عناروين إضافية: Sweet Discoveries: Unraveling the Complex World of Sugars in Health and Disease

مستخلص: Glycans, which are complex assemblies of sugars, are the most prevalent class of macromolecules, surpassing nucleic acids, proteins and lipids. Glycans are essential for life, as they are a required energy source, provide protection against cellular stresses and shape cellular structure. During this course, we will explore the many roles glycans play in human health and disease. For example, we will learn about the healthy glycosylation patterns of many mammalian proteins and the dynamic changes that glycan structures undergo during early development and cancer metastasis, the influence of dietary carbohydrates on glycan metabolism, and the role of densely glycosylated proteins involved in HIV infectivity. Concurrently, we will learn about the chemical and biological techniques used to detect and visualize glycans by in vitro and whole-animal metabolic labeling approaches, how to profile protein-glycan interactions using high-throughput glycan arrays, and about the development of new carbohydrate-based therapeutics and vaccines to target HIV, influenza and bacterial pathogens. The course will focus on the primary research literature, and we will learn practical laboratory techniques, experimental design and how to interpret data and critique the conclusions offered by authors.This course is one of many Advanced Undergraduate Seminars offered by the Biology Department at MIT. These seminars are tailored for students with an interest in using primary research literature to discuss and learn about current biological research in a highly interactive setting. Many instructors of the Advanced Undergraduate Seminars are postdoctoral scientists with a strong interest in teaching.

مصطلحات الفهرس: Glycans, glycobiology, glycosylation patterns, glycoproteins, glycan metabolism, glycosylated proteins, protein-glycan interactions, high-throughput glycan arrays, O-glycans, N-linked glycosylation, glycosyl-amino acids, Metabolic glycan labeling, synthetic antigens, 260204

URL: https://hdl.handle.net/1721.1/148354

المصدر: Research outputs 2022 to 2026

مستخلص: The use of an altered immunoglobulin G (IgG) N-glycan pattern as an inflammation metric has been reported in subclinical atherosclerosis and metabolic disorders, both of which are important risk factors in cardiovascular health. However, the usable capacity of IgG N-glycosylation profiles for the risk stratification of cardiovascular diseases (CVDs) remains unknown. This study aimed to develop a cardiovascular aging index for tracking cardiovascular risk using IgG N-glycans. This cross-sectional investigation enrolled 1465 individuals aged 40–70 years from the Busselton Healthy and Ageing Study. We stepwise selected the intersection of altered N-glycans using feature-selection methods in machine learning (recursive feature elimination and penalized regression algorithms) and developed an IgG N-glycosylation cardiovascular age (GlyCage) index to reflect the deviation from calendar age attributable to cardiovascular risk. The strongest contributors to GlyCage index were fucosylated N-glycans with bisecting N-acetylglucosamine (GlcNAc) (glycan peak 6 (GP6), FA2B,) and digalactosylated N-glycans with bisecting GlcNAc (GP13, A2BG2). A one-unit increase of GlyCage was significantly associated with a higher Framingham ten-year cardiovascular risk (odds ratio (OR), 1.09; 95% confidence interval (95% CI): 1.05–1.13) and probability of CVDs (OR, 1.07; 95% CI: 1.01–1.13) independent of calendar age. Individuals with excessive GlyCage (exceeding a calendar age > 3 years) had an increased cardiovascular risk and probability of CVDs, with adjusted ORs of 2.22 (95% CI: 1.41–3.53) and 2.71 (95% CI: 1.25–6.41), respectively. The area under curve (AUC) values of discriminating high cardiovascular risk and events were 0.73 and 0.65 for GlyCage index, and 0.65 and 0.63 for calendar age. The GlyCage index developed in this study can thus be used to track cardiovascular health using IgG N-glycosylation profiles. The distance between GlyCage and calendar age independently indicates the ca

مصطلحات الفهرس: [RSTDPub], Cardiovascular aging, Feature selection, Glycosylation, IgG N-glycosylation cardiovascular age, Immunoglobulin G, Inflammation, Machine learning, Medicine and Health Sciences, text

URL: https://ro.ecu.edu.au/ecuworks2022-2026/3012

المصدر: Rudman , N , Kaur , S , Simunović , V , Kifer , D , Šoić , D , Keser , T , Štambuk , T , Klarić , L , Pociot , F , Morahan , G & Gornik , O 2023 , ' Integrated glycomics and genetics analyses reveal a potential role for N-glycosylation of plasma proteins and IgGs, as well as the complement system, in the development of type 1 diabetes ' , Diabetologia , vol. 66 , no. 6 , pp. 1071-1083 .

