Post-translational protein modification, including phosphorylation, is generally quick and reversible, facilitating rapid biologic adjustments to altered cellular physiologic demands. In addition to protein phosphoryl...Post-translational protein modification, including phosphorylation, is generally quick and reversible, facilitating rapid biologic adjustments to altered cellular physiologic demands. In addition to protein phosphorylation, other post-translational modifications have been identified. Intracellular protein O-glycosylation, the addition of the simple sugar O-linked N-acetylglucosamine (O-G1cNAc) to serine/threonine residues, is a relatively recently identified post-translational modification that has added to the complexity by which protein function is regulated. Two intracellular enzymes, O-GlcNAc transferase and O-GlcNAcase, catalyze the addition and removal, respectively, of O-GlcNAc to serine and threonine side-chain hydroxyl groups. Numerous proteins, including enzymes, transcription factors, receptors and structural proteins have been shown to be modified by intracellular O-glycosylation. In this review, the mechanism and relevance of O-GlcNAc protein modification are discussed in the context of cell adhesion and several representative diseases.展开更多
O-glycosylation is an ancient yet underappreciated protein posttranslational modification,on which many bacteria and viruses heavily rely to perform critical biological functions involved in numerous infectious diseas...O-glycosylation is an ancient yet underappreciated protein posttranslational modification,on which many bacteria and viruses heavily rely to perform critical biological functions involved in numerous infectious diseases or even cancer.But due to the innate complexity of O-glycosylation,research techniques have been limited to study its exact role in viral attachment and entry,assembly and exit,spreading in the host cells,and the innate and adaptive immunity of the host.Recently,the advent of many newly developed methodologies(e.g.,mass spectrometry,chemical biology tools,and molecular dynamics simulations)has renewed and rekindled the interest in viral-related O-glycosylation in both viral proteins and host cells,which is further fueled by the COVID-19 pandemic.In this review,we summarize recent advances in viral-related O-glycosylation,with a particular emphasis on the mucin-type O-linkedα-N-acetylgalactosamine(O-GalNAc)on viral proteins and the intracellular O-linkedβ-N-acetylglucosamine(O-GlcNAc)modifications on host proteins.We hope to provide valuable insights into the development of antiviral reagents or vaccines for better prevention or treatment of infectious diseases.展开更多
A hydrogen bond-assisted α-selective glycosylation reaction by using 4,6-dibenzyloxy-1,3,5-triazin-2-yl(DBT) β-glycosyl donors was developed for the efficient construction of 1,2-cis-α-glycosidic bond in natural pr...A hydrogen bond-assisted α-selective glycosylation reaction by using 4,6-dibenzyloxy-1,3,5-triazin-2-yl(DBT) β-glycosyl donors was developed for the efficient construction of 1,2-cis-α-glycosidic bond in natural products. This method was applied successfully to the direct synthesis of complex oligosaccharidederived glycolipids with simple protecting chemistry. Mechanistic studies using the NMR spectroscopy and DFT calculation provide a proof of concept for hydrogen bond-assisted glycosylation reaction towardsα-specific construction of O-glycosidic linkage.展开更多
Liver cancer can be an aggressive disease,and is highly prevalent in Asia and Africa.However,its currently approved therapeutic strategies are far from satisfactory.Recent progress in genomic,proteomic and glycomic pr...Liver cancer can be an aggressive disease,and is highly prevalent in Asia and Africa.However,its currently approved therapeutic strategies are far from satisfactory.Recent progress in genomic,proteomic and glycomic profiling technologies have enabled the identification of biomarkers that significantly correlate with clinical outcomes.Many biomarkers are related to O-glycosylation of glycoproteins,which belong to an important but less-explored field of liver cancer biology.Here,we review these clinical studies and discuss potential underlying mechanisms.展开更多
Numerous studies on cancers, biopharmaceuticals, and clinical trials have necessitated comprehensive and precise analysis of protein O-glycosylation. However, the lack of updated and convenient databases deters the st...Numerous studies on cancers, biopharmaceuticals, and clinical trials have necessitated comprehensive and precise analysis of protein O-glycosylation. However, the lack of updated and convenient databases deters the storage of and reference to emerging O-glycoprotein data. To resolve this issue, an O-glycoprotein repository named OGP was established in this work.It was constructed with a collection of O-glycoprotein data from different sources. OGP contains 9354 O-glycosylation sites and 11,633 site-specific O-glycans mapping to 2133 O-glycoproteins, and it is the largest O-glycoprotein repository thus far.Based on the recorded O-glycosylation sites, an O-glycosylation site prediction tool was developed. Moreover, an OGP-based website is already available(http://www.oglyp.org/). The website comprises four specially designed and user-friendly modules:statistical analysis, database search, site prediction, and data submission. The first version of OGP repository and the website allow users to obtain various O-glycoprotein-related information, such as protein accession Nos., O-glycosylation sites,O-glycopeptide sequences, site-specific O-glycan structures, experimental methods, and potential O-glycosylation sites.O-glycosylation data mining can be performed efficiently on this website, which will greatly facilitate related studies. In addition, the database is accessible from OGP website(http://www.oglyp.org/download.php).展开更多
