Sialyltransferase

唾液酸转移酶
  • 文章类型: Journal Article
    阿尔茨海默病(Alzheimer’sdisease,AD)是一种以蛋白质沉积异常为特征的神经退行性疾病。全球有惊人的3000万人受到影响,AD引起了重大的公共卫生问题。在抑制关键酶如β-位点淀粉样前体蛋白裂解酶1和γ-分泌酶或增强淀粉样蛋白-β清除的同时,一直被认为是治疗AD的合理策略,它们的功效因无效而受到损害。此外,我们对AD发病机制的理解仍不完全.正常衰老与大脑中葡萄糖摄取的下降有关,一个在AD患者中加剧的过程,导致关键翻译后修饰的显着损害:糖基化。糖基化,细胞内次级蛋白质加工的精细调节机制,在调节重要功能,如突触发生,神经发生,轴突引导,以及中枢神经系统的学习和记忆。高级糖组学分析揭示了关键AD相关蛋白的异常糖基化与疾病的发作和进展密切相关。在这种情况下,我们旨在深入研究糖基化在AD的病因和发病机制中的复杂作用和潜在机制。通过强调靶向糖基化作为治疗AD的有希望和替代治疗途径的潜力,我们努力为这种衰弱状态的治疗策略的发展做出贡献.
    Alzheimer\'s disease (AD) is a prevalent neurodegenerative disorder characterized by abnormal protein deposition. With an alarming 30 million people affected worldwide, AD poses a significant public health concern. While inhibiting key enzymes such as β-site amyloid precursor protein-cleaving enzyme 1 and γ-secretase or enhancing amyloid-β clearance, has been considered the reasonable strategy for AD treatment, their efficacy has been compromised by ineffectiveness. Furthermore, our understanding of AD pathogenesis remains incomplete. Normal aging is associated with a decline in glucose uptake in the brain, a process exacerbated in patients with AD, leading to significant impairment of a critical post-translational modification: glycosylation. Glycosylation, a finely regulated mechanism of intracellular secondary protein processing, plays a pivotal role in regulating essential functions such as synaptogenesis, neurogenesis, axon guidance, as well as learning and memory within the central nervous system. Advanced glycomic analysis has unveiled that abnormal glycosylation of key AD-related proteins closely correlates with the onset and progression of the disease. In this context, we aimed to delve into the intricate role and underlying mechanisms of glycosylation in the etiopathology and pathogenesis of AD. By highlighting the potential of targeting glycosylation as a promising and alternative therapeutic avenue for managing AD, we strive to contribute to the advancement of treatment strategies for this debilitating condition.
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  • 文章类型: Journal Article
    唾液酸(SA),作为多糖的最终表位,可以充当多糖链末端的帽,以防止其过度扩张。唾液酸化是将SA残基转移到多糖上的酶促过程,并由一组称为唾液酸转移酶(SiaTs)的酶催化。值得注意的是,当消化性癌症发生时,糖蛋白的唾液酸化水平显著改变。这种改变与这些癌症的进展密切相关。在这次审查中,从改变SiaTs表达水平和改变糖蛋白唾液酸化模式的角度来看,我们总结了胃癌(GC)的发病机制,结直肠癌(CRC),胰腺导管腺癌(PDAC),和肝细胞癌(HCC)。此外,我们提出了不同消化道肿瘤的潜在早期诊断生物标志物和预后指标.最后,总结唾液酸化对消化系统肿瘤的治疗价值。
    Sialic acid (SA), as the ultimate epitope of polysaccharides, can act as a cap at the end of polysaccharide chains to prevent their overextension. Sialylation is the enzymatic process of transferring SA residues onto polysaccharides and is catalyzed by a group of enzymes known as sialyltransferases (SiaTs). It is noteworthy that the sialylation level of glycoproteins is significantly altered when digestive cancer occurs. And this alteration exhibits a close correlation with the progression of these cancers. In this review, from the perspective of altered SiaTs expression levels and changed glycoprotein sialylation patterns, we summarize the pathogenesis of gastric cancer (GC), colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and hepatocellular carcinoma (HCC). Furthermore, we propose potential early diagnostic biomarkers and prognostic indicators for different digestive cancers. Finally, we summarize the therapeutic value of sialylation in digestive system cancers.
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  • 文章类型: Journal Article
    背景:糖基化异常,由特定的糖基转移酶催化,是癌症的主要特征之一。在糖基转移酶亚家族中,唾液酸转移酶(SiaTs)是与肿瘤相关事件密切相关的重要组成部分,如肿瘤生长,转移和血管生成。考虑到SiaTs和癌症之间的关系,本研究试图利用SiaTs相关基因(SRGs)建立有效的预后模型,以预测膀胱癌患者的预后和治疗反应性.
    方法:RNA-seq数据,我们下载了临床信息和基因组突变数据(TCGA-BLCA和GSE13507数据集).分析了20个SiaTs的综合景观,用“DESeq2”R包筛选差异表达的SiaTs相关基因。ConsensusClusterPlus被应用于聚类,随后用Kaplan-Meier曲线进行生存分析。用单变量Cox比例风险回归分析确定总生存相关的SRGs,并进行最小绝对收缩和选择算子(LASSO)回归分析以生成SRGs相关的预后模型。预测值用Kaplan-Meier图和受试者工作特征(ROC)曲线估计,通过构建的列线图和决策曲线进一步验证。
    结果:在膀胱癌组织中,20个SiaTs中的17个在CNV变化和体细胞突变的情况下差异表达。根据20个SiaTs的表达式确定了两个SiaTs_簇,并根据SiaTs_Clusters之间差异表达基因的表达鉴定了两个基因_Clusters。SRGs相关的预后模型由7个关键基因(CD109、TEAD4、FN1、TM4SF1、CDCA7L、ATOH8和GZMA),结果预测的准确性通过ROC曲线和构建的列线图进行验证。与SRGs相关的预后特征可以将患者分为高危和低危组,高危人群的预后较差,更丰富的免疫浸润,和更高的免疫检查点基因表达。此外,来自SRGs相关预后模型的风险评分可用作评估患者对药物治疗反应性的预测指标.
    结论:SRGs相关的预后特征可能有助于预测膀胱癌患者的生存结果和治疗反应,促进个性化治疗和适当医疗决策的发展。
    BACKGROUND: Aberrant glycosylation, catalyzed by the specific glycosyltransferase, is one of the dominant features of cancers. Among the glycosyltransferase subfamilies, sialyltransferases (SiaTs) are an essential part which has close linkages with tumor-associated events, such as tumor growth, metastasis and angiogenesis. Considering the relationship between SiaTs and cancer, the current study attempted to establish an effective prognostic model with SiaTs-related genes (SRGs) to predict patients\' outcome and therapeutic responsiveness of bladder cancer.
    METHODS: RNA-seq data, clinical information and genomic mutation data were downloaded (TCGA-BLCA and GSE13507 datasets). The comprehensive landscape of the 20 SiaTs was analyzed, and the differentially expressed SiaTs-related genes were screened with \"DESeq2\" R package. ConsensusClusterPlus was applied for clustering, following with survival analysis with Kaplan-Meier curve. The overall survival related SRGs were determined with univariate Cox proportional hazards regression analysis, and the least absolute shrinkage and selection operator (LASSO) regression analysis was performed to generate a SRGs-related prognostic model. The predictive value was estimated with Kaplan-Meier plot and the receiver operating characteristic (ROC) curve, which was further validated with the constructed nomogram and decision curve.
    RESULTS: In bladder cancer tissues, 17 out of the 20 SiaTs were differentially expressed with CNV changes and somatic mutations. Two SiaTs_Clusters were determined based on the expression of the 20 SiaTs, and two gene_Clusters were identified based on the expression of differentially expressed genes between SiaTs_Clusters. The SRGs-related prognostic model was generated with 7 key genes (CD109, TEAD4, FN1, TM4SF1, CDCA7L, ATOH8 and GZMA), and the accuracy for outcome prediction was validated with ROC curve and a constructed nomogram. The SRGs-related prognostic signature could separate patients into high- and low-risk group, where the high-risk group showed poorer outcome, more abundant immune infiltration, and higher expression of immune checkpoint genes. In addition, the risk score derived from the SRGs-related prognostic model could be utilized as a predictor to evaluate the responsiveness of patients to the medical therapies.