مستخلص: Aims/hypothesis: We previously demonstrated that N-glycosylation of plasma proteins and IgGs is different in children with recent-onset type 1 diabetes compared with their healthy siblings. To search for genetic variants contributing to these changes, we undertook a genetic association study of the plasma protein and IgG N-glycome in type 1 diabetes. Methods: A total of 1105 recent-onset type 1 diabetes patients from the Danish Registry of Childhood and Adolescent Diabetes were genotyped at 183,546 genetic markers, testing these for genetic association with variable levels of 24 IgG and 39 plasma protein N-glycan traits. In the follow-up study, significant associations were validated in 455 samples. Results: This study confirmed previously known plasma protein and/or IgG N-glycosylation loci (candidate genes MGAT3, MGAT5 and ST6GAL1, encoding beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase, alpha-1,6-mannosylglycoprotein 6-beta-N-acetylglucosaminyltransferase and ST6 beta-galactoside alpha-2,6-sialyltransferase 1 gene, respectively) and identified novel associations that were not previously reported for the general European population. First, novel genetic associations of IgG-bound glycans were found with SNPs on chromosome 22 residing in two genomic intervals close to candidate gene MGAT3; these include core fucosylated digalactosylated disialylated IgG N-glycan with bisecting N-acetylglucosamine (GlcNAc) (pdiscovery=7.65 × 10−12, preplication=8.33 × 10−6 for the top associated SNP rs5757680) and core fucosylated digalactosylated glycan with bisecting GlcNAc (pdiscovery=2.88 × 10−10, preplication=3.03 × 10−3 for the top associated SNP rs137702). The most significant genetic associations of IgG-bound glycans were those with MGAT3. Second, two SNPs in high linkage disequilibrium (missense rs1047286 and synonymous rs2230203) located on chromosome 19 within

مصطلحات الفهرس: C3, GWAS, IgG N-glycosylation, MGAT3, plasma protein N-glycosylation, ST6GAL1, type 1 diabetes, article

URL: https://curis.ku.dk/portal/da/publications/integrated-glycomics-and-genetics-analyses-reveal-a-potential-role-for-nglycosylation-of-plasma-proteins-and-iggs-as-well-as-the-complement-system-in-the-development-of-type-1-diabetes(2ca131f4-5c64-483d-a94c-1b1509b9d33c).html
https://doi.org/10.1007/s00125-023-05881-z
https://curis.ku.dk/ws/files/375300233/s00125_023_05881_z.pdf

المؤلفون: Aldonza, Mark Borris D

مستخلص: Cancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post- translational cancer hallmark and the consequences thereof remain elusive. Here, we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted therapies. Large-scale pharmacogenomics revealed that fucosylation genes display widespread association with resistance to these therapies. In cancer cell cultures, xenograft mouse models, and patients, targeted kinase inhibitors distinctively induced core fucosylation of secreted proteins less than 60 kDa. Label-free proteomics of N-glycoproteomes identified fucosylation of the antioxidant PON1 as a critical component of the therapy-induced secretome (TIS). N-glycosylation of TIS and target core fucosylation of PON1 are mediated by the fucose salvage-FUT8-SLC35C1 axis with PON3 directly modulating GDP-Fuc transfer on PON1 scaffolds. Core fucosylation in the Golgi impacts PON1 stability and folding prior to secretion, promoting a more degradation-resistant PON1. Global and PON1-specific secretome de-N-glycosylation both limited the expansion of resistant clones in a tumor regression model. We defined the resistance-associated transcription factors (TFs) and genes modulated by the N-glycosylated TIS via a focused and transcriptome-wide analyses. These genes characterize the oxidative stress, inflammatory niche, and unfolded protein response as important factors for this modulation. Our findings demonstrate that core fucosylation is a common modification indirectly induced by targeted therapies that paradoxically promotes resistance.