A linear 7-step synthesis of vildagliptin-β-O-glucuronide (2) starting from commercially available D-glucurono-6, 3-lactone (3) was herein achieved with 11.3% overall yield. Efficient preparation of compound 6 in pu...A linear 7-step synthesis of vildagliptin-β-O-glucuronide (2) starting from commercially available D-glucurono-6, 3-lactone (3) was herein achieved with 11.3% overall yield. Efficient preparation of compound 6 in pure α form was obtained, which was proved critical to achieve high anomeric selectivity in β-O-glycosylation later. The direct β-O-glycosylation of vildagliptin (1) containing both a tertiary alcohol and a secondary amine was studied and achieved in good yield. The deprotection step to afford product was delicately executed to avoid hydrolysis of nitrile group. The target compound 2 was obtained after purification by reversed-phase C18 chromatography.展开更多
Glycosylation is one of the most extensive post-translation modifications of proteins. Although lots of computational models have been developed to predict the glycosylation sites, none of them considered the tissue a...Glycosylation is one of the most extensive post-translation modifications of proteins. Although lots of computational models have been developed to predict the glycosylation sites, none of them considered the tissue and cell specificity of glycosylation. Here, we built a two-step computational method GlycoCell to predict the cell-specific O-GalNAc glycosylation, the most complex type of O-glycosylation reported so far, in 12 human cell types. The first step predicted whether a site had the potential to be O-glycosylated. The model achieved an accuracy of 0.83. The second step predicted whether a potential glycosite would be O-glycosylated in the given cell type. For 12 cell types, a model was built for each cell type. The accuracies for these models ranged from 0.78 to 0.87. To facilitate the usage of GlycoCell for the public, a web server was built which is available at http://www.biomedcloud.com.cn/GlyoCell/main.htm. It could be useful for investigating the cell-specific O-glycosylation in human.展开更多
Core 1 synthase glycoprotein-N-acetylgalactosamine 3-β-galactosyltransferase 1(C1GALT1)is known to play a critical role in the development of gastric cancer,but few studies have elucidated associations between geneti...Core 1 synthase glycoprotein-N-acetylgalactosamine 3-β-galactosyltransferase 1(C1GALT1)is known to play a critical role in the development of gastric cancer,but few studies have elucidated associations between genetic variants in C1GALT1 and gastric cancer risk.By using the genome-wide association study data from the database of Genotype and Phenotype(dbGAP),we evaluated such associations with a multivariable logistic regression model and identified that the rs35999583 G>C in C1GALT1 was associated with gastric cancer risk(odds ratio,0.83;95% confidence interval[CI],0.75-0.92;P=3.95×10^(-4)).C1GALT1 mRNA expression levels were significantly higher in gastric tumor tissues than in normal tissues,and gastric cancer patients with higher C1GALT1 mRNA levels had worse overall survival rates(hazards ratio,1.33;95%CI,1.05-1.68;P_(log-rank)=1.90×10^(-2)).Furthermore,we found that C1GALT1 copy number differed in various immune cells and that C1GALT1 mRNA expression levels were positively correlated with the infiltrating levels of CD4^(+)T cells and macrophages.These results suggest that genetic variants of C1GALT1 may play an important role in gastric cancer risk and provide a new insight for C1GALT1 into a promising predictor of gastric cancer susceptibility and immune status.展开更多
Podoplanin (PDPN) is a mucin-type O-glycoprotein expressed in diverse cell types, such as lymphatic endothelial cells (LECs) in the vascular system and fibroblastic reticular cells (FRCs) in lymph nodes. PDPN on...Podoplanin (PDPN) is a mucin-type O-glycoprotein expressed in diverse cell types, such as lymphatic endothelial cells (LECs) in the vascular system and fibroblastic reticular cells (FRCs) in lymph nodes. PDPN on LECs or FRCs activates CLEC-2 in platelets, triggering platelet activation and/or aggregation through downstream signaling events, including activation of Syk kinase. This mechanism is required to initiate and maintain separation of blood and lymphatic vessels and to stabilize high endothelial venule integrity within lymph nodes. In the vascular system, normal expression of PDPN at the LEC surface requires transcriptional activation of Pdpn by Proxl and modification of PDPN with core 1-derived O-glycans. This review provides a comprehensive overview of the roles of PDPN in vascular development and lymphoid organ maintenance and discusses the mechanisms that regulate PDPN expression related to its function.展开更多
基金supported by NIH RO1 (No. AI49427) to Dr David S.Rubenstein
文摘Post-translational protein modification, including phosphorylation, is generally quick and reversible, facilitating rapid biologic adjustments to altered cellular physiologic demands. In addition to protein phosphorylation, other post-translational modifications have been identified. Intracellular protein O-glycosylation, the addition of the simple sugar O-linked N-acetylglucosamine (O-G1cNAc) to serine/threonine residues, is a relatively recently identified post-translational modification that has added to the complexity by which protein function is regulated. Two intracellular enzymes, O-GlcNAc transferase and O-GlcNAcase, catalyze the addition and removal, respectively, of O-GlcNAc to serine and threonine side-chain hydroxyl groups. Numerous proteins, including enzymes, transcription factors, receptors and structural proteins have been shown to be modified by intracellular O-glycosylation. In this review, the mechanism and relevance of O-GlcNAc protein modification are discussed in the context of cell adhesion and several representative diseases.
基金supported by the grants from the National Natural Science Foundation of China(32271285,31872720,82272306,and 82072270)the R&D Program of Beijing Municipal Education Commission(KZ202210028043)+3 种基金the Taishan Scholars Program(tstp20221142)the Academic Promotion Program of Shandong First Medical University(2019LJ001)the Beijing National LaboratorfyorMolecular Sciences(BNLMS202108)the Chinese Academy of Sciences Pioneer Hundred Talents Program.
文摘O-glycosylation is an ancient yet underappreciated protein posttranslational modification,on which many bacteria and viruses heavily rely to perform critical biological functions involved in numerous infectious diseases or even cancer.But due to the innate complexity of O-glycosylation,research techniques have been limited to study its exact role in viral attachment and entry,assembly and exit,spreading in the host cells,and the innate and adaptive immunity of the host.Recently,the advent of many newly developed methodologies(e.g.,mass spectrometry,chemical biology tools,and molecular dynamics simulations)has renewed and rekindled the interest in viral-related O-glycosylation in both viral proteins and host cells,which is further fueled by the COVID-19 pandemic.In this review,we summarize recent advances in viral-related O-glycosylation,with a particular emphasis on the mucin-type O-linkedα-N-acetylgalactosamine(O-GalNAc)on viral proteins and the intracellular O-linkedβ-N-acetylglucosamine(O-GlcNAc)modifications on host proteins.We hope to provide valuable insights into the development of antiviral reagents or vaccines for better prevention or treatment of infectious diseases.
基金financially supported by the State Key Laboratory of Natural and Biomimetic Drugs (No. K202216)the National Natural Science Foundation of China (Nos. 21907004 and 81821004)+2 种基金the National Key R&D Program of China (No.2018YFA0507602)the Beijing Outstanding Young Scientist Program(No. BJJWZYJH01201910001001)a Grant-in-Aid for Scientific Research from the Ministry of Education,Culture,Sports,Science and Technology,Japan。
文摘A hydrogen bond-assisted α-selective glycosylation reaction by using 4,6-dibenzyloxy-1,3,5-triazin-2-yl(DBT) β-glycosyl donors was developed for the efficient construction of 1,2-cis-α-glycosidic bond in natural products. This method was applied successfully to the direct synthesis of complex oligosaccharidederived glycolipids with simple protecting chemistry. Mechanistic studies using the NMR spectroscopy and DFT calculation provide a proof of concept for hydrogen bond-assisted glycosylation reaction towardsα-specific construction of O-glycosidic linkage.
基金This project was supported by Chang Gung Medical Foundation(CMRPG1B0571,CIRPG3B0032,CMRPG3F1601).
文摘Liver cancer can be an aggressive disease,and is highly prevalent in Asia and Africa.However,its currently approved therapeutic strategies are far from satisfactory.Recent progress in genomic,proteomic and glycomic profiling technologies have enabled the identification of biomarkers that significantly correlate with clinical outcomes.Many biomarkers are related to O-glycosylation of glycoproteins,which belong to an important but less-explored field of liver cancer biology.Here,we review these clinical studies and discuss potential underlying mechanisms.
基金supported by grants from the National Key R&D Program of China(Grant Nos.2018YFC0910300,2016YFA0501303,and 2016YFB0201702)the National Natural Science Foundation of China(Grant No.91853102)the innovative research team of high-level local university in Shanghai。
文摘Numerous studies on cancers, biopharmaceuticals, and clinical trials have necessitated comprehensive and precise analysis of protein O-glycosylation. However, the lack of updated and convenient databases deters the storage of and reference to emerging O-glycoprotein data. To resolve this issue, an O-glycoprotein repository named OGP was established in this work.It was constructed with a collection of O-glycoprotein data from different sources. OGP contains 9354 O-glycosylation sites and 11,633 site-specific O-glycans mapping to 2133 O-glycoproteins, and it is the largest O-glycoprotein repository thus far.Based on the recorded O-glycosylation sites, an O-glycosylation site prediction tool was developed. Moreover, an OGP-based website is already available(http://www.oglyp.org/). The website comprises four specially designed and user-friendly modules:statistical analysis, database search, site prediction, and data submission. The first version of OGP repository and the website allow users to obtain various O-glycoprotein-related information, such as protein accession Nos., O-glycosylation sites,O-glycopeptide sequences, site-specific O-glycan structures, experimental methods, and potential O-glycosylation sites.O-glycosylation data mining can be performed efficiently on this website, which will greatly facilitate related studies. In addition, the database is accessible from OGP website(http://www.oglyp.org/download.php).
文摘A linear 7-step synthesis of vildagliptin-β-O-glucuronide (2) starting from commercially available D-glucurono-6, 3-lactone (3) was herein achieved with 11.3% overall yield. Efficient preparation of compound 6 in pure α form was obtained, which was proved critical to achieve high anomeric selectivity in β-O-glycosylation later. The direct β-O-glycosylation of vildagliptin (1) containing both a tertiary alcohol and a secondary amine was studied and achieved in good yield. The deprotection step to afford product was delicately executed to avoid hydrolysis of nitrile group. The target compound 2 was obtained after purification by reversed-phase C18 chromatography.
文摘Glycosylation is one of the most extensive post-translation modifications of proteins. Although lots of computational models have been developed to predict the glycosylation sites, none of them considered the tissue and cell specificity of glycosylation. Here, we built a two-step computational method GlycoCell to predict the cell-specific O-GalNAc glycosylation, the most complex type of O-glycosylation reported so far, in 12 human cell types. The first step predicted whether a site had the potential to be O-glycosylated. The model achieved an accuracy of 0.83. The second step predicted whether a potential glycosite would be O-glycosylated in the given cell type. For 12 cell types, a model was built for each cell type. The accuracies for these models ranged from 0.78 to 0.87. To facilitate the usage of GlycoCell for the public, a web server was built which is available at http://www.biomedcloud.com.cn/GlyoCell/main.htm. It could be useful for investigating the cell-specific O-glycosylation in human.
基金funded by the National Key R&D Program of China(Grant Nos.2018YFC1313100 and 2018YFC1313102)the National Natural Science Foundation of China(Grant No.81773539)+1 种基金Collaborative Innovation Center for Cancer Personalized Medicinethe Priority Academic Program Development of Jiangsu Higher Education Institutions(Public Health and Preventive Medicine).
文摘Core 1 synthase glycoprotein-N-acetylgalactosamine 3-β-galactosyltransferase 1(C1GALT1)is known to play a critical role in the development of gastric cancer,but few studies have elucidated associations between genetic variants in C1GALT1 and gastric cancer risk.By using the genome-wide association study data from the database of Genotype and Phenotype(dbGAP),we evaluated such associations with a multivariable logistic regression model and identified that the rs35999583 G>C in C1GALT1 was associated with gastric cancer risk(odds ratio,0.83;95% confidence interval[CI],0.75-0.92;P=3.95×10^(-4)).C1GALT1 mRNA expression levels were significantly higher in gastric tumor tissues than in normal tissues,and gastric cancer patients with higher C1GALT1 mRNA levels had worse overall survival rates(hazards ratio,1.33;95%CI,1.05-1.68;P_(log-rank)=1.90×10^(-2)).Furthermore,we found that C1GALT1 copy number differed in various immune cells and that C1GALT1 mRNA expression levels were positively correlated with the infiltrating levels of CD4^(+)T cells and macrophages.These results suggest that genetic variants of C1GALT1 may play an important role in gastric cancer risk and provide a new insight for C1GALT1 into a promising predictor of gastric cancer susceptibility and immune status.
基金Acknowledgements This study was supported by a grant from the National Natural Science Foundation of China (No. 31400692).
文摘Podoplanin (PDPN) is a mucin-type O-glycoprotein expressed in diverse cell types, such as lymphatic endothelial cells (LECs) in the vascular system and fibroblastic reticular cells (FRCs) in lymph nodes. PDPN on LECs or FRCs activates CLEC-2 in platelets, triggering platelet activation and/or aggregation through downstream signaling events, including activation of Syk kinase. This mechanism is required to initiate and maintain separation of blood and lymphatic vessels and to stabilize high endothelial venule integrity within lymph nodes. In the vascular system, normal expression of PDPN at the LEC surface requires transcriptional activation of Pdpn by Proxl and modification of PDPN with core 1-derived O-glycans. This review provides a comprehensive overview of the roles of PDPN in vascular development and lymphoid organ maintenance and discusses the mechanisms that regulate PDPN expression related to its function.