    CONCLUSIONS: The SRGs-related prognostic signature could potentially aid in the prediction of the survival outcome and therapy response for patients with bladder cancer, contributing to the development of personalized treatment and appropriate medical decisions.
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  • 文章类型: Journal Article
    唾液酸化畸变通过改变信号通路与肺癌的发展有关。因此,迫切需要确定肺腺癌(LUAD)发展中的关键唾液酸转移酶,非小细胞肺癌是一种常见的恶性亚型。在这里,通过系统地研究ST3GAL家族成员在几个公共数据库中的表达水平,我们一致发现LUAD样本中ST3GAL6的频繁下调.它的下调与阶段显著负相关,并且在近端增殖性分子亚型中显着降低,并预测不良的临床结局。通过蛋白质-蛋白质相互作用网络分析和验证,我们发现ST3GAL6缺乏通过激活的EGFR/MAPK信号促进LUAD细胞侵袭,伴随着基质金属蛋白酶2和9的表达水平升高,这可以被EGFR抑制剂部分逆转,吉非替尼。此外,ST3GAL6水平受到ST3GAL6-AS1的正调控,ST3GAL6-AS1是一种对其宿主基因的反义长链非编码RNA。ST3GAL6-AS1的下调也预示着LUAD患者的预后较差,并促进LUAD细胞的侵袭,重述其宿主基因的功能,ST3GAL6.总之,ST3GAL6-AS1调节的ST3GAL6是LUAD患者中经常下调的唾液酸转移酶,并负调节EGFR信号传导,这可以作为LUAD患者的一个有前途的独立预后标志物。
    Sialylation aberration has been implicated in lung cancer development by altering signaling pathways. Hence, it is urgent to identify key sialyltransferases in the development of lung adenocarcinoma (LUAD), which is a common malignant subtype of non-small cell lung cancer. Herein, by systematically investigating the expression levels of ST3GAL family members in several public databases, we consistently found the frequent downregulation of ST3GAL6 in LUAD samples. Its downregulation is significantly negatively associated with stage, and significantly reduced in proximal-proliferative molecular subtype and predicts poor clinical outcomes. By protein-protein interaction network analysis and validation, we found that ST3GAL6 deficiency promotes LUAD cell invasiveness with the activated EGFR/MAPK signaling, accompanied by the elevated expression levels of matrix metalloproteinases 2 and 9, which can be partially reversed by EGFR inhibitor, gefitinib. Additionally, the ST3GAL6 level was positively regulated by ST3GAL6-AS1, an antisense long non-coding RNA to its host gene. The downregulation of ST3GAL6-AS1 also heralds a worse prognosis in LUAD patients and promotes LUAD cell invasiveness, recapitulating the function of its host gene, ST3GAL6. Altogether, ST3GAL6-AS1-regulated ST3GAL6 is a frequently downregulated sialyltransferase in LUAD patients and negatively regulates EGFR signaling, which can serve as a promising independent prognostic marker in LUAD patients.