مصطلحات الفهرس: Animals, Humans, Mice, Aryldialkylphosphatase, Protein Processing, Post-Translational, Glycosylation, Secretome, biochemistry, cancer, cancer biology, chemical biology, drug resistance, fucosylation, human, n-linked glycosylation, secretome, targeted therapy, Genetics, Cancer, Aetiology, 2.1 Biological and endogenous factors, Human, Biochemistry and Cell Biology, publication

URL: https://escholarship.org/uc/item/0514n7d8
https://escholarship.org/

المصدر: Larsen , I S B , Povolo , L , Zhou , L , Tian , W , Mygind , K J , Hintze , J , Jiang , C , Hartill , V , Prescott , K , Johnson , C A , Mullegama , S V , McConkie-Rosell , A , McDonald , M , Hansen , L , Vakhrushev , S Y , Schjoldager , K T , Clausen , H , Worzfeld , T , Joshi , H J & Halim , A 2023 , ' The SHDRA syndrome-associated gene TMEM260 encodes a protein-specific O-mannosyltransferase ' , Proceedings of the National Academy of Sciences of the United States of America , vol. 120 , no. 21 , pp. e2302584120 .

مستخلص: Mutations in the TMEM260 gene cause structural heart defects and renal anomalies syndrome, but the function of the encoded protein remains unknown. We previously reported wide occurrence of O-mannose glycans on extracellular immunoglobulin, plexin, transcription factor (IPT) domains found in the hepatocyte growth factor receptor (cMET), macrophage-stimulating protein receptor (RON), and plexin receptors, and further demonstrated that two known protein O-mannosylation systems orchestrated by the POMT1/2 and transmembrane and tetratricopeptide repeat-containing proteins 1-4 gene families were not required for glycosylation of these IPT domains. Here, we report that the TMEM260 gene encodes an ER-located protein O-mannosyltransferase that selectively glycosylates IPT domains. We demonstrate that disease-causing TMEM260 mutations impair O-mannosylation of IPT domains and that TMEM260 knockout in cells results in receptor maturation defects and abnormal growth of 3D cell models. Thus, our study identifies the third protein-specific O-mannosylation pathway in mammals and demonstrates that O-mannosylation of IPT domains serves critical functions during epithelial morphogenesis. Our findings add a new glycosylation pathway and gene to a growing group of congenital disorders of glycosylation.

مصطلحات الفهرس: congenital disorders of glycosylation, glycoproteomics, glycosylation, O-mannosylation, plexin, article

URL: https://curis.ku.dk/portal/da/publications/the-shdra-syndromeassociated-gene-tmem260-encodes-a-proteinspecific-omannosyltransferase(37ed9483-7df3-4710-afce-da630b828289).html
https://doi.org/10.1073/pnas.2302584120
https://curis.ku.dk/ws/files/347698503/pnas.2302584120.pdf

المؤلفون: Hooijschuur, Kevin

مستخلص: The complement system is one of the earliest defense mechanisms that pathogens encounter. This ancient system consists of a cascade of glycoproteins that leads to cell lysis and labelling of pathogens or compromised host cells for immune response and phagocytosis. Nearly all complement proteins are modified with glycans. Glycosylation is one of the most common, but also one of the most complex protein modifications. Glycans can play major roles in protein folding, protein orientation, kinetics, and activity. While the structures and functions of glycans in the complement system have been studied broadly, many unresolved questions remain. Developments in glycan analysis methods and functional assays gradually improves the knowledge and characterization of complement glycoproteins in the last few years, but further developments will be required to study this system in detail. This review evaluates the current state of the art concerning glycosylation of major complement proteins, and provides a brief introduction on both glycosylation and the complement system. From this broad overview, several complement glycoproteins will be highlighted for their interesting characteristics and functions.

