预约演示

更新于：2025-05-07

PTDSS2

更新于：2025-05-07

基本信息

别名

phosphatidylserine synthase 2、PSS-2、PSS2

+ [3]

简介

Catalyzes a base-exchange reaction in which the polar head group of phosphatidylethanolamine (PE) or phosphatidylcholine (PC) is replaced by L-serine (PubMed:19014349). Catalyzes the conversion of phosphatatidylethanolamine and does not act on phosphatidylcholine (PubMed:19014349). Can utilize both phosphatidylethanolamine (PE) plasmalogen and diacyl PE as substrate and the latter is six times better utilized, indicating the importance of an ester linkage at the sn-1 position (By similarity). Although it shows no sn-1 fatty acyl preference, exhibits significant preference towards docosahexaenoic acid (22:6n-3) compared with 18:1 or 20:4 at the sn-2 position (By similarity).

关联

项与 PTDSS2 相关的药物

US12240855

专利挖掘

靶点

PTDSS1 x PTDSS2

作用机制-

在研机构

Daiichi Sankyo Co., Ltd.

原研机构

Daiichi Sankyo Co., Ltd.

在研适应症

肿瘤

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PTDSS2 相关的临床结果

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100 项与 PTDSS2 相关的转化医学

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0 项与 PTDSS2 相关的专利（医药）

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项与 PTDSS2 相关的文献（医药）

2024-04-01·iScience

A prognostic and immune related risk model based on zinc homeostasis in hepatocellular carcinoma

Article

作者: Xia, Fengyan ; Ye, Runxin ; Shi, Yifei ; Gao, Yuan ; Yu, Xiao-Fang

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. The dysfunction of zinc homeostasis participates in the early and advancing malignancy of HCC. However, the prognostic ability of zinc homeostasis in HCC has not been clarified yet. Here, we showed a zinc-homeostasis related risk model in HCC. Five signature genes including ADAMTS5, PLOD2, PTDSS2, KLRB1, and UCK2 were screened out via survival analyses and regression algorithms to construct the nomogram with clinical characteristics. Experimental researches indicated that UCK2 participated in the progression of HCC. Patients with higher risk scores always had worse outcomes and were more associated with immune suppression according to the analyses of immune related-pathway activation, cell infiltration, and gene expression. Moreover, these patients were likely to exhibit more sensitivity to sorafenib and other antitumor drugs. This study highlights the significant prognostic role of zinc homeostasis and suggests potential treatment strategies in HCC.

2023-11-01·Journal of Lipid Research

Disease-related PSS1 mutant impedes the formation and function of osteoclasts

Article

作者: Arai, Hiroyuki ; Shimanaka, Yuta ; Sawada, Koki ; Iwata, Tsumugi ; Sugahara, Sari ; Kono, Nozomu ; Aoki, Junken ; Ishino, Yuki

Phosphatidylserine (PS) is an acidic phospholipid that is involved in various cellular events. Heterologous dominant mutations have been identified in the gene encoding PS synthase 1 (PSS1) in patients with a congenital disease called Lenz-Majewski syndrome (LMS). Patients with LMS show various symptoms, including craniofacial/distal-limb bone dysplasia and progressive hyperostosis. The LMS-causing gain-of-function mutants of PSS1 (PSS1^LMS) have been shown to synthesize PS without control, but why the uncontrolled synthesis would lead to LMS is unknown. Here we investigated the effect of PSS1^LMS on osteoclasts (OCs) to elucidate the causative mechanism of LMS. PSS1^LMS did not affect the expression of OC-related genes but inhibited the formation, multinucleation, and activity of OCs. Especially, OCs expressing PSS1^LMS showed abnormal patterns and dynamics of actin podosome clusters, which have roles in OC migration and fusion. PSS1^LMS did not affect the level of PS but changed the acyl chain compositions of PS and phosphatidylethanolamine, and decreased the level of phosphatidylinositol. The introduction of a catalytically inactive mutation into PSS^LMS canceled the changes in phospholipids and the phenotypes observed in OCs expressing PSS1^LMS. A gain-of-function mutant of PSS2 (PSS2 R97K) also impaired OC formation and caused changes in phospholipid composition similar to the changes caused by PSS1^LMS. Our results suggest that uncontrolled PS synthesis by PSS1^LMS causes changes in the quantity or fatty acid composition of certain phospholipid classes, impairing OC formation and function, which might be a cause of osteosclerosis in patients with LMS.

2023-04-28·Animals : an open access journal from MDPI

RNA Sequencing (RNA-Seq) Analysis Reveals Liver Lipid Metabolism Divergent Adaptive Response to Low- and High-Salinity Stress in Spotted Scat (Scatophagus argus).

Article

作者: Huang, Yang ; Zhu, Chunhua ; Jiang, Dongneng ; Tian, Changxu ; Deng, Siping ; Chen, Jieqing ; Cai, Bosheng ; Li, Guangli ; Shi, Hongjuan

Spotted scat (Scatophagus argus) can tolerate a wide range of salinity fluctuations. It is a good model for studying environmental salinity adaptation. Lipid metabolism plays an important role in salinity adaptation in fish. To elucidate the mechanism of lipid metabolism in the osmoregulation, the liver transcriptome was analyzed after 22 d culture with a salinity of 5 ppt (Low-salinity group: LS), 25 ppt (Control group: Ctrl), and 35 ppt (High-salinity group: HS) water by using RNA sequencing (RNA-seq) in spotted scat. RNA-seq analysis showed that 1276 and 2768 differentially expressed genes (DEGs) were identified in the LS vs. Ctrl and HS vs. Ctrl, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the pathways of steroid hormone biosynthesis, steroid biosynthesis, glycerophospholipid metabolism, glycerolipid metabolism, and lipid metabolism were significantly enriched in the LS vs. Ctrl. The genes of steroid biosynthesis (sqle, dhcr7, and cyp51a1), steroid hormone biosynthesis (ugt2a1, ugt2a2, ugt2b20, and ugt2b31), and glycerophospholipid metabolism (cept1, pla2g4a, and ptdss2) were significantly down-regulated in the LS vs. Ctrl. The pathways related to lipid metabolisms, such as fatty acid metabolism, fatty acid biosynthesis, peroxisome proliferator-activated receptor (PPAR) signaling pathway, adipocytokine signaling pathway, fatty acid degradation, and unsaturated fatty acid biosynthesis, were significantly enriched in the HS vs. Ctrl. The genes of unsaturated fatty acid biosynthesis (scd1, hacd3, fads2, pecr, and elovl1) and adipocytokine signaling pathway (g6pc1, socs1, socs3, adipor2, pck1, and pparα) were significantly up-regulated in the HS vs. Ctrl. These results suggest that the difference in liver lipid metabolism is important to adapt to low- and high-salinity stress in spotted scat, which clarifies the molecular regulatory mechanisms of salinity adaptation in euryhaline fish.

项与 PTDSS2 相关的新闻（医药）

2024-08-29

·生物探索

Cell | 李晓淳研究组揭示磷脂酰丝氨酸合成及其抑制从而促进LDL吸收的分子机制

引言磷脂酰丝氨酸（PS）是细胞膜中最丰富的带负电荷的磷脂，在细胞膜结构、细胞凋亡、血液凝固和病毒感染等生理过程中发挥关键作用。在哺乳动物细胞中，PS的生合成发生在内质网中，磷脂酰丝氨酸合成酶（包括PSS1和PSS2）通过钙离子依赖的方式利用丝氨酸将磷脂酰胆碱（PC）或磷脂酰乙醇胺（PE）的极性头基替换，生成PS【1】。PSS1的功能获得性突变会显著增加PS的产量，并引起名为Lenz-Majewski综合症（LMS）的罕见遗传病，其特征包括智力障碍和骨骼发育不良【2】。最新研究表明，PSS1特异性抑制剂在PTDSS2缺乏的癌症和B细胞淋巴瘤的治疗中显示出潜在的应用价值【3,4】。低密度脂肪蛋白（LDL）通常被称做“坏”胆固醇，LDL在血液中的积累会引发心脑血管疾病和中风。目前，关于治疗高血脂的药物主要作用在增加细胞表面的LDL受体，提高LDL的吸收来减少其在血液中的积累。2020年，1985年诺贝尔奖生理学或医学奖得主Mike Brown 和Joe Goldstein的研究组发现PSS1调控LDL中的胆固醇从细胞膜转运至内质网的过程，其缺失会导致胆固醇在细胞膜上的积累【5,6】。关于PSS1催化PS合成的分子机制、特异性抑制剂的作用机制以及其在LDL代谢调控中的作用仍然不明确。 2024年8月28日，美国德州大学西南医学中心李晓淳研究组在Cell杂志上发表了题为Molecular insights into Human phosphatidylserine synthases 1 reveal its inhibition promotes LDL uptake的研究论文。该研究首次报告了人源PSS1的2.7 Å分辨率的冷冻电镜结构。 PSS1包含10个跨膜螺旋呈现出此前未报道过的拓扑结构。其第1至3和9个跨膜螺旋参与形成二聚化界面，第4至8个跨膜螺旋在内质网腔内侧参与形成催化活性中心，并在其中观察到了内源的底物PE和钙离子。此外，在活性中心的另一侧观察到了两个PS的结合位点，这些位点与LMS致病性功能获得性突变（L265P和P269S）相关。功能研究和分子动力学模拟表明，PS通过变构调节的方式抑制PSS1的催化活性。通过对突变体P269S的结构分析表明，在无PS结合的情况下，PSS1会发生构象变化使得底物磷脂和丝氨酸更容易进入催化活性中心。进一步功能研究表明PSS1利用催化残基组氨酸来激活被钙离子稳定的丝氨酸来完成磷脂头的交换反应。这个反应机理与其研究组发现的MBOAT家族的催化机制类似【7,8】。通过对PSS1与其特异性抑制剂DS55980254复合物结构的解析，作者观察到抑制剂结合在催化中心旁边的口袋。序列比对分析和分子模拟等实验阐明了抑制剂的特异性和与PS类似的变构调节机理。他们的研究进一步揭示，PSS1缺失会导致内质网胆固醇浓度下降，导致SREBP-2途径的激活。细胞实验表明PSS1抑制剂能够显著提高细胞表面LDLR的数量，从而促进LDL的摄取。与目前广泛应用于临床的他汀类药物不同，DS55980254不会抑制胆固醇合成酶羟甲基戊二酸单酰辅酶A（HMGCR）的活性，也不会导致HMGCR在内质网的积累，有可能避免他汀药物所产生的副作用。由于细胞中还广泛存在PSS2，特异性抑制PSS1的活性也不会导致细胞因PS缺失而死亡。这些发现阐述了通过调控磷脂代谢来控制胆固醇吸收的概念，为开发新型降胆固醇药物提供了理论依据。模式图（Credit: Cell）参考文献 1. J. E. Vance, Historical perspective: phosphatidylserine and phosphatidylethanolamine from the 1800s to the present. Journal of lipid research 59, 923-944 (2018). 2. S. B. Sousa et al., Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome. Nature genetics 46, 70-76 (2014). 3. J. Omi et al., Phosphatidylserine synthesis controls oncogenic B cell receptor signaling in B cell lymphoma. The Journal of cell biology 223, (2024). 4. Y. Yoshihama et al., Potent and Selective PTDSS1 Inhibitors Induce Collateral Lethality in Cancers with PTDSS2 Deletion. Cancer research 82, 4031-4043 (2022). 5. M. N. Trinh et al., Interplay between Asters/GRAMD1s and phosphatidylserine in intermembrane transport of LDL cholesterol. Proceedings of the National Academy of Sciences of the United States of America 119, (2022). 6. M. N. Trinh et al., Last step in the path of LDL cholesterol from lysosome to plasma membrane to ER is governed by phosphatidylserine. Proceedings of the National Academy of Sciences of the United States of America 117, 18521-18529 (2020). 7. T. Long, Y. Sun, A. Hassan, X. Qi, X. Li, Structure of nevanimibe-bound tetrameric human ACAT1. Nature 581, 339-343 (2020). 8. Y. Liu et al., Mechanisms and inhibition of Porcupine-mediated Wnt acylation. Nature 607, 816-822 (2022). https://doi.org/10.1016/j.cell.2024.08.004 责编|探索君排版|探索君文章来源|“BioArt” 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 Cell | 是什么决定了细胞的大小？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 CRISPR技术进化史 | 24年Cell综述

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