更新于：2024-11-01

PGAM5

更新于：2024-11-01

基本信息

别名

Bcl-XL-binding protein v68、BXLBv68、MGC5352

+ [4]

简介

Displays phosphatase activity for serine/threonine residues, and, dephosphorylates and activates MAP3K5 kinase. Has apparently no phosphoglycerate mutase activity. May be regulator of mitochondrial dynamics. Substrate for a KEAP1-dependent ubiquitin ligase complex. Contributes to the repression of NFE2L2-dependent gene expression. Acts as a central mediator for programmed necrosis induced by TNF, by reactive oxygen species and by calcium ionophore.

关联

项与 PGAM5 相关的药物

LFHP-1c

靶点

PGAM5

作用机制

PGAM5 inhibitors

在研机构

Guangdong Longfu Medicine Co. Ltd.

原研机构

Guangdong Longfu Medicine Co. Ltd.

在研适应症

缺血性卒中

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PGAM5 相关的临床结果

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100 项与 PGAM5 相关的转化医学

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0 项与 PGAM5 相关的专利（医药）

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240

项与 PGAM5 相关的文献（医药）

2024-12-01·Computational and Structural Biotechnology Journal

Identification and validation of protein biomarkers for predicting gastrointestinal stromal tumor recurrence

Article

作者: Li, Jie ; He, Yixuan ; Kang, Weiming ; Sun, Juan ; Ye, Xin

We conducted a proteomic analysis using mass spectrometry to identify and validate protein biomarkers for accurately predicting recurrence risk in gastrointestinal stromal tumors (GIST) patients, focusing on differentially expressed proteins in metastatic versus primary GIST tissues. We selected five biomarkers-GPX4, RBM4, TPM3, PFKFB2, and PGAM5-and validated their expressions in primary tumors of recurrent and non-recurrent GIST patients via immunohistochemistry. Our analysis of the association between these biomarkers with recurrence-free survival (RFS) and overall survival (OS), along with their interrelationships, revealed that immunohistochemistry confirmed significantly higher expressions of these biomarkers in primary GIST tissues of recurrent patients. Kaplan-Meier survival analysis showed that high expressions of GPX4, RBM4, TPM3, PFKFB2, and PGAM5 correlated with lower RFS, and GPX4 and RBM4 with lower OS. All biomarker pairs showed positive associations, with high expressions correlating with increased recurrence rates, and GPX4 and RBM4 with higher mortality rates. In conclusion, the biomarkers GPX4, RBM4, TPM3, PFKFB2, and PGAM5 are clinically relevant for predicting GIST recurrence, with their high expressions in primary tumors linked to poorer RFS and OS. They serve as potential prognostic indicators, enabling early treatment and improved outcomes. The observed interrelationships among these biomarkers further validate their accuracy in predicting GIST recurrence.

2024-12-01·Brain Research

The KEAP1/PGAM5/AIFM1-Mediated oxeiptosis pathway in Alzheimer’s disease

Article

BACKGROUNDAlzheimer's Disease (AD) is a neurodegenerative disease with mitochondrial dysfunction and oxidative stress. Oxeiptosis is a cell death pathway sensitive to reactive oxygen species (ROS). This study investigates the role of oxeiptosis pathway and mitochondrial damage in AD.METHODSAn AD model was developed in C57BL/6 mice by injecting Aβ_1-42 oligomers into the brain. Cognitive function was tested using the Morris water maze. Exposure of HT22 mouse hippocampal neurons to H₂O₂ induces oxidative stress. Protein levels of KEAP1, PGAM5 and AIFM1 were analyzed by western blot, and mitochondrial damage was observed with electron microscopy. Cell survival rates were using the CCK8 assay and flow cytometry after knocking down KEAP1, PGAM5 and AIFM1.RESULTSThe protein concentrations of KEAP1, PGAM5 and AIFM1 were found to be elevated in the hippocampal tissues of AD mice compared to control group, accompanied by mitochondrial damage in the hippocampal neurons of the AD group. Similarly, in the HT22 oxidative stress model, there was an increase in the protein levels of KEAP1, PGAM5 and AIFM1, along with observed mitochondrial damage. Following individual and combined knockdown of KEAP1, PGAM5 and AIFM1, cell survival rates under oxidative stress conditions were higher compared to H₂O₂ group, with no significant difference in cell survival rates among the knockdown groups.CONCLUSIONThis research underscores the critical role of the KEAP1/PGAM5/AIFM1-mediated oxeiptosis pathway in neuronal cell death, offering insights into potential therapeutic targets for mitigating neurodegeneration in AD.