مصطلحات الفهرس: Glycosylation, the attachment of oligosaccharides to proteins, is one of the most important and complex modifications on proteins and plays a role in many processes and diseases. The complement system is a part of the innate immune system that consists of several tens of proteins, which interact with each other, and with proteins outside the complement system. This review assesses the glycosylation of the complement proteins., Master Thesis, Student Thesis

URL: https://studenttheses.uu.nl/handle/20.500.12932/43578

المصدر: Larsen , I S B , Povolo , L , Zhou , L , Tian , W , Mygind , K J , Hintze , J , Jiang , C , Hartill , V , Prescott , K , Johnson , C A , Mullegama , S V , McConkie-Rosell , A , McDonald , M , Hansen , L , Vakhrushev , S Y , Schjoldager , K T , Clausen , H , Worzfeld , T , Joshi , H J & Halim , A 2023 , ' The SHDRA syndrome-associated gene TMEM260 encodes a protein-specific O-mannosyltransferase ' , Proceedings of the National Academy of Sciences of the United States of America , vol. 120 , no. 21 , pp. e2302584120 .

مستخلص: Mutations in the TMEM260 gene cause structural heart defects and renal anomalies syndrome, but the function of the encoded protein remains unknown. We previously reported wide occurrence of O-mannose glycans on extracellular immunoglobulin, plexin, transcription factor (IPT) domains found in the hepatocyte growth factor receptor (cMET), macrophage-stimulating protein receptor (RON), and plexin receptors, and further demonstrated that two known protein O-mannosylation systems orchestrated by the POMT1/2 and transmembrane and tetratricopeptide repeat-containing proteins 1-4 gene families were not required for glycosylation of these IPT domains. Here, we report that the TMEM260 gene encodes an ER-located protein O-mannosyltransferase that selectively glycosylates IPT domains. We demonstrate that disease-causing TMEM260 mutations impair O-mannosylation of IPT domains and that TMEM260 knockout in cells results in receptor maturation defects and abnormal growth of 3D cell models. Thus, our study identifies the third protein-specific O-mannosylation pathway in mammals and demonstrates that O-mannosylation of IPT domains serves critical functions during epithelial morphogenesis. Our findings add a new glycosylation pathway and gene to a growing group of congenital disorders of glycosylation.

مصطلحات الفهرس: congenital disorders of glycosylation, glycoproteomics, glycosylation, O-mannosylation, plexin, article

URL: https://curis.ku.dk/portal/da/publications/the-shdra-syndromeassociated-gene-tmem260-encodes-a-proteinspecific-omannosyltransferase(37ed9483-7df3-4710-afce-da630b828289).html
https://doi.org/10.1073/pnas.2302584120
https://curis.ku.dk/ws/files/347698503/pnas.2302584120.pdf

المصدر: Research outputs 2022 to 2026

مستخلص: Background: Observational studies demonstrated a bidirectional association between type 2 diabetes (T2D) and hypertension, whereas Mendelian randomization (MR) analyses supported the causality from T2D to hypertension but not causal from hypertension to T2D. We previously found that IgG N-glycosylation is associated with both T2D and hypertension, and thus IgG N-glycosylation might link the causality between them. Methods: We carried out a genome-wide association study (GWAS) to identify IgG N-glycosylation-quantitative-trait loci (QTLs) integrating GWAS for T2D and hypertension and then performed bidirectional univariable and multivariable MR analyses to infer the causal association among them. The inverse-variance-weighted (IVW) analysis was performed as the primary analysis, followed by some sensitivity analyses to explore the stability of the results. Results: Six putatively causal IgG N-glycans for T2D and four for hypertension were identified in the IVW method. Genetically predicted T2D increased the risk of hypertension (odds ratio [OR] = 1.177, 95% confidence interval (95% CI) = 1.037–1.338, P = 0.012) and vice versa (OR = 1.391, 95% CI = 1.081–1.790, P = 0.010). Multivariable MR showed that T2D remained at risk effect with hypertension ([OR] = 1.229, 95% CI = 1.140–1.325, P = 7.817 × 10–8) after conditioning on T2D-related IgG-glycans. Conversely, hypertension was associated with higher T2D risk (OR = 1.287, 95% CI = 1.107–1.497, P = 0.001) after adjusting for related IgG-glycans. No evidence of horizontal pleiotropy was observed, as MR‒Egger regression provided P values for intercept > 0.05. Conclusion: Our study validated the mutual causality between T2D and hypertension from the perspective of IgG N-glycosylation, further validating the “common soil” hypothesis underlying the pathogenesis of T2D and hypertension.

