更新于：2024-11-01

SGMS1

更新于：2024-11-01

基本信息

别名

Medulla oblongata-derived protein、MGC17342、MOB

+ [7]

简介

Major sphingomyelin synthase at the Golgi apparatus (PubMed:17449912, PubMed:14685263). Catalyzes the reversible transfer of phosphocholine moiety in sphingomyelin biosynthesis: in the forward reaction transfers phosphocholine head group of phosphatidylcholine (PC) on to ceramide (CER) to form ceramide phosphocholine (sphingomyelin, SM) and diacylglycerol (DAG) as by-product, and in the reverse reaction transfers phosphocholine from SM to DAG to form PC and CER. The direction of the reaction depends on the levels of CER and DAG in Golgi membranes (PubMed:14685263, PubMed:17449912, PubMed:14976195, PubMed:17982138, PubMed:19454763). Does not use free phosphorylcholine or CDP-choline as donor (PubMed:14976195, PubMed:14685263). Regulates receptor-mediated signal transduction via mitogenic DAG and proapoptotic CER, as well as via SM, a structural component of membrane rafts that serve as platforms for signal transduction and protein sorting (PubMed:14976195, PubMed:17449912, PubMed:17982138). Plays a role in secretory transport via regulation of DAG pool at the Golgi apparatus and its downstream effects on PRKD1 (PubMed:18370930, PubMed:21980337).

关联

项与 SGMS1 相关的药物

Idroxioleic Acid

靶点

SGMS1

作用机制

SGMS1刺激剂

在研机构

Laminar Pharmaceuticals SA (Spain)

原研机构

Laminar Pharmaceuticals SA (Spain)

在研适应症

胶质瘤 [+4]

非在研适应症

神经痛

最高研发阶段临床3期

首次获批国家/地区-

首次获批日期1800-01-20

项与 SGMS1 相关的临床试验

NCT04299191 / Recruiting临床1/2期

Study of LAM561 Acid in Pediatric Patients With Malignant Glioma and Other Advanced Solid Tumors

An open label, non-randomized study in pediatric patients with advanced high-grade gliomas and other solid tumors.
The study will be performed in two phases: a dose escalation phase in up to 18 patients following a standard "3+3" design to establish dose-limiting toxicity (DLT) and a "safe" dose of LAM561 followed by an expanded safety cohort of up to 10 patients treated at the Maximum Tolerated Dose (MTD). If the MTD is well tolerated in the expanded safety cohort, that dose becomes the Recommended Phase 2 Dose (RP2D).
Glioma patients and other solid tumor patients (including non-glial brain tumors) will be treated as a single cohort. Patients with either tumor type will be allowed to enroll on the study as positions are made available. No tumor type will be given priority over another and there is no minimum number of glioma patients or solid tumor patients that must be enrolled on the trial.

开始日期2020-09-01

申办/合作机构

Laminar Pharmaceuticals SA (Spain)

[+3]

NCT04250922 / Active, not recruiting临床2/3期

A Randomized, Double-blind, Placebo-controlled Adjuvant Trial in Newly Diagnosed Primary Glioblastoma Subjects to Assess the Efficacy and Safety of LAM561 in Combination With Radiotherapy and Temozolomide Standard of Care Treatment.

The proposed Phase IIB/III randomized, double-blind, placebo-controlled trial in subjects with newly diagnosed primary glioblastoma multiforme (ndGBM) aims to compare the efficacy and safety of LAM561 versus placebo, given with standard of care (SoC) therapy of radiation therapy plus temozolomide (TMZ), followed by an adjuvant treatment of 6 month period of TMZ and then LAM561 or placebo in monotherapy.

开始日期2019-12-01

申办/合作机构

Laminar Pharmaceuticals SA (Spain)

[+2]

NCT04148573 / Completed临床2期

Randomized, Double-blind, Placebo Controlled, Parallel, Multicentric, Phase IIa Clinical Trial to Evaluate Safety, Tolerability, Therapeutic Efficacy of Daily Oral Treatment NFX88 on Neuropathic Pain in Patients With Spinal Cord Injury

In summary, this small-scale study is designed to demonstrate that the NFX88 is safe and well tolerated, as well as preliminary evidence of improvement in the score of VAS, PD-Q, and PGIC scales.