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  • 文章类型: Journal Article
    由于流感病毒的高突变率和耐药性的迅速增加,发现具有广谱抗病毒活性的宿主靶向抗病毒药物势在必行。考虑到流感大流行期间对抗病毒药物的迫切需求与药物发现和开发的长期过程之间的差异,从市场上的抗病毒药物中探索基于宿主的抗病毒药物和策略是可行的。在目前的研究中,阿比多尔(ARB)的抗病毒机制,在病毒复制的早期阶段具有有效活性的广谱抗病毒药物,从宿主细胞的血凝素(HA)受体方面进行了研究。通过使用基于TiO2-PGC芯片-Q-TOFMS的深入糖漫学方法,首次全面分析了16人支气管上皮(16-HBE)细胞上HA的潜在结合受体的N-聚糖。通过采用基于ChipLC-QQQMS的超高灵敏度定性方法,仔细检查了它们在ARB和病毒治疗时的相对水平,表明ARB治疗导致唾液酸(SA)连接的N-聚糖(SA受体)的显着和广泛的减少,从而损害了病毒在SA受体上的滚动和进入。ARB的SA降低作用被证明是由于其对唾液酸转移酶(ST)的抑制作用,16-HBE细胞的ST3GAL4和ST6GAL1。STS的沉默,天然ST抑制剂,以及唾液酸酶处理16-HBE细胞,导致类似的有效抗病毒活性,而ST诱导剂导致ARB的抗病毒作用减弱。这些观察结果共同表明ST抑制参与ARB的抗病毒作用。重要性这项研究揭示了,第一次,ST抑制和导致的宿主细胞SA受体的破坏可能是ARB抗病毒活性的潜在机制。最近,ST抑制已被提出作为一种新型的宿主靶向抗病毒方法,目前正在探索几种化合物。ARB是市场上第一个被发现具有ST抑制功能的抗病毒药物。这将为ARB的临床使用提供重要证据,例如与神经氨酸酶(NA)抑制剂组合以发挥最佳的抗病毒作用,等。更重要的是,作为一种可以抑制STs表达的试剂,ARB可以作为发现和开发宿主靶向抗病毒药物的新型先导化合物。
    Due to the high mutation rate of influenza virus and the rapid increase of drug resistance, it is imperative to discover host-targeting antiviral agents with broad-spectrum antiviral activity. Considering the discrepancy between the urgent demand of antiviral drugs during an influenza pandemic and the long-term process of drug discovery and development, it is feasible to explore host-based antiviral agents and strategies from antiviral drugs on the market. In the current study, the antiviral mechanism of arbidol (ARB), a broad-spectrum antiviral drug with potent activity at early stages of viral replication, was investigated from the aspect of hemagglutinin (HA) receptors of host cells. N-glycans that act as the potential binding receptors of HA on 16-human bronchial epithelial (16-HBE) cells were comprehensively profiled for the first time by using an in-depth glycomic approach based on TiO2-PGC chip-Q-TOF MS. Their relative levels upon the treatment of ARB and virus were carefully examined by employing an ultra-high sensitive qualitative method based on Chip LC-QQQ MS, showing that ARB treatment led to significant and extensive decrease of sialic acid (SA)-linked N-glycans (SA receptors), and thereby impaired the virus utilization on SA receptors for rolling and entry. The SA-decreasing effect of ARB was demonstrated to result from its inhibitory effect on sialyltransferases (ST), ST3GAL4 and ST6GAL1 of 16-HBE cells. Silence of STs, natural ST inhibitors, as well as sialidase treatment of 16-HBE cells, resulted in similar potent antiviral activity, whereas ST-inducing agent led to the diminished antiviral effect of ARB. These observations collectively suggesting the involvement of ST inhibition in the antiviral effect of ARB. IMPORTANCE This study revealed, for the first time, that ST inhibition and the resulted destruction of SA receptors of host cells may be an underlying mechanism for the antiviral activity of ARB. ST inhibition has been proposed as a novel host-targeting antiviral approach recently and several compounds are currently under exploration. ARB is the first antiviral drug on the market that was found to possess ST inhibiting function. This will provide crucial evidence for the clinical usages of ARB, such as in combination with neuraminidase (NA) inhibitors to exert optimized antiviral effect, etc. More importantly, as an agent that can inhibit the expression of STs, ARB can serve as a novel lead compound for the discovery and development of host-targeting antiviral drugs.
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  • 文章类型: Journal Article
    Caveolin-1 (Cav-1) is a constitutive protein within caveolar membranes. Previous studies from our group and others indicated that Cav-1 could mediate N-glycosylation, α2,6-sialylation, and fucosylation in mouse hepatocarcinoma cells in vitro. However, little is known about the effect of Cav-1 expression on glycosylation modifications in vivo. In this study, the N-glycan profiles in serum from Cav-1-/- mice were investigated by lectin microarray and mass spectrometric analysis approaches. The results showed that levels of multi-antennary branched, α2,6-sialylated, and galactosylated N-glycans increased, while high-mannose typed and fucosylated N-glycans decreased in the serum of Cav-1-/- mice, compared with that of wild-type mice. Furthermore, the real-time quantitative PCR analysis indicated that α2,6-sialyltransferase gene expression decreased significantly in Cav-1-/- mouse organ tissues, but α2,3- and α2,8-sialyltransferase did not. Of them, both mRNA and protein expression levels of the β-galactoside α2,6-sialyltransferase 1 (ST6Gal-I) had dramatically reduced in Cav-1-/- mice organ tissues, which was consistent with the α2,6-sialyl Gal/GalNAc level reduced significantly in tissues instead of serum from Cav-1-/- mice. These results provide for the first time the N-glycans profile of Cav-1-/- mice serum, which will facilitate understanding the function of Cav-1 from the perspective of glycosylation.
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  • 文章类型: Journal Article
    UNASSIGNED:为了减少世界卫生组织列出的与红肉相关的健康风险,本文提出的工作旨在阐明在体内实验动物中补充5'-CMP的饲料与N-羟乙酰神经氨酸(Neu5Gc)之间的相互作用。5\'-将CMP添加到90-的饮食中,180-,和270天大的香猪,30天后,Neu5Gc含量,物理化学参数,用高效液相色谱-荧光检测法测定肌肉和内脏的游离氨基酸含量。使用分子对接研究了5'-CMP影响Neu5Gc含量的机理。结果表明,5'-CMP显着降低了180日龄香猪的Neu5Gc含量(P<0.05),但对90和270日龄香猪的Neu5Gc含量没有影响。180日龄香猪的Umami氨基酸显着增加。在90和270天大的猪中,组氨酸增加了10.38和17.87%,分别。其他游离氨基酸减少或不受影响。此外,补充5'-CMP的日粮不影响香猪的最长肌的理化参数。5'-CMP可以占据几乎所有的唾液酸转移酶活性位点残基,但不能占据His302,并显示出对唾液酸转移酶活性的抑制。研究结果为屠宰前红肉中Neu5Gc的后续还原提供了实验依据。
    UNASSIGNED: In order to reduce the health risks associated with red meat as listed by the World Health Organization, the work presented in this article aimed to elucidate the interaction between 5\'-CMP-supplemented feed and N-glycolylneuraminic acid (Neu5Gc) in experimental animals in vivo. 5\'-CMP was added to the diet of 90-, 180-, and 270-day-old Xiang pigs, and after 30 days, the Neu5Gc contents, physicochemical parameters, and free amino acid contents of muscle and internal viscera were measured by high-performance liquid chromatography coupled with fluorescence detection. The mechanism by which 5\'-CMP affects Neu5Gc contents was investigated using molecular docking. Results show that 5\'-CMP significantly decreased the Neu5Gc content in 180-day-old Xiang pigs (P < 0.05) but had no effect on the Neu5Gc contents in 90- and 270-day-old Xiang pigs. Umami amino acids were significantly increased in 180-day-old Xiang pigs. In the 90- and 270-day-old pigs, histidine increased by 10.38 and 17.87%, respectively. The other free amino acids were either reduced or not affected. Moreover, the 5\'-CMP-supplemented diet did not affect the physicochemical parameters of the longissimus muscle in the Xiang pigs. 5\'-CMP could occupy almost all the sialyltransferase active-site residues but not His302 and showed inhibition of the sialyltransferase activity. The results provided an experimental basis for the subsequent reduction of Neu5Gc in red meat before slaughter.
    CONCLUSIONS:
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  • 文章类型: Journal Article
    Sialylation is the addition of sialic acids to the terminus of various glycoconjugates, and it is involved in many essential biological processes, such as cell adhesion, signal transduction, immune regulation, etc. The levels of sialylation in a cell are tightly regulated by two groups of enzymes, sialyltransferases (STs, responsible for sialylation) and sialidases (responsible for desialylation). Many studies have reported that the occurrence, development, and survival rates of tumors are significantly associated with STs\' abnormal changes. In recent years, the morbidity and mortality rates of gynecological malignant tumors have been continuously rising, which has caused great harm to women\'s reproduction and health. Abnormal changes of STs in gynecological malignant tumor cell membranes cause the changes of expression of sialic acids, promoting cell migration and, eventually, leading to tumor metastasis. In this review, we outlined the biological characteristics of STs and summarized the expression profiles of 20 STs in different tumors via transcriptome data from Gene Expression Profiling Interactive Analysis (GEPIA) database. Moreover, STs\' functions in four common gynecological tumors (ovarian cancer, cervical cancer, endometrial cancer, and gestational trophoblast tumor) were reviewed.
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  • 文章类型: Journal Article
    唾液酸,九碳酸性糖的一个子集,通常作为聚糖的末端糖存在于细胞表面的糖蛋白或糖脂上。唾液酸通过碳水化合物-蛋白质相互作用在许多生理和病理过程中发挥重要作用。包括细胞-细胞通信,细菌和病毒感染。特别是,在肿瘤中唾液酸过度,以及它们在肿瘤生长和转移中的作用,已被广泛描述。最近的研究表明,异常唾液酸化是肿瘤细胞逃避免疫监视和保持恶性的重要途径。在这篇文章中,我们概述了人类唾液酸代谢途径的知识现状,肿瘤中唾液酸过度的功能,以及最近的唾液酸标记和分析技术。预计将提供唾液酸代谢的简要介绍,并在唾液酸研究中提供先进的分析策略。
    Sialic acids, a subset of nine carbon acidic sugars, often exist as the terminal sugars of glycans on either glycoproteins or glycolipids on the cell surface. Sialic acids play important roles in many physiological and pathological processes via carbohydrate-protein interactions, including cell-cell communication, bacterial and viral infections. In particular, hypersialylation in tumors, as well as their roles in tumor growth and metastasis, have been widely described. Recent studies have indicated that the aberrant sialylation is a vital way for tumor cells to escape immune surveillance and keep malignance. In this article, we outline the present state of knowledge on the metabolic pathway of human sialic acids, the function of hypersialylation in tumors, as well as the recent labeling and analytical techniques for sialic acids. It is expected to offer a brief introduction of sialic acid metabolism and provide advanced analytical strategies in sialic acid studies.
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  • 文章类型: Journal Article
    Sialic acid (Sia), the acylated derivative of the nine-carbon sugar neuraminic acid, is a terminal component of the oligosaccharide chains of many glycoproteins and glycolipids. In light of its important biological and pathological functions, the relationship between Sia and coronary artery disease (CAD) has been drawing great attentions recently. Large-scale epidemiological surveys have uncovered a positive correlation between plasma total Sia and CAD risk. Further research demonstrated that N-Acetyl-Neuraminic Acid, acting as a signaling molecule, triggered myocardial injury via activation of Rho/ROCK-JNK/ERK signaling pathway both in vitro and in vivo. Moreover, there were some evidences showing that the aberrant sialylation of low-density lipoprotein, low-density lipoprotein receptor and blood cells was involved in the pathological process of atherosclerosis. Significantly, the Sia regulates immune response by binding to sialic acid-binding immunoglobulin-like lectin (Siglecs). The Sia-Siglecs axis is involved in the immune inflammation of atherosclerosis. The generation of Sia and sialylation of glycoconjugate both depend on many enzymes, such as sialidase, sialyltransferase and trans-sialidase. Abnormal activation or level of these enzymes associated with atherosclerosis, and inhibitors of them might be new CAD treatments. In this review, we focus on summarizing current understanding of Sia metabolism and of its relevance to atherosclerosis.
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