更新于：2024-05-01

PPP4C

protein phosphatase 4 catalytic subunit

更新于：2024-05-01

基本信息

别名

PP-X、PP4、PP4C

+ [6]

简介

Protein phosphatase that is involved in many processes such as microtubule organization at centrosomes, maturation of spliceosomal snRNPs, apoptosis, DNA repair, tumor necrosis factor (TNF)-alpha signaling, activation of c-Jun N-terminal kinase MAPK8, regulation of histone acetylation, DNA damage checkpoint signaling, NF-kappa-B activation and cell migration. The PPP4C-PPP4R1 PP4 complex may play a role in dephosphorylation and regulation of HDAC3. The PPP4C-PPP4R2-PPP4R3A PP4 complex specifically dephosphorylates H2AX phosphorylated on Ser-140 (gamma-H2AX) generated during DNA replication and required for DNA double strand break repair. Dephosphorylates NDEL1 at CDK1 phosphorylation sites and negatively regulates CDK1 activity in interphase (By similarity). In response to DNA damage, catalyzes RPA2 dephosphorylation, an essential step for DNA repair since it allows the efficient RPA2-mediated recruitment of RAD51 to chromatin.

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0 项与 PPP4C 相关的专利（医药）

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290

项与 PPP4C 相关的文献（医药）

2024-02-18·Microorganisms

Possible Role of CHAD Proteins in Copper Resistance.

Article

作者: Gabriela González-Madrid ; Claudio A Navarro ; José Acevedo-López ; Luis H Orellana ; Carlos A Jerez

Conserved Histidine Alpha-helical Domain (CHAD) proteins attached to the surface of polyphosphate (PolyP) have been studied in some bacteria and one archaeon. However, the activity of CHAD proteins is unknown beyond their interaction with PolyP granules. By using bioinformatic analysis, we report that several species of the biomining acidophilic bacteria contain orthologs of CHAD proteins with high sequence identity. Furthermore, the gene coding for the CHAD protein is in the same genetic context of the enzyme polyphosphate kinase (PPK), which is in charge of PolyP synthesis. Particularly, the group of ppk and CHAD genes is highly conserved. Metallosphaera sedula and other acidophilic archaea used in biomining also contain CHAD proteins. These archaea show high levels of identity in genes coding for a cluster having the same organization. Amongst these genes are chad and ppx. In general, both biomining bacteria and archaea contain high PolyP levels and are highly resistant to heavy metals. Therefore, the presence of this conserved genetic organization suggests a high relevance for their metabolism. It has been formerly reported that a crystallized CHAD protein contains a copper-binding site. Based on this previous knowledge, in the present report, it was determined that all analyzed CHAD proteins are very conserved at their structural level. In addition, it was found that the lack of YgiF, an Escherichia coli CHAD-containing protein, decreases copper resistance in this bacterium. This phenotype was not only complemented by transforming E. coli with YgiF but also by expressing CHAD from Acidithiobacillus ferrooxidans in it. Interestingly, the strains in which the possible copper-binding sites were mutated were also more metal sensitive. Based on these results, we propose that CHAD proteins are involved in copper resistance in microorganisms. These findings are very interesting and may eventually improve biomining operations in the future.

2024-02-09·Translational psychiatry

Pramipexole restores behavioral inhibition in highly impulsive rats through a paradoxical modulation of frontostriatal networks.

Article

作者: Robin Magnard ; Maxime Fouyssac ; Yvan M Vachez ; Yifeng Cheng ; Thibault Dufourd ; Carole Carcenac ; Sabrina Boulet ; Patricia H Janak ; Marc Savasta ; David Belin ; Sebastien Carnicella