开始日期2019-10-01

申办/合作机构

Neurofix SL初创企业

100 项与 SGMS1 相关的临床结果

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100 项与 SGMS1 相关的转化医学

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0 项与 SGMS1 相关的专利（医药）

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418

项与 SGMS1 相关的文献（医药）

2024-12-01·International Immunopharmacology

SMS2 siRNA inhibits pancreatic tumor growth by tumor microenvironment modulation

Article

作者: Jiang, Xin ; Yuan, Ziqing ; Dong, Jibin ; Yu, Ker ; Ding, Tingbo

The massive infiltration of suppressor immune cells within the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is a major cause of treatment resistance. Reducing this infiltration may represent a potentially effective therapeutic strategy. Sphingomyelin synthase 2 (SMS2) is a crucial enzyme for sphingomyelin synthesis, contributing significantly to the integrity and function of the plasma membrane. In this study, we developed a self-assembling SMS2 siRNA gene expression plasmid for in vivo delivery. The SMS2 siRNA specifically inhibits SMS2 expression while preserving the expression and activity of SMS1. Administration of the self-assembling SMS2 siRNA suppresses tumor growth in a murine model of Panc02 pancreatic carcinoma, modulates the polarization of tumor-associated macrophages (TAMs), and reduces the infiltration of tumor-associated neutrophils (TANs) by regulating the NF-κB/CXCL5 pathway. Consequently, utilizing SMS2 siRNA to improve the local immunosuppressive microenvironment holds promise for pancreatic cancer therapy.

2024-10-29·Proceedings of the National Academy of Sciences

Substrate specificity controlled by the exit site of human P4-ATPases, revealed by de novo point mutations in neurological disorders

Article

作者: Sullivan, Jennifer A. ; Kárteszi, Judit ; Calianese, David C. ; McNiven, Vanda ; Nagata, Shigekazu ; Noji, Tomoyasu ; Shashi, Vandana ; Jordanova, Albena ; Ramos, Luiza Lorena Pires ; Schoch, Kelly ; Ishikita, Hiroshi

The maintenance of lipid asymmetry on the plasma membrane is regulated by flippases, such as ATP8A2, ATP11A, and ATP11C, which translocate phosphatidylserine and phosphatidylethanolamine from the outer leaflet to the inner leaflet. We previously identified a patient-derived point mutation (Q84E) in ATP11A at the phospholipid entry site, which acquired the ability to flip phosphatidylcholine (PtdCho). This mutation led to elevated levels of sphingomyelin (SM) in the outer leaflet of the plasma membrane. We herein present two de novo ATP11A dominant mutations (E114G and S399L) in heterozygous patients exhibiting neurological and developmental disorders. These mutations, situated near the predicted phospholipid exit site, similarly confer the ability for ATP11A to recognize PtdCho as a substrate, resulting in its internalization into cells. Cells expressing these mutants had increased SM levels on their surface, attributed to the up-regulated expression of the sphingomyelin synthase-1 gene, rendering them more susceptible to SM phosphodiesterase-mediated cell lysis. Corresponding mutations in ATP11C and ATP8A2, paralogs of ATP11A, exerted similar effects on PtdCho-flipping activity and increased SM levels on the cell surface. Molecular dynamics simulations, based on the ATP11C structure, suggest that the E114G and S399L mutations enhance ATP11C’s affinity toward PtdCho. These findings underscore the importance of the well-conserved exit and entry sites in determining phospholipid substrate specificity and indicate that aberrant flipping of PtdCho contributes to neurological disorders.

2024-10-07·Journal of Cell Biology

De novo lipid synthesis and polarized prenylation drive cell invasion through basement membrane

Article

作者: Park, Kieop ; Sherwood, David R. ; Soh, Adam W.J. ; Thendral, Siddharthan B. ; Garde, Aastha ; Chi, Qiuyi

To breach the basement membrane, cells in development and cancer use large, transient, specialized lipid-rich membrane protrusions. Using live imaging, endogenous protein tagging, and cell-specific RNAi during Caenorhabditis elegans anchor cell (AC) invasion, we demonstrate that the lipogenic SREBP transcription factor SBP-1 drives the expression of the fatty acid synthesis enzymes POD-2 and FASN-1 prior to invasion. We show that phospholipid-producing LPIN-1 and sphingomyelin synthase SMS-1, which use fatty acids as substrates, produce lysosome stores that build the AC’s invasive protrusion, and that SMS-1 also promotes protrusion localization of the lipid raft partitioning ZMP-1 matrix metalloproteinase. Finally, we discover that HMG-CoA reductase HMGR-1, which generates isoprenoids for prenylation, localizes to the ER and enriches in peroxisomes at the AC invasive front, and that the final transmembrane prenylation enzyme, ICMT-1, localizes to endoplasmic reticulum exit sites that dynamically polarize to deliver prenylated GTPases for protrusion formation. Together, these results reveal a collaboration between lipogenesis and a polarized lipid prenylation system that drives invasive protrusion formation.

项与 SGMS1 相关的新闻（医药）

2024-02-27

·生物探索

Nat Struct Mol Biol | 韩晓/李锴发现M2巨噬细胞促进米色脂肪生成的潜在机制

引言鞘磷脂(Sphingomyelin, SM)在调节哺乳动物膜特性中起着关键作用，是一个重要的生物活性分子库。SM的生物合成是由鞘磷脂合成酶(sphingomyelin synthase, SMS)家族介导的，包括SMS1、SMS2和SMSr相关成员。虽然SMS1和SMS2具有SMS活性，但SMSr具有神经酰胺磷酸乙醇胺合成酶活性。2024年2月22日，上海交通大学曹禹、赵杰、姚德强及复旦大学周璐共同通讯在Nature Structural & Molecular Biology （IF 16.8）在线发表题为“Cryo-EM structure of human sphingomyelin synthase and its mechanistic implications for sphingomyelin synthesis”的研究论文，该研究测定了与神经酰胺、二酰基甘油/磷酸乙醇胺和神经酰胺/磷酸乙醇胺(CPE)配合物的人SMSr的冷冻电镜结构。鞘脂是真核生物中一类重要的脂类，其含量影响膜组织和动力学及其周围的膜蛋白。SMs是哺乳动物鞘脂的主要形式，广泛分布于哺乳动物细胞的外质小叶中，与胆固醇等多种生物活性分子结合。与甘油磷脂形成的相对“软”的膜结构相反，在膜中加入SMs形成了一个“硬”的屏蔽状区域，防止机械应变和温度变化。被称为“脂筏”的富含SMs的微结构域存在于细胞膜上，这些微结构域形成特定的条件来调节膜蛋白的功能。例如，免疫受体，包括T细胞受体和B细胞受体，以及其他免疫信号成分，如酪氨酸激酶FYN、CD40和CD154，在受体激活后被转运到脂筏中，从而促进免疫细胞的增殖和激活。此外，SM代谢还产生和消耗多种生物活性脂质，包括中间体鞘氨醇、二酰基甘油(DAG)和神经酰胺及其衍生物鞘氨醇-1-磷酸和神经酰胺-L-磷酸。这些化合物在细胞凋亡、炎症、细胞周期和血管生成等广泛的生物学途径中发挥信号功能。hSMS催化CPE/SM合成两步反应示意图（Credit: Nature Structural & Molecular Biology）哺乳动物体内SMs的生物合成从丝氨酸和棕榈酰辅酶A在内质网(ER)内缩合生成3-酮鞘氨酸开始，最后由磷脂酰胆碱(PC)/磷脂酰乙醇胺(PE)将磷脂胆碱(PCho)/磷酸乙醇胺(PEA)转移到神经酰胺，从而生成SM或神经酰胺磷酸乙醇胺(CPE)，具体取决于反应中的含磷酸基团供体(PC或PE)。SM/CPE合成的最后一步由SMS家族催化，该家族在哺乳动物中包括三个主要成员：SMS1, SMS2和SMSr。研究表明SMS1是SM的主要产生酶，SMSr是CPE合成酶，而SMS2是同时产生SM和CPE的双功能酶。功能失调的SMSs会破坏脂质稳态，导致严重的生理后果。相比之下，缺乏SMS2的小鼠对高脂肪饮食表现出更好的耐受性，肥胖症状减轻，胰岛素敏感性增加，动脉粥样硬化减少，这表明SMS2抑制剂具有治疗潜力。虽然SMSr缺乏确实会影响细胞和循环中的测试脂质(神经酰胺、SM、胆固醇和甘油三酯)，但它可能对PE代谢有重要影响。然而，对于这些酶催化的生化过程的分子机制以及在SMS1、SMS2和SMSr中观察到的底物特异性知之甚少，这限制了人们对它们的反应和亚型特异性抑制剂的开发。该研究报告了人类SMSr (hSMSr)的冷冻电镜结构以及用于CPE合成的底物/产物。结构显示出六聚体排列，反应室位于跨膜螺旋之间。在该结构中，发现了一个催化五联体E-H / D-H-D，位于反应室亲脂段和亲水段之间的界面。此外，该研究揭示了由SMSr催化的两步合成过程，包括PE-PLC(磷脂酰乙醇胺-磷脂酶C)水解和随后将磷酸乙醇胺部分转移到神经酰胺。该研究为SMSr的催化机制提供了新的见解，并扩展了人们对鞘脂代谢的理解。原文链接https://www.nature.com/articles/s41594-024-01237-2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

2022-07-04

·生物谷

外泌体: 神经酰胺转运蛋白在细胞外小泡生物发生和鞘磷脂组成中的作用

鞘磷脂神经酰胺在体内外细胞外囊泡(EV)的形成中起重要作用。中性鞘磷脂酶2 (N-SMase 2)在质膜和/或内体系统产生神经酰胺，调节EV的生物发生。鞘磷脂神经酰胺在体内外细胞外囊泡(EV)的形成中起重要作用。中性鞘磷脂酶2 (N-SMase 2)在质膜和/或内体系统产生神经酰胺，调节EV的生物发生。通过分解鞘磷脂(SM)，N-sMase 2增加了神经酰胺的膜水平，由于其特殊的锥形结构，神经酰胺有利于膜的萌发。这一过程被认为独立于运输所需的内体分选复合体(ESCRT)。然而，鞘磷脂代谢中的其他酶也被证明调节EV的形成，如鞘磷脂合成酶1(SMS1)和鞘磷脂合成酶2(SMS2)，它们分别在跨高尔基体和质膜上将神经酰胺转化为SM。神经鞘脂神经酰胺诱导细胞外小泡(EVS)的形成。这条途径是如何被调控的，目前还不完全清楚。图片来源: https://doi.org/10.1002/jev2.12233 近日，来自肯塔基大学的研究者们在J Extracell Vesicles杂志上发表了题为“Function of ceramide transfer protein for biogenesis and sphingolipid composition of extracellular vesicles”的文章，该研究发现CERT在调节EVS的鞘脂组成和生物发生方面具有功能，它将神经酰胺与ESCRT依赖的途径联系起来。在本研究中，研究者报道神经酰胺运输蛋白(CERT)在接触部位的内质网(ER)和多囊泡内小体之间介导神经酰胺的非囊泡性运输。这一过程依赖于CERT的PH结构域与PI4KIIα在内体产生的PI4P的相互作用。此外，在携带神经酰胺的CERT的起始域和Tsg101蛋白之间形成了一个复合体，Tsg101蛋白是运输所需的内体分选复合体(ESCRT-I)的一部分。抑制神经酰胺的生物合成减少了CERT-Tsg101复合体的形成。CERT的过度表达增加了EV的分泌，而它的抑制则减少了EV的形成以及EV中神经酰胺和鞘磷脂的浓度。 EV生物发生中CERT功能的示意图图片来源: https://doi.org/10.1002/jev2.12233 总之，本研究报道了CERT进入内吞途径，并被分类到MVE，在MVE中CERT和Tsg101之间形成了一个复合体，该复合体由神经酰胺的生物合成促进。CERT在接触部位介导神经酰胺在内质网和晚期内小体/MVE之间的直接运输，这决定了EVS的神经酰胺含量。 CERT在神经细胞中的过表达增加了EV的分泌，而药物HPA-12抑制CERT则减少了EV的形成以及EV中神经酰胺和SM的浓度。该研究数据支持CERT在调节EVS的生物发生和鞘脂组成方面的一个新功能，该功能将神经酰胺连接到ESCRT依赖的途径。（生物谷 Bioon.com）参考文献 Simone M. Crivelli et al. Function of ceramide transfer protein for biogenesis and sphingolipid composition of extracellular vesicles. J Extracell Vesicles. 2022 Jun;11(6):e12233. doi: 10.1002/jev2.12233.