Elucidating Human Milk Oligosaccharide biosynthetic genes through network-based multiomics integration

Kellman, Benjamin P.; Richelle, Anne; Yang, Jeong‐Yeh; Chapla, Digantkumar; Chiang, Austin W. T.; Najera, Julia A.; Bao, Bokan; Koga, Natália Massaco; Mohammad, Mahmoud A.; Bruntse, Anders Bech; Haymond, Morey W.; Moremen, Kelley W.; Bode, