acid oxidation by inhibiting PPARA transcriptional activation (PubMed:24043310). Impairs SIRT1-PPARA interaction probably through the regulation of NAD(+) levels (PubMed:24043310). Down-regulates insulin secretion (PubMed:17715127). |
关联
靶点 |
作用机制 |
在研机构 |
原研机构 |
在研适应症 |
非在研适应症 |
最高研发阶段 |
首次获批国家/地区 |
首次获批日期 |
100 项与 SIRT4 相关的临床结果
登录后查看更多信息
100 项与 SIRT4 相关的转化医学
登录后查看更多信息
登录后查看更多信息
2024-12-01Redox report : communications in free radical research
Glutamine sustains energy metabolism and alleviates liver injury in burn sepsis by promoting the assembly of mitochondrial HSP60-HSP10 complex via SIRT4 dependent protein deacetylation.
Article
作者: Yongjun Yang ; Qian Chen ; Shijun Fan ; Yongling Lu ; Qianyin Huang ; Xin Liu ; Xi Peng
Burns and burn sepsis, characterized by persistent and profound hypercatabolism, cause energy metabolism dysfunction that worsens organ injury and systemic disorders. Glutamine (Gln) is a key nutrient that remarkably replenishes energy metabolism in burn and sepsis patients, but its exact roles beyond substrate supply is unclear. In this study, we demonstrated that Gln alleviated liver injury by sustaining energy supply and restoring redox balance. Meanwhile, Gln also rescued the dysfunctional mitochondrial electron transport chain (ETC) complexes, improved ATP production, reduced oxidative stress, and protected hepatocytes from burn sepsis injury. Mechanistically, we revealed that Gln could activate SIRT4 by upregulating its protein synthesis and increasing the level of Nicotinamide adenine dinucleotide (NAD+), a co-enzyme that sustains the activity of SIRT4. This, in turn, reduced the acetylation of shock protein (HSP) 60 to facilitate the assembly of the HSP60-HSP10 complex, which maintains the activity of ETC complex II and III and thus sustain ATP generation and reduce reactive oxygen species release. Overall, our study uncovers a previously unknown pharmacological mechanism involving the regulation of HSP60-HSP10 assembly by which Gln recovers mitochondrial complex activity, sustains cellular energy metabolism and exerts a hepato-protective role in burn sepsis.
2024-02-13Cell discovery
Ketogenic diet-produced β-hydroxybutyric acid accumulates brain GABA and increases GABA/glutamate ratio to inhibit epilepsy.
Article
作者: Ya-Nan Qiao ; Lei Li ; Song-Hua Hu ; Yuan-Xin Yang ; Zhen-Zhen Ma ; Lin Huang ; Yan-Peng An ; Yi-Yuan Yuan ; Yan Lin ; Wei Xu ; Yao Li ; Peng-Cheng Lin ; Jing Cao ; Jian-Yuan Zhao ; Shi-Min Zhao
Ketogenic diet (KD) alleviates refractory epilepsy and reduces seizures in children. However, the metabolic/cell biologic mechanisms by which the KD exerts its antiepileptic efficacy remain elusive. Herein, we report that KD-produced β-hydroxybutyric acid (BHB) augments brain gamma-aminobutyric acid (GABA) and the GABA/glutamate ratio to inhibit epilepsy. The KD ameliorated pentetrazol-induced epilepsy in mice. Mechanistically, KD-produced BHB, but not other ketone bodies, inhibited HDAC1/HDAC2, increased H3K27 acetylation, and transcriptionally upregulated SIRT4 and glutamate decarboxylase 1 (GAD1). BHB-induced SIRT4 de-carbamylated and inactivated glutamate dehydrogenase to preserve glutamate for GABA synthesis, and GAD1 upregulation increased mouse brain GABA/glutamate ratio to inhibit neuron excitation. BHB administration in mice inhibited epilepsy induced by pentetrazol. BHB-mediated relief of epilepsy required high GABA level and GABA/glutamate ratio. These results identified BHB as the major antiepileptic metabolite of the KD and suggested that BHB may serve as an alternative and less toxic antiepileptic agent than KD.
2024-02-06Molecules and cells
Mitochondrial Sirtuins: Energy Dynamics and Cancer Metabolism.
Review
作者: Hojun Lee ; Haejin Yoon
Mitochondria are pivotal for energy regulation and are linked to cancer. Mitochondrial sirtuins, SIRT3, SIRT4, and SIRT5, play crucial roles in cancer metabolism. This review explores their impact on cellular processes, with a focus on the NAD+ interplay and the modulation of their enzymatic activities. The varied roles of SIRT3, SIRT4, and SIRT5 in metabolic adaptation and cancer are outlined, emphasizing their tumor suppressor or oncogenic nature. We propose new insights into sirtuin biology, and cancer therapeutics, suggesting an integrated proteomics and metabolomics approach for a comprehensive understanding of mitochondrial sirtuins in cancer.
2024-03-23
分析
对领域进行一次全面的分析。
登录
或
立即开始免费试用!
智慧芽新药情报库是智慧芽专为生命科学人士构建的基于AI的创新药情报平台，助您全方位提升您的研发与决策效率。
立即开始数据试用!
智慧芽新药库数据也通过智慧芽数据服务平台，以API或者数据包形式对外开放，助您更加充分利用智慧芽新药情报信息。
生物序列数据库
生物药研发创新
免费使用
化学结构数据库
小分子化药研发创新
免费使用