مصطلحات الفهرس: [RSTPub], Bidirectional Mendelian randomization, Glycosylation, Hypertension, IgG N-glycosylation quantitative trait loci, Type 2 diabetes, Medicine and Health Sciences, text

URL: https://ro.ecu.edu.au/ecuworks2022-2026/2405

عناروين إضافية: Sweet Discoveries: Unraveling the Complex World of Sugars in Health and Disease

مستخلص: Glycans, which are complex assemblies of sugars, are the most prevalent class of macromolecules, surpassing nucleic acids, proteins and lipids. Glycans are essential for life, as they are a required energy source, provide protection against cellular stresses and shape cellular structure. During this course, we will explore the many roles glycans play in human health and disease. For example, we will learn about the healthy glycosylation patterns of many mammalian proteins and the dynamic changes that glycan structures undergo during early development and cancer metastasis, the influence of dietary carbohydrates on glycan metabolism, and the role of densely glycosylated proteins involved in HIV infectivity. Concurrently, we will learn about the chemical and biological techniques used to detect and visualize glycans by in vitro and whole-animal metabolic labeling approaches, how to profile protein-glycan interactions using high-throughput glycan arrays, and about the development of new carbohydrate-based therapeutics and vaccines to target HIV, influenza and bacterial pathogens. The course will focus on the primary research literature, and we will learn practical laboratory techniques, experimental design and how to interpret data and critique the conclusions offered by authors.This course is one of many Advanced Undergraduate Seminars offered by the Biology Department at MIT. These seminars are tailored for students with an interest in using primary research literature to discuss and learn about current biological research in a highly interactive setting. Many instructors of the Advanced Undergraduate Seminars are postdoctoral scientists with a strong interest in teaching.

مصطلحات الفهرس: Glycans, glycobiology, glycosylation patterns, glycoproteins, glycan metabolism, glycosylated proteins, protein-glycan interactions, high-throughput glycan arrays, O-glycans, N-linked glycosylation, glycosyl-amino acids, Metabolic glycan labeling, synthetic antigens, 260204

URL: https://hdl.handle.net/1721.1/148354

المؤلفون: Bai, Yuanyuan

المصدر: ChemSusChem; vol 15, iss 9, e202102539; 1864-5631

مستخلص: Innovation in process development is essential for applying biocatalysis in industrial and laboratory production of organic compounds, including beneficial carbohydrates such as human milk oligosaccharides (HMOs). HMOs have attracted increasing attention for their potential application as key ingredients in products that can improve human health. To efficiently access HMOs through biocatalysis, a combined substrate and process engineering strategy is developed, namely multistep one-pot multienzyme (MSOPME) design. The strategy allows access to a pure tagged HMO in a single reactor with a single C18-cartridge purification process, despite the length of the target. Its efficiency is demonstrated in the high-yielding (71-91 %) one-pot synthesis of twenty tagged HMOs (83-155 mg), including long-chain oligosaccharides with or without fucosylation or sialylation up to nonaoses from a lactoside without the isolation of the intermediate oligosaccharides. Gram-scale synthesis of an important HMO derivative - tagged lacto-N-fucopentaose-I (LNFP-I) - proceeds in 84 % yield. Tag removal is carried out in high efficiency (94-97 %) without the need for column purification to produce the desired natural HMOs with a free reducing end. The method can be readily adapted for large-scale synthesis and automation to allow quick access to HMOs, other glycans, and glycoconjugates.

مصطلحات الفهرس: Milk, Human, Humans, Polysaccharides, Oligosaccharides, Glycosylation, Biocatalysis, biocatalysis, carbohydrates, chemoenzymatic synthesis, glycosylation, oligosaccharides, Generic health relevance, Analytical Chemistry, Other Chemical Sciences, Chemical Engineering, General Chemistry, Organic Chemistry, article

URL: https://escholarship.org/uc/item/26t447sz
https://escholarship.org/