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Inhibitors of dermatan sulfate epimerase 1 decreased accumulation of glycosaminoglycans in mucopolysaccharidosis type I fibroblasts. 硫酸皮质酯表聚酶1抑制剂可减少粘多糖病I型成纤维细胞中糖胺聚糖的积累。
IF 3.4 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-04-24 DOI: 10.1093/glycob/cwae025
Marco Maccarana, Binjie Li, Honglian Li, Jianping Fang, Mingjia Yu, Jin-Ping Li

Genetic deficiency of alpha-L-iduronidase causes mucopolysaccharidosis type I (MPS-I) disease, due to accumulation of glycosaminoglycans (GAGs) including chondroitin/dermatan sulfate (CS/DS) and heparan sulfate (HS) in cells. Currently, patients are treated by infusion of recombinant iduronidase or by hematopoietic stem cell transplantation. An alternative approach is to reduce the L-iduronidase substrate, through limiting the biosynthesis of iduronic acid. Our earlier study demonstrated that ebselen attenuated GAGs accumulation in MPS-I cells, through inhibiting iduronic acid producing enzymes. However, ebselen has multiple pharmacological effects, which prevents its application for MPS-I. Thus, we continued the study by looking for novel inhibitors of dermatan sulfate epimerase 1 (DS-epi1), the main responsible enzyme for production of iduronic acid in CS/DS chains. Based on virtual screening of chemicals towards chondroitinase AC, we constructed a library with 1,064 compounds that were tested for DS-epi1 inhibition. Seventeen compounds were identified to be able to inhibit 27%-86% of DS-epi1 activity at 10 μM. Two compounds were selected for further investigation based on the structure properties. The results show that both inhibitors had a comparable level in inhibition of DS-epi1while they had negligible effect on HS epimerase. The two inhibitors were able to reduce iduronic acid biosynthesis in CS/DS and GAG accumulation in WT and MPS-I fibroblasts. Docking of the inhibitors into DS-epi1 structure shows high affinity binding of both compounds to the active site. The collected data indicate that these hit compounds may be further elaborated to a potential lead drug used for attenuation of GAGs accumulation in MPS-I patients.

α-L-iduronidase基因缺乏症会导致粘多糖病Ⅰ型(MPS-Ⅰ),其病因是细胞内糖胺聚糖(GAGs)(包括硫酸软骨素/硫酸软骨素(CS/DS)和硫酸肝素(HS))的积累。目前,患者可通过输注重组iduronidase或造血干细胞移植进行治疗。另一种方法是通过限制iduronic酸的生物合成来减少L-iduronidase底物。我们早前的研究表明,依布硒可通过抑制iduronic酸生成酶,减少MPS-I细胞中GAGs的积累。然而,依布硒具有多种药理作用,这阻碍了它在 MPS-I 中的应用。因此,我们继续进行研究,寻找新型的皮聚硫酸酯表聚酶 1(DS-epi1)抑制剂,该酶是 CS/DS 链中产生iduronic 酸的主要责任酶。在对软骨素酶 AC 的化学物质进行虚拟筛选的基础上,我们构建了一个包含 1,064 种化合物的化合物库,并对这些化合物进行了 DS-epi1 抑制测试。经鉴定,17 种化合物在 10 μM 的浓度下可抑制 27%-86% 的 DS-epi1 活性。根据其结构特性,选择了两个化合物进行进一步研究。结果表明,这两种抑制剂对DS-epi1的抑制水平相当,而对HS表聚酶的影响可以忽略不计。这两种抑制剂都能减少CS/DS中的iduronic酸生物合成以及WT和MPS-I成纤维细胞中的GAG积累。抑制剂与 DS-epi1 结构的对接显示,这两种化合物与活性位点的结合亲和力很高。收集到的数据表明,这些命中化合物可能会被进一步加工成一种潜在的先导药物,用于减轻 MPS-I 患者体内 GAGs 的积累。
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引用次数: 0
Relevance of glyco-biomakers and glycan profiles in cancer stem cells. 癌症干细胞中的糖生物制造者和糖概况的相关性。
IF 3.4 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-04-24 DOI: 10.1093/glycob/cwad019
Rohit Pujari, Shiv Kumar Dubey

Altered and aberrant glycosylation signatures have been linked to being a hallmark in a variety of human disorders including cancer. Cancer stem cells (CSCs), capable of self-renewal and differentiation, have recently been credited with a unique notion of disease genesis and implicated as the cause for initiation and recurrence of the disease in a new regime of neoplastic transformations hypothesis. Many biomarkers relating to diagnostic and prognostic intents have been discovered using the ubiquitous and abundant surface glycan patterns on CSCs. Various technological advancements have been developed to identify and determine concerns with glycosylation structure. However, the nature and purpose of the glycan moiety on these glycosylation pattern have not yet been thoroughly investigated. This review, thus, summarizes the process of glycosylation in CSCs, variations in glycosylation patterns in various stem cells, aberrant glycosylation patterns in cancer, the role of glycosylation in tumor cell adhesion, cell-matrix interactions, and signaling, as well as cancer detection and treatment. The function of carbohydrates as prospective serum biomarkers, some clinically authorized biomarkers, and potential novel biomarkers relating to cancer disease diagnosis and prognosis are also discussed in the review.

糖基化特征的改变和异常已被认为是包括癌症在内的多种人类疾病的标志。癌症干细胞具有自我更新和分化能力,最近被认为具有独特的疾病起源概念,并在新的肿瘤转化假说中被认为是疾病发生和复发的原因。利用癌症干细胞无处不在的丰富表面聚糖模式,人们发现了许多与诊断和预后相关的生物标志物。目前已开发出各种先进技术,用于识别和确定与糖基化结构有关的问题。然而,这些糖基化模式上的聚糖分子的性质和目的尚未得到深入研究。因此,本综述总结了干细胞中的糖基化过程、各种干细胞中糖基化模式的变化、癌症中的异常糖基化模式、糖基化在肿瘤细胞粘附、细胞与基质相互作用和信号传导中的作用以及癌症检测和治疗。综述中还讨论了碳水化合物作为前瞻性血清生物标志物的功能、一些临床认可的生物标志物以及与癌症疾病诊断和预后有关的潜在新型生物标志物。
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引用次数: 0
Glyco-Forum. Glyco-Forum.
IF 4.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-04-24 DOI: 10.1093/glycob/cwae034
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引用次数: 0
Glyco-Forum. Glyco-Forum.
IF 4.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-04-24 DOI: 10.1093/glycob/cwae034
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引用次数: 0
Variability of human Alpha-1-acid glycoprotein N-glycome in a Caucasian population. 高加索人群中人类α-1-酸糖蛋白 N-糖蛋白的变异性。
IF 3.4 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-04-24 DOI: 10.1093/glycob/cwae031
Frano Vučković, Mislav Novokmet, Dinko Šoić, Jerko Štambuk, Ivana Kolčić, Ozren Polašek, Gordan Lauc, Olga Gornik, Toma Keser

Aim: Alpha-1-acid glycoprotein (AGP) is a highly glycosylated protein in human plasma and one of the most abundant acute phase proteins in humans. Glycosylation plays a crucial role in its biological functions, and alterations in AGP N-glycome have been associated with various diseases and inflammatory conditions. However, large-scale studies of AGP N-glycosylation in the general population are lacking.

Methods: Using recently developed high-throughput glycoproteomic workflow for site-specific AGP N-glycosylation analysis, 803 individuals from the Croatian island of Korcula were analyzed and their AGP N-glycome data associated with biochemical and physiological traits, as well as different environmental factors.

Results: After regression analysis, we found that AGP N-glycosylation is strongly associated with sex, somewhat less with age, along with multiple biochemical and physiological traits (e.g. BMI, triglycerides, uric acid, glucose, smoking status, fibrinogen).

