bims-meglyc 2024-10-06 papers

Issue of 2024–10–06
three papers selected by
Silvia Radenkovic, UMC Utrecht

Glycobiology. 2024 Sep 30. pii: cwae076. [Epub ahead of print]34(11):

N-glycoproteomic and proteomic alterations in SRD5A3-deficient fibroblasts.

Kishore Garapati, Wasantha Ranatunga, Neha Joshi, Rohit Budhraja, Saniha Sabu, Kristin A Kantautas, Graeme Preston, Ethan O Perlstein, Tamas Kozicz, Eva Morava, Akhilesh Pandey.

SRD5A3-CDG is a congenital disorder of glycosylation (CDG) resulting from pathogenic variants in SRD5A3 and follows an autosomal recessive inheritance pattern. The enzyme encoded by SRD5A3, polyprenal reductase, plays a crucial role in synthesizing lipid precursors essential for N-linked glycosylation. Despite insights from functional studies into its enzymatic function, there remains a gap in understanding global changes in patient cells. We sought to identify N-glycoproteomic and proteomic signatures specific to SRD5A3-CDG, potentially aiding in biomarker discovery and advancing our understanding of disease mechanisms. Using tandem mass tag (TMT)-based relative quantitation, we analyzed fibroblasts derived from five patients along with control fibroblasts. N-glycoproteomics analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified 3,047 glycopeptides with 544 unique N-glycosylation sites from 276 glycoproteins. Of these, 418 glycopeptides showed statistically significant changes with 379 glycopeptides decreased (P < 0.05) in SRD5A3-CDG patient-derived samples. These included high mannose, complex and hybrid glycan-bearing glycopeptides. High mannose glycopeptides from protocadherin Fat 4 and integrin alpha-11 and complex glycopeptides from CD55 were among the most significantly decreased glycopeptides. Proteomics analysis led to the identification of 5,933 proteins, of which 873 proteins showed statistically significant changes. Decreased proteins included cell surface glycoproteins, various mitochondrial protein populations and proteins involved in the N-glycosylation pathway. Lysosomal proteins such as N-acetylglucosamine-6-sulfatase and procathepsin-L also showed reduced levels of phosphorylated mannose-containing glycopeptides. Our findings point to disruptions in glycosylation pathways as well as energy metabolism and lysosomal functions in SRD5A3-CDG, providing clues to improved understanding and management of patients with this disorder.

Keywords: CDG type I; N-glycosylation; dolichol; lipid-linked oligosaccharide; polyprenol

DOI: https://doi.org/10.1093/glycob/cwae076

Methods Mol Biol. 2025 ;2855 555-571

Application of a Computational Metabolomics Workflow for the Diagnosis of Inborn Errors of Metabolism in a Laboratory Setting.

Udo F H Engelke, Alan Zammit, Albert Gerritsen, Marloes A H M Michels, Karlien L M Coene, Leo A J Kluijtmans, Purva Kulkarni.

Inborn errors of metabolism constitute a set of hereditary diseases that impose severe medical and physical challenges in the affected individual, in particular, for the pediatric patient population. Timely diagnosis is crucial for these patients, as any delay could result in irreversible health damage, underscoring the importance of early initiation of personalized treatment. Current routine diagnostic screening for inborn errors of metabolism relies on various targeted analyses of established biomarkers. However, this approach is time-consuming, focuses on a limited number of tests (based on clinical information) with a relatively small number of biomarkers, and does not facilitate the identification of new markers. In contrast, untargeted metabolomics-based screening offers a more efficient diagnostic solution, by assessing thousands of metabolites across multiple metabolic pathways in a single test. This not only saves time but also conserves resources for clinicians, the diagnostic laboratory, and for patients.This chapter describes the computational workflow of our "Next Generation Metabolic Screening" approach, which is a metabolomics-based method that is currently applied at the Translational Metabolic Laboratory of the Radboud University Medical Center (the Netherlands) for the diagnosis of inborn errors of metabolism.

Keywords: Bioinformatics workflow; Diagnostics; Inborn errors of metabolism; Mass spectrometry; Untargeted metabolomics

DOI: https://doi.org/10.1007/978-1-0716-4116-3_30

Cell Death Discov. 2024 Sep 30. 10(1): 415

Biological function of sialic acid and sialylation in human health and disease.

Wengen Zhu, Yue Zhou, Linjuan Guo, Shenghui Feng.

Sialic acids are predominantly found at the terminal ends of glycoproteins and glycolipids and play key roles in cellular communication and function. The process of sialylation, a form of post-translational modification, involves the covalent attachment of sialic acid to the terminal residues of oligosaccharides and glycoproteins. This modification not only provides a layer of electrostatic repulsion to cells but also serves as a receptor for various biological signaling pathways. Sialylation is involved in several pathophysiological processes. Given its multifaceted involvement in cellular functions, sialylation presents a promising avenue for therapeutic intervention. Current studies are exploring agents that target sialic acid residues on sialoglycans or the sialylation process. These efforts are particularly focused on the fields of cancer therapy, stroke treatment, antiviral strategies, and therapies for central nervous system disorders. In this review, we aimed to summarize the biological functions of sialic acid and the process of sialylation, explore their roles in various pathophysiological contexts, and discuss their potential applications in the development of novel therapeutics.

DOI: https://doi.org/10.1038/s41420-024-02180-3