Impulse control disorders (ICDs), a wide spectrum of maladaptive behaviors which includes pathological gambling, hypersexuality and compulsive buying, have been recently suggested to be triggered or aggravated by treatments with dopamine D_2/3 receptor agonists, such as pramipexole (PPX). Despite evidence showing that impulsivity is associated with functional alterations in corticostriatal networks, the neural basis of the exacerbation of impulsivity by PPX has not been elucidated. Here we used a hotspot analysis to assess the functional recruitment of several corticostriatal structures by PPX in male rats identified as highly (HI), moderately impulsive (MI) or with low levels of impulsivity (LI) in the 5-choice serial reaction time task (5-CSRTT). PPX dramatically reduced impulsivity in HI rats. Assessment of the expression pattern of the two immediate early genes C-fos and Zif268 by in situ hybridization subsequently revealed that PPX resulted in a decrease in Zif268 mRNA levels in different striatal regions of both LI and HI rats accompanied by a high impulsivity specific reduction of Zif268 mRNA levels in prelimbic and cingulate cortices. PPX also decreased C-fos mRNA levels in all striatal regions of LI rats, but only in the dorsolateral striatum and nucleus accumbens core (NAc Core) of HI rats. Structural equation modeling further suggested that the anti-impulsive effect of PPX was mainly attributable to the specific downregulation of Zif268 mRNA in the NAc Core. Altogether, our results show that PPX restores impulse control in highly impulsive rats by modulation of limbic frontostriatal circuits.

2024-02-02·International journal of biological macromolecules

Structure of the exopolyphosphatase (PPX) from Zymomonas mobilis reveals a two-magnesium-ions PPX.

Article

作者: Zuokun Lu ; Yongsheng Hu ; Jiazhan Wang ; Bingyang Zhang ; Yanyan Zhang ; Zhaohui Cui ; Liang Zhang ; Aili Zhang

Rapid adaptation of metabolic capabilities is crucial for bacterial survival in habitats with fluctuating nutrient availability. In such conditions, the bacterial stringent response is a central regulatory mechanism activated by nutrient starvation or other stressors. This response is primarily controlled by exopolyphosphatase/guanosine pentaphosphate phosphohydrolase (PPX/GPPA) enzymes. To gain further insight into these enzymes, the high-resolution crystal structure of PPX from Zymomonas mobilis (ZmPPX) was determined at 1.8 Å. The phosphatase activity of PPX was strictly dependent on the presence of divalent metal cations. Notably, the structure of ZmPPX revealed the presence of two magnesium ions in the active site center, which is atypical compared to other PPX structures where only one divalent ion is observed. ZmPPX exists as a dimer in solution and belongs to the "long" PPX group consisting of four domains. Remarkably, the dimer configuration exhibits a substantial and deep aqueduct with positive potential along its interface. This aqueduct appears to extend towards the active site region, suggesting that this positively charged aqueduct could potentially serve as a binding site for polyP.

项与 PPP4C 相关的新闻（医药）

2024-03-19

·今日头条

今日Cell：国内团队发现新肠道激素，连起肠肝轴胆固醇代谢调控

03月19日的《热心肠日报》，我们解读了 15 篇文献，关注：肠肝轴，胆固醇，免疫耐受，IL-22，肠道应激，阿司匹林，IBD，肠脑轴，乳糜泻，Novonesis，Slimbiotics，i-Health，英赛飞影，海南三叶制药厂，百奥泰。该篇日报由R·AI辅助创作生成，人工审核校对。国内团队Cell：发现调控胆固醇代谢的新肠道激素 Cell——[64.5] ① 清华大学王一国、南方医科大学南方医院张惠杰与团队研究发现了一种新肠道激素Cholesin（肠抑脂素），其具有抑制肝脏胆固醇合成、降低血液胆固醇水平的作用；② Cholesin由此前功能未知的基因编码（人类 C7orf50 ，小鼠 3110082I17Rik ）；③ 肠道的胆固醇吸收可诱导Cholesin生成，肠细胞中，NPC1L1介导的胆固醇摄取促进Cholesin分泌；④ SNP变异rs1007765（位于 Cholesin 基因3'端附近）能上调 Cholesin 表达，并与人类血浆胆固醇水平呈负相关；⑤ 机制上，Cholesin进入肝脏后，通过结合孤儿G蛋白偶联受体GPr146，抑制cAMP/PKA-ERK1/2信号通路，从而抑制肝脏中SREBP2控制的胆固醇合成，减少极低密度脂蛋白分泌，降低血浆胆固醇水平；⑥ Cholesin治疗可改善模型小鼠血脂和动脉粥样硬化，与他汀类药物联用效果更佳；⑦ 因此，肠道胆固醇吸收通过Cholesin-GPR146轴抑制肝脏胆固醇合成，为治疗相关疾病提供了新思路。【原文信息】 A gut-derived hormone regulates cholesterol metabolism 2024-03-18 , doi: 10.1016/j.cell.2024.02.024 Science子刊：肠道细菌衍生的血清素促进生命早期的免疫耐受 Science Immunology——[24.8] ① 本研究揭示了特定肠道细菌通过增加血清素的可用性，在新生儿肠道中塑造T细胞对膳食抗原和共生菌的反应，从而促进早期生命中的免疫耐受；② 新生儿肠道中富含包括血清素在内的神经递质，且特定细菌直接产生血清素，并通过下调单胺氧化酶A以限制血清素的分解；③ 血清素直接作用于T细胞，增加细胞内吲哚-3-乙醛并抑制mTOR激活，从而促进调节性T细胞的分化；④ 新生小鼠口服血清素可产生T细胞介导的针对膳食抗原和共生菌的长期特异性免疫耐受；⑤ 本研究表明新生儿肠道细菌衍生的血清素在生命早期免疫耐受中的关键作用。【原文信息】 Gut bacteria-derived serotonin promotes immune tolerance in early life 2024-03-15 , doi: 10.1126/sciimmunol.adj4775 Nature子刊：IL-22如何调节肠道，改善肥胖相关代谢紊乱？ Nature Communications——[16.6] ① 通过构建肠上皮、肝脏和白色脂肪组织（WAT）特异性Il22ra1敲除小鼠，研究组织特异性IL-22RA1信号在介导长期高脂饮食（HFD）驱动的代谢紊乱中的重要性；② 肠上皮和肝脏特异性IL-22RA1信号可提全身高性的糖代谢；③ 肠道IL-22RA1信号以菌群依赖方式介导肝脏和WAT代谢；④ 颤杆菌属与WAT炎症增加有关，并由表达Mmp12的巨噬细胞引起；⑤ 机制上，IL-22及其诱导的IL-18调控肠道脂质代谢基因的转录，而潘氏细胞特异性IL-22RA1信号部分介导HFD后的全身性糖代谢；⑥ 本研究揭示了肠道特异性IL-22RA1信号在调节肠道代谢及缓解系统性肥胖相关疾病中的关键作用。【原文信息】 Intestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders 2024-02-21 , doi: 10.1038/s41467-024-45568-6 肠道应激如何导致血脂异常？ Theranostics——[12.4] ① 本研究评估核糖体应激反应在肠肝脂质调节中的作用；② 利用化学核糖体失活应激剂（RIS）处理模型，发现RIS促进肠肝脂质积累，同时降低正常和饮食诱导肥胖小鼠血液中的低密度脂蛋白胆固醇；③ 核糖体应激显著调节胆固醇输入相关途径，尤其是通过转录和转录后调控增加肠道低密度脂蛋白受体（LDLR）的水平；④ LDLR增加可促进肠肝胆固醇的积累，导致核糖体应激响应下的血脂异常；⑤ 炎症和肥胖相关的肠道模型中进一步证实以上结论；⑥ 本研究为理解慢性人类疾病中应激响应性代谢重编程提供了新的分子机制。