2024-10-02·Autophagy

PGAM5 interacts with and maintains BNIP3 to license cancer-associated muscle wasting

Article

作者: Yan, Xinyi ; Lai, Nianhong ; Gao, Baogui ; Gu, Anna Meilin ; Sun, Xuegang ; La, Lei ; Han, Qinrui ; Zhang, Qingyuan ; Chen, Chunhui ; Zhang, Qingling ; Wang, Hao ; Ma, Ye

Regressing the accelerated degradation of skeletal muscle protein is a significant goal for cancer cachexia management. Here, we show that genetic deletion of Pgam5 ameliorates skeletal muscle atrophy in various tumor-bearing mice. pgam5 ablation represses excessive myoblast mitophagy and effectively suppresses mitochondria meltdown and muscle wastage. Next, we define BNIP3 as a mitophagy receptor constitutively associating with PGAM5. bnip3 deletion restricts body weight loss and enhances the gastrocnemius mass index in the age- and tumor size-matched experiments. The NH₂-terminal region of PGAM5 binds to the PEST motif-containing region of BNIP3 to dampen the ubiquitination and degradation of BNIP3 to maintain continuous mitophagy. Finally, we identify S100A9 as a pro-cachectic chemokine via activating AGER/RAGE. AGER deficiency or S100A9 inhibition restrains skeletal muscle loss by weakening the interaction between PGAM5 and BNIP3. In conclusion, the AGER-PGAM5-BNIP3 axis is a novel but common pathway in cancer-associated muscle wasting that can be targetable. Abbreviation: AGER/RAGE: advanced glycation end-product specific receptor; BA1: bafilomycin A₁; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; Ckm-Cre: creatinine kinase, muscle-specific Cre; CM: conditioned medium; CON/CTRL: control; CRC: colorectal cancer; FUNDC1: FUN14 domain containing 1; MAP1LC3A/LC3A: microtubule associated protein 1 light chain 3 alpha; PGAM5: PGAM family member 5, mitochondrial serine/threonine protein phosphatase; S100A9: S100 calcium binding protein A9; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TIMM23: translocase of inner mitochondrial membrane 23; TSKO: tissue-specific knockout; VDAC1: voltage dependent anion channel 1.

项与 PGAM5 相关的新闻（医药）

2024-03-03

·今日头条

再次发力！复旦张英梅教授、葛均波院士等合作发文

本文为转化医学网原创，转载请注明出处作者：Sophia 导读：众所周知，炎症小体活化和热噬细胞死亡有助于心血管疾病的发病机制，例如心肌缺血—再灌注（I/R）损伤，但其潜在调节机制仍知之甚少。 2024年2月28日，复旦大学张英梅、葛均波联合中国科学院分子细胞科学卓越创新中心胡荣贵共同在《Cell Discovery》上发表题为“The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through inhibiting pyroptosis via negative regulation of PGAM5/MAVS/NLRP3 axis”的研究论文，研究表明E3泛素连接酶MARCH2通过负调控PGAM5/MAVS/NLRP3轴抑制心肌焦亡，保护心肌缺血再灌注损伤。 https://www.nature.com/articles/s41421-023-00622-3 研究背景 01 炎性小体是一种大分子结构，负责感知损伤并引发一系列炎症反应。炎症小体最具特征的传感器是NACHT、LRR和PYD结构域蛋白3 (NLRP3)，它们在无菌炎症反应中被激活。NLRP3炎症小体激活有助于许多炎症性疾病的病理生理学。例如，由损伤相关分子模式（DAMP）激活的 NLRP3 炎症小体参与非酒精性脂肪性肝病的发病机制。此外，发现 NLRP3 和炎性细胞因子 IL-18 和 IL-1β 的表达水平在动脉粥样硬化斑块发展中升高。此外，NLRP3 的敲除（KO）通过消除活性氧（ROS）和线粒体损伤诱发的炎症小体激活来防止高脂肪饮食引起的肥胖和胰岛素抵抗。心肌梗死（MI）仍然是全球残疾和死亡的主要原因之一。及时恢复通过闭塞冠状动脉的血流是心肌梗死患者的最佳操作。然而，这种再灌注可能会激活心肌的级联有害损伤，称为缺血再灌注（I/R）损伤。新出现的证据表明，炎症小体的激活是炎症驱动的心肌 I/R 损伤的一个组成部分。已知抑制 NLRP3 炎症小体激活可限制心肌 I/R 损伤后的梗死面积和心功能障碍。因此，鉴定 NLRP3 炎症小体的内源性调节剂以抑制其激活可能在临床上有益。研究结果 02 我们的研究结果表明，MARCH2 对心肌 I/R 损伤、炎症小体激活和心肌细胞焦亡具有突出的心脏保护作用。MARCH2 在 ICM 患者和 I/R 激发小鼠心脏中上调。MARCH2 消融术加重了 I/R 诱发的心肌损伤，梗死面积、超声心动图参数和心肌细胞力学证明了这一点。我们的进一步分析表明， MARCH2 通过介导其 K48 连接的 polyUb 促进 PGAM5 的降解，以及通过 PGAM5/MAVS/NLRP3 依赖性机制缓解 I/R 损伤后的炎症反应和热沉细胞死亡（图 8j）。特别是，PGAM5-MAVS 缩合物介导 NLRP3 炎症小体的激活，可能充当 PGAM5/MAVS/NLRP3 海绵并促进 GSDMD 和 IL-18 的 caspase-1 依赖性切割。此外，使用 AAV9-cTnT-MARCH2 异位表达 MARCH2 可有效改善 I/R 损伤诱发的心肌损伤。在这种情况下，MARCH2 对 I/R 诱发的心肌损伤有益。 MARCH2 功能在 I/R 损伤中的工作模型。 MARCH2 通过促进 PGAM5 的 K48 连接的 polyUb 与 PGAM5 相互作用并促进其降解，从而抑制 MAVS/NLRP3 炎症小体通路和心肌细胞焦亡的活性。研究结论 03 总之，我们的研究结果不仅确立了 E3 连接酶 MARCH2 作为对抗心肌 I/R 损伤的新型心脏保护分子，而且还确定了一种以前未知的机制，该机制负调控 PGAM5/MAVS/NLRP3 炎症小体信号传导和焦亡，以维持哺乳动物心脏的稳态和正常功能。因此，靶向 MARCH2 可能代表了对抗心肌损伤的新机会。参考资料： https://www.nature.com/articles/s41421-023-00622-3 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 上海｜3月01日-02日 ▶第三届长三角单细胞组学技术应用论坛暨空间组学前沿论坛将在上海召开，诚邀您的参与！点击对应文字查看详情