Conclusion: For the first time we have extensively explored the inter-individual variability of AGP N-glycome in a general human population, demonstrating its changes with sex, age, biochemical, and physiological status of individuals, providing the baseline for future population and clinical studies.

目的:α-1-酸糖蛋白(AGP)是人体血浆中高度糖基化的蛋白质,也是人体中含量最高的急性期蛋白质之一。糖基化对其生物功能起着至关重要的作用,AGP N-糖蛋白的改变与多种疾病和炎症有关。然而,目前还缺乏对普通人群中 AGP N-糖基化的大规模研究:方法:利用最近开发的高通量糖蛋白组工作流程进行特异性 AGP N-糖基化分析,对克罗地亚科尔丘拉岛的 803 人进行了分析,并将他们的 AGP N-糖基化数据与生化和生理特征以及不同的环境因素联系起来:结果:经过回归分析,我们发现 AGP N-糖基化与性别密切相关,与年龄的关系较小,同时还与多种生化和生理特征(如体重指数、甘油三酯、尿酸、葡萄糖、吸烟状况、纤维蛋白原)有关:我们首次在普通人群中广泛探讨了 AGP N-糖蛋白的个体间变异性,展示了其随个体的性别、年龄、生化和生理状态而发生的变化,为未来的人群和临床研究提供了基线。
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引用次数: 0
Glyco You Should Know. 你应该知道的 Glyco
IF 4.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-04-19 DOI: 10.1093/glycob/cwae022
Emily Kukan
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引用次数: 0
Site-specific immobilization of the endosialidase reveals QSOX2 is a novel polysialylated protein. 内糖苷酶的位点特异性固定揭示了 QSOX2 是一种新型多糖苷化蛋白。
IF 3.4 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-04-19 DOI: 10.1093/glycob/cwae026
Carmanah Hunter, Tahlia Derksen, Sogand Makhsous, Matt Doll, Samantha Rodriguez Perez, Nichollas E Scott, Lisa M Willis

Polysialic acid (polySia) is a linear polymer of α2,8-linked sialic acid residues that is of fundamental biological interest due to its pivotal roles in the regulation of the nervous, immune, and reproductive systems in healthy human adults. PolySia is also dysregulated in several chronic diseases, including cancers and mental health disorders. However, the mechanisms underpinning polySia biology in health and disease remain largely unknown. The polySia-specific hydrolase, endoneuraminidase NF (EndoN), and the catalytically inactive polySia lectin EndoNDM, have been extensively used for studying polySia. However, EndoN is heat stable and remains associated with cells after washing. When studying polySia in systems with multiple polysialylated species, the residual EndoN that cannot be removed confounds data interpretation. We developed a strategy for site-specific immobilization of EndoN on streptavidin-coated magnetic beads. We showed that immobilizing EndoN allows for effective removal of the enzyme from samples, while retaining hydrolase activity. We used the same strategy to immobilize the polySia lectin EndoNDM, which enabled the enrichment of polysialylated proteins from complex mixtures such as serum for their identification via mass spectrometry. We used this methodology to identify a novel polysialylated protein, QSOX2, which is secreted from the breast cancer cell line MCF-7. This method of site-specific immobilization can be utilized for other enzymes and lectins to yield insight into glycobiology.

多聚糖酸(polySia)是一种由α2,8-连接的半乳淀粉酸残基组成的线性聚合物,由于它在调节健康成年人的神经、免疫和生殖系统中起着关键作用,因此具有重要的生物学意义。在一些慢性疾病中,包括癌症和精神疾病,PolySia 也会失调。然而,polySia 在健康和疾病中的生物学机制在很大程度上仍不为人所知。多聚糖特异性水解酶--内酰氨基苷酶 NF(EndoN)和无催化活性的多聚糖凝集素 EndoNDM 已被广泛用于研究多聚糖。然而,EndoN 具有热稳定性,在洗涤后仍与细胞相关联。在含有多种多淀粉酰化物种的系统中研究多淀粉酰化时,无法去除的残留 EndoN 会干扰数据解读。我们开发了一种在链霉亲和素包被的磁珠上特异性固定 EndoN 的策略。我们的研究表明,固定 EndoN 可以有效去除样品中的酶,同时保留水解酶的活性。我们用同样的策略固定了多糖凝集素 EndoNDM,这样就能从血清等复杂混合物中富集多糖基化蛋白质,并通过质谱进行鉴定。我们利用这种方法鉴定了乳腺癌细胞系 MCF-7 分泌的一种新型多糖基化蛋白质 QSOX2。这种位点特异性固定方法可用于其他酶和凝集素,以深入了解糖生物学。
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引用次数: 0
Asian Community of Glycoscience and Glycotechnology (ACGG) conference report 2023. 亚洲糖科学和糖技术协会(ACGG)2023 年会议报告。
IF 4.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-04-19 DOI: 10.1093/glycob/cwae017
Kavita Y Hiremath
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引用次数: 0
Crystal structure of mango α1,3/α1,4-fucosyltransferase elucidates unique elements that regulate Lewis A-dominant oligosaccharide assembly. 芒果α1,3/α1,4-岩藻糖基转移酶的晶体结构阐明了调控路易斯a型寡糖组装的独特因素。
IF 3.4 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-04-19 DOI: 10.1093/glycob/cwae015
Takahiro Okada, Takamasa Teramoto, Hideyuki Ihara, Yoshitaka Ikeda, Yoshimitsu Kakuta

In various organisms, α1,3/α1,4-fucosyltransferases (CAZy GT10 family enzymes) mediate the assembly of type I (Galβ1,3GlcNAc) and/or type II (Galβ1,4GlcNAc)-based Lewis structures that are widely distributed in glycoconjugates. Unlike enzymes of other species, plant orthologues show little fucosyltransferase activity for type II-based glycans and predominantly catalyze the assembly of the Lewis A structure [Galβ1,3(Fucα1,4)GlcNAc] on the type I disaccharide unit of their substrates. However, the structural basis underlying this unique substrate selectivity remains elusive. In this study, we investigated the structure-function relationship of MiFUT13A, a mango α1,3/α1,4-fucosyltransferase. The prepared MiFUT13A displayed distinct α1,4-fucosyltransferase activity. Consistent with the enzymatic properties of this molecule, X-ray crystallography revealed that this enzyme has a typical GT-B fold-type structure containing a set of residues that are responsible for its SN2-like catalysis. Site-directed mutagenesis and molecular docking analyses proposed a rational binding mechanism for type I oligosaccharides. Within the catalytic cleft, the pocket surrounding Trp121 serves as a binding site, anchoring the non-reducing terminal β1,3-galactose that belongs to the type I disaccharide unit. Furthermore, Glu177 was postulated to function as a general base catalyst through its interaction with the 4-hydroxy group of the acceptor N-acetylglucosamine residue. Adjacent residues, specifically Thr120, Thr157 and Asp175 were speculated to assist in binding of the reducing terminal residues. Intriguingly, these structural elements were not fully conserved in mammalian orthologue which also shows predominant α1,4-fucosyltransferase activity. In conclusion, we have proposed that MiFUT13A generates the Lewis A structure on type I glycans through a distinct mechanism, divergent from that of mammalian enzymes.

在各种生物体中,α1,3/α1,4-岩藻糖基转移酶(CAZy GT10 家族酶)介导 I 型(Galβ1,3GlcNAc)和/或 II 型(Galβ1,4GlcNAc)路易斯结构的组装,这些结构广泛分布于糖共轭物中。与其他物种的酶不同,植物直向同源物对基于 II 型的聚糖几乎不显示岩藻糖基转移酶活性,而主要催化其底物 I 型二糖单元上 Lewis A 结构[Galβ1,3(Fucα1,4)GlcNAc]的组装。然而,这种独特底物选择性的结构基础仍未确定。在本研究中,我们研究了芒果α1,3/α1,4-岩藻糖基转移酶 MiFUT13A 的结构-功能关系。制备的 MiFUT13A 具有独特的 α1,4-岩藻糖基转移酶活性。与该分子的酶特性相一致,X 射线晶体学显示该酶具有典型的 GT-B 折叠型结构,其中包含一组负责 S N2 类催化作用的残基。定点突变和分子对接分析提出了 I 型寡糖的合理结合机制。在催化裂隙中,围绕 Trp 121 的口袋是一个结合位点,锚定了属于 I 型二糖单元的非还原末端 β1,3-半乳糖。此外,Glu177 通过与接受者 N-乙酰葡糖胺残基的 4-羟基相互作用,被推测具有一般碱催化剂的功能。相邻的残基,特别是 Thr120、Thr157 和 Asp175 被推测为协助还原末端残基的结合。耐人寻味的是,这些结构元素在哺乳动物的同源物中并不完全保守,而哺乳动物的同源物也显示出主要的α1,4-岩藻糖基转移酶活性。总之,我们认为 MiFUT13A 是通过一种不同于哺乳动物酶的独特机制在 I 型聚糖上生成 Lewis A 结构的。
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引用次数: 0
Glycosylation as a tracer of off-target Cre-lox activation in development. 糖基化作为发育过程中 Cre-lox 脱靶激活的示踪剂。
IF 3.4 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-04-19 DOI: 10.1093/glycob/cwae023
Leandre M Glendenning, Kalob M Reynero, Brian A Cobb

The Cre-lox system is one of the most widely used methods for lineage-specific and inducible genome editing in vivo. However, incomplete penetrance and off-target effects due to transient promoter expression in a stem or pluripotent precursor cell can be problematic and difficult to detect, especially if the target gene is not normally present in the fully differentiated but off-target cells. Yet, the loss of the target gene through the transient expression of Cre may impact the differentiation of those cells by virtue of transient expression in a precursor population. In these situations, off-target effects in an unknown precursor cell can, at best, complicate conclusions drawn from the model, and at worst, invalidate all data generated from that knockout strain. Thus, identifying Cre-driver promoter expression along entire cell lineages is crucial to improve rigor and reproducibility. As an example, transient expression in an early precursor cell has been documented in a variety of Cre strains such as the Tie2-based Cre-driver system that is used as an "endothelial cell-specific" model 1. Yet, Tie2 is now known to be transiently expressed in a stem cell upstream of both hematopoietic and endothelial cell lineages. Here, we use the Tie2 Cre-driver strain to demonstrate that due to its ubiquitous nature, plasma membrane glycans are a useful marker of both penetrance and specificity of a Cre-based knockout.

Cre-lox系统是最广泛应用的体内特异性和诱导性基因组编辑方法之一。然而,在干细胞或多能前体细胞中瞬时表达启动子导致的不完全穿透性和脱靶效应可能会带来问题,而且难以检测,尤其是当目标基因通常不存在于完全分化但脱靶的细胞中时。然而,由于在前体细胞中的瞬时表达,Cre瞬时表达导致的靶基因缺失可能会影响这些细胞的分化。在这种情况下,未知前体细胞的脱靶效应轻则会使模型得出的结论复杂化,重则会使该基因敲除株产生的所有数据无效。因此,确定整个细胞系的 Cre 驱动启动子表达对于提高严谨性和可重复性至关重要。举例来说,早期前体细胞中的瞬时表达已在多种 Cre 株系中得到证实,例如基于 Tie2 的 Cre 驱动系统被用作 "内皮细胞特异性 "模型 1。然而,现在已知Tie2可在造血细胞系和内皮细胞系上游的干细胞中短暂表达。在这里,我们利用 Tie2 Cre 驱动株证明,由于其无处不在的特性,质膜糖是基于 Cre 基因敲除的穿透性和特异性的有用标记。
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引用次数: 0
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Glycobiology
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