【原文信息】 Gut ribotoxic stress responses facilitate dyslipidemia via metabolic reprogramming: an environmental health prediction 2024-01-20 , doi: 10.7150/thno.88586 国内团队：阿司匹林如何维持肠道免疫稳态？ Advanced Science——[15.1] ① 复旦大学余巍、于肖飞团队揭示了阿司匹林通过乙酰化组蛋白去乙酰化酶（HDACs）SIRT1以维持肠道免疫稳态的新机制；② 通过同位素标记的阿司匹林和质谱分析，发现阿司匹林可直接乙酰化包括SIRT1在内的10种HDACs蛋白；③ 阿司匹林乙酰化SIRT1的第408位赖氨酸，破坏其去乙酰化活性，影响底物结合亲和力；④ 阿司匹林通过抑制SIRT1，增加乙酰化p53水平，促进p53依赖的细胞凋亡；⑤ SIRT1乙酰化模拟突变小鼠中促炎细胞因子产生减少，并有助于维持肠道免疫稳态；⑥ 本研究表明SIRT1乙酰化内部功能位点在维持肠道免疫稳态中的重要性，并解释了阿司匹林作为传统抗炎药发挥作用。【原文信息】 Aspirin-Mediated Acetylation of SIRT1 Maintains Intestinal Immune Homeostasis 2024-03-14 , doi: 10.1002/advs.202306378 国内团队：自噬相关蛋白AMBRA1抑制生物制剂疗效，加重肠炎 Cell Death and Differentiation——[12.4] ① 上海交通大学医学院附属新华医院杜鹏、刘辰莹、陈颖伟与团队揭示了自噬相关蛋白AMBRA1在肠道炎症反应中的促炎作用和自噬非依赖的NF-κB激活分子机制，提示靶向AMBRA1是增强生物制剂IFX抗炎疗效的新策略；② 首先构建 Villin-Ambra1flox/flox 肠上皮细胞特异性敲除小鼠，在DSS急性小鼠肠炎模型中，证实敲除 Ambra1 显著抑制肠炎反应，并增强抗TNF-α生物制剂夫利西单抗（IFX）的靶向抗炎作用；③ AMBRA1与IKK激酶复合物及PP4R1/PP4c蛋白磷酸酶复合体互作，通过N端结构域（1-532 AA）竞争性抑制PP4R1/PP4c与IKK复合物的结合，从而拮抗了PP4R1/PP4c对IKK的去磷酸化作用，进而促进NF-κB通路激活，加重肠道炎症反应；④ 在炎症刺激条件下，IKKα通过磷酸化AMBRA1第1043位丝氨酸，抑制CUL4A与AMBRA1的蛋白互作以及CUL4A对AMBRA1的K48多聚泛素化修饰，从而增强AMBRA1的蛋白稳定性；⑤ 通过对IBD患者的IFX治疗后临床缓解及无缓解的肠道组织分析发现，AMBRA1在IFX治疗临床无缓解的肠道炎症组织中显著增高，而在IFX治疗后临床缓解的组织中表达明显减少，与IBD患者的临床治疗预后相关。【原文信息】 AMBRA1 promotes intestinal inflammation by antagonizing PP4R1/PP4c mediated IKK dephosphorylation in an autophagy-independent manner 2024-02-29 , doi: 10.1038/s41418-024-01275-9 全面解析炎症性肠病的肠外表现 Gastroenterology——[29.4] ① 本研究是迄今为止最大规模的关于炎症性肠病（IBD）患者肠外表现（EIM）的多队列综合性分析，揭示了与EIM并发症相关的临床、血清学和遗传因素；② 大多数EIM在女性、患有结肠病变的CD患者以及需要手术的患者中更为常见，吸烟增加EIM的风险，除了原发性硬化性胆管炎PSC；③ 观察到多个血清学关联，包括PSC（ANCA, ASCA, anti-CBir1）和任何EIM（ANCA, ASCA, anti-I2）；④ 在MHC和CPEB4中发现了全基因组显著关联，遗传关联提示TNF、JAK-STAT和IL6可能是EIM的潜在治疗靶点；⑤ 与先前报道相反，这项研究的受试者中只有2%有多个EIMs，且大多数共存现象是负相关的；⑥ 研究确定了与EIMs相关的人口统计学、临床和遗传学关联，揭示了潜在的机制，并涉及新颖和现有的药物靶点，为IBD管理提供了更个性化的方法。