2024-03-02

·生物探索

Cell Discov | 复旦大学张英梅/葛均波等合作揭示MARCH2对抗心肌缺血再灌注伤害的机制

引言炎症小体激活和焦亡会促进心肌缺血-再灌注(I/R)损伤，但其潜在的调节机制尚不清楚。2024年2月28日，复旦大学张英梅、葛均波及中国科学院分子细胞科学卓越创新中心胡荣贵共同通讯在Cell Discovery（IF 34）在线发表题为“The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through inhibiting pyroptosis via negative regulation of PGAM5/MAVS/NLRP3 axis”的研究论文，该研究表明E3泛素连接酶MARCH2通过负调控PGAM5/MAVS/NLRP3轴抑制心肌焦亡，保护心肌缺血再灌注损伤。炎症小体是一种大分子结构，负责感知损伤并引发一系列炎症反应。炎症小体最具特征的传感器是NACHT、LRR和PYD结构域蛋白3 (NLRP3)，它们在无菌炎症反应中被激活。炎症小体传感器NLRP3的激活会募集含有caspase-募集结构域(ASC)和效应蛋白caspase-1的接头凋亡相关斑点样蛋白，通过促进焦亡直接触发严重的组织损伤，并通过IL-18的分泌间接触发。新出现的证据表明，炎症小体的激活是炎症驱动的心肌I/R损伤的一个组成部分。抑制NLRP3炎性小体激活可以限制心肌I/R损伤后的梗死面积和心功能障碍。因此，鉴定内源性NLRP3炎症小体的调节剂以抑制其激活可能对临床有益。I/R损伤中MARCH2功能的工作模型（Credit: Cell Discovery）泛素(Ub)-蛋白酶体系统调节许多细胞过程中的蛋白质降解和稳态。因此，识别关键的泛素化相关调节剂可能减轻心肌I/R损伤。为此，研究人员对心肌I/R损伤小鼠的心脏样本进行了单细胞RNA测序(scRNA-seq)。研究发现E3连接酶膜相关环指蛋白2 (MARCH2)上调，MARCH2是MARCH E3 Ub连接酶亚家族的成员，包括11个成员，主要定位于内质网、核内体、高尔基体、线粒体和质膜。已知MARCH2通过与syntaxin-616相互作用调节核内体和反面高尔基管网结构。之间的囊泡运输以及回收核内体。研究还显示，MARCH2通过促进CFTR的泛素化和降解以及激活PIK3CA-AKT-mTOR通路，负向调节肿瘤细胞的自噬。利用MARCH2 KO和AAV9cTnT-MARCH2转染小鼠模型，该研究表明，MARCH2改善心肌I/R损伤并抑制NLRP3炎症小体的激活。研究发现，MARCH2与磷酸甘油酸突变酶家族成员5 (PGAM5)相互作用，促进其与K48相关的泛素化和降解。PGAM5的泛素非依赖性降解导致PGAM5-线粒体抗病毒信号蛋白(MAVS)相分离凝聚物的抑制和下游NLRP3炎症小体的激活。这些发现证明了MARCH2作为心肌I/R损伤的新治疗靶点的重要作用。原文链接https://www.nature.com/articles/s41421-023-00622-3责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文Nature | 癌症与神经系统的致命舞蹈

蛋白降解靶向嵌合体