【原文信息】 Comprehensive association analyses of extraintestinal manifestations in inflammatory bowel disease 2024-02-27 , doi: 10.1053/j.gastro.2024.02.026 溃疡性结肠炎患者的焦虑抑郁症状或与肠道菌群有关 Gut Microbes——[12.2] ① 本研究揭示出溃疡性结肠炎（UC）患者肠道菌群通过降低结肠中神经肽Y（NPY）表达，从而导致焦虑和抑郁行为；② 将UC患者（UC-FMT）和对照（HC-FMT）的粪菌移植到小鼠，通过RNA-seq检测小鼠结肠基因的表达，结果显示两组小鼠的结肠基因表达具有显著差异，UC-FMT小鼠结肠中神经肽信号通路下调，包括NPY表达下调；③ 相比于HC-FMT，UC-FMT小鼠的结肠和血浆中NPY蛋白水平也降低；④ 口服给予从UC患者粪便中分离的蒙氏肠球菌（EM）能够降低小鼠结肠中的NPY表达，并诱发肠炎、焦虑和抑郁样行为，而腹腔注射外源性NPY能显著缓解EM诱发的焦虑和抑郁样行为；⑤ EM给药的小鼠其血浆和海马中NPY蛋白水平也降低，且荚膜多糖与EM诱导的NPY表达下调相关；⑥ 与健康对照组相比，UC患者炎症性结肠中NPY表达显著降低。【原文信息】 Regulation of colonic neuropeptide Y expression by the gut microbiome in patients with ulcerative colitis and its association with anxiety- and depression-like behavior in mice 2024-02-25 , doi: 10.1080/19490976.2024.2319844 肠道菌群影响IBD相关脊柱关节炎的治疗效果 Cell Reports Medicine——[14.3] ① 本研究揭示了硫唑嘌呤治疗炎症性肠病（IBD）相关的外周脊柱关节炎（pSpA）的临床疗效与肠道菌群之间的机制联系；② 纳入22名IBD-pSpA患者中，使用硫唑嘌呤治疗后，临床反应者的肠道菌群中富含产丁酸的普拉梭菌Fp；③ 硫唑嘌呤能促进Fp中丁酸合成基因的转录和丁酸的产生，但过量的叶酸会抑制这一过程；④ 硫唑嘌呤治疗可增强粪便中丁酸的产生，并限制野生型和反应者（而非非反应者）菌群定植的小鼠结肠炎；⑤ Fp足以恢复硫唑嘌呤对非反应者菌群定植的无菌小鼠结肠炎的保护作用；⑥ 本研究为IBD-pSpA的诊断和治疗提供了新的指导。【原文信息】 The gut microbiome regulates the clinical efficacy of sulfasalazine therapy for IBD-associated spondyloarthritis 2024-02-12 , doi: 10.1016/j.xcrm.2024.101431 乳糜泻自身免疫的机制（综述） Gut——[24.5] ① 乳糜泻是一种食物不耐受，也是一种自身免疫性疾病，具有高度疾病特异性的转谷氨酰胺酶2自身抗体；② 目前，如果儿童血清中含有高水平的抗转谷氨酰胺酶2的IgA抗体，就可诊断为乳糜泻；③ 抗转谷氨酰胺酶2抗体是谷蛋白免疫反应的一部分，这一过程的分子机制已经被破解；④ 谷蛋白肽是转谷氨酰胺酶2的良好底物，会被转谷氨酰胺酶2捕获，然后通过乳糜泻相关HLA分子HLA-DQ2和HLA-DQ8以脱酰胺肽的形式呈递给CD4+ T细胞；⑤ 转谷氨酰胺酶2特异性B细胞及其B细胞受体（膜结合免疫球蛋白）在谷蛋白肽呈递到T细胞的过程中至关重要；⑥ 转谷氨酰胺酶2特异性B细胞会与捕获谷蛋白肽的转谷氨酰胺酶2结合（半抗原载体样复合物），进而在T细胞的帮助下，变成产生抗转谷氨酰胺酶2抗体的浆细胞。【原文信息】 Coeliac disease: the paradox of diagnosing a food hypersensitivity disorder with autoantibodies 2024-02-20 , doi: 10.1136/gutjnl-2023-331595 Novonesis旗下益生菌新健康声明获加拿大卫生部批准 ① 3月15日，Novonesis宣布，旗下植物乳杆菌Clepius L. plantarum的2项健康声明获得加拿大卫生部批准，成为加拿大首株被认为具有缓解压力和促进胃肠健康双重益处的益生菌；② 临床前实验数据表明，该菌株具有良好的胃肠耐受性，并展现出有助于维持肠道屏障完整性以及抗病原体、抗炎和产胆盐水解酶等特性；③ 此次批准基于一系列临床研究和数据，其中一项随机双盲、安慰剂对照、多中心和剂量范围研究结果显示，该菌株无论是低剂量（1010 CFU）还是高剂量（1011 CFU）均可显著改善胃肠道症状，如腹痛和腹胀等；④ 此外，据报道，该菌株还有望通过日常补充来缓解压力。【原文信息】 Novonesis touts pioneering probiotic Clepius L. Plantarum’s approval for gut and brain health claims 2024-03-15 , nutrition insight Slimbiotics与i-Health达成益生菌商业化新合作 ① 近日，奥地利初创公司Slimbiotics与DSM旗下子公司i-Health宣布达成合作，后者将帮助前者把代谢健康益生菌引入北美和中国市场；② Slimbiotics的代谢健康益生菌为发酵乳杆菌（ L. fermentum ）K7-Lb1、K8-Lb1和K11-Lb3，筛选自肯尼亚Mbeere地区的自然发酵面团Kimere；③ 三株菌株将通过Culturelle和Estroven品牌实现商业化；④ 发表于 Nutrients 杂志上的临床研究结果显示，补充三株菌株组合3个月，能显著降低体脂肪量、体重、腰围、BMI等指标。【原文信息】 DSM i-Health partners with Slimbiotics for metabolic health probiotics 2024-03-14 , nutraingredients-usa 无线内镜厂商「英赛飞影」宣布完成天使轮融资 ① 近日，苏州英赛飞影医疗科技有限公司宣布完成天使轮融资；② 本轮融资由国仟创投、接力基金及苏州器械产业集团共同投资；③ 融资资金将用于公司核心产品智能无线硬镜和软镜的研发投入、产能扩建及市场开拓等；④ 英赛飞影的智能无线内镜产品具备无线、超低延迟、易携、高清晰度等特点，适用于多种医疗场景；⑤ 目前，两款核心产品已完成开发并进入临床试验阶段，预计将于2024年下半年获批。【原文信息】英赛飞影完成天使轮融资，开启“无线”创新之路 2024-03-18 , 动脉网海南三叶制药厂：奥美拉唑肠溶胶囊过评 ① 3月18日，国家药监局发布了新一批药品批准证明文件送达信息；② 本批次共16个受理号获批，其中海南三叶制药厂的奥美拉唑肠溶胶囊的一致性评价受理号获批；③ 奥美拉唑肠溶胶囊由阿斯利康研发，用于治疗胃、十二指肠溃疡、反流性食管炎等疾病；④ 其于1988年在欧盟和中国获批上市，是第一个上市的质子泵抑制剂。【原文信息】刚刚，国家药监局发布16个新批件，1个大品种过评！ 2024-03-18 , 新康界百奥泰2款生物类似药授权海外，达成600万美元协议 ① 3月18日，百奥泰生物宣布，已与SteinCares就2款在研生物类似药签订授权许可与商业化协议；② 百奥泰将BAT2506注射液和BAT2606注射液在巴西及拉丁美洲地区的商业化权益许可授予SteinCares；③ 此次协议总金额最高达600万美元（约合人民币4318.86万），包括120万美元首付款和最高480万美元的里程碑付款；④ 此外，双方还约定了将净销售额的两位数百分比作为收入分成；⑤ BAT2506是一款戈利木单抗生物类似药，原研戈利木单抗（Simponi）来自强生，靶向TNF-α，获批用于类风湿性关节炎、强直性脊柱炎、银屑病关节炎、溃疡性结肠炎等自免疾病；⑥ BAT2606是一款美泊利珠单抗生物类似药，原研美泊利珠单抗（Nucala）由GSK开发，主要用于嗜酸性粒细胞哮喘、支气管哮喘等免疫炎症性疾病。【原文信息】 600万美元！百奥泰2款生物类似药授权海外 2024-03-18 , 医药魔方感谢本期日报的审核者：mildbreeze，圆圈儿，章台柳，九卿臣，lxx，Alex Zhang 点击阅读过去10天的日报： 0318 | NEJM双发：大肠癌无创检测取得新突破 0317 | Cell子刊：多组学+长追踪，深度解析人体菌群动态和与宿主的互作 0316 | 国内团队34页综述详解：用饮食干预对抗疾病 0315 | 顶刊小高潮：王良静等Cell重磅突破，Science三文聚焦肠菌 0314 | 今日Nature：抵御肠道感染，菌群色氨酸代谢物有新招 0313 | 朱书/潘文等Cell子刊新发现：肠菌胆汁酸代谢如何影响大肠癌抗肿瘤免疫？ 0312 | 65分综述详解ILC3：守护肠道健康的重要免疫细胞 0311 | 分析81万人数据：根除幽门螺杆菌，还能防肠癌？ 0310 | 癌症治疗中的饮食干预：评估252项临床试验有何发现？ 0309 | AGA最新指南：基于粪便菌群的疗法在胃肠疾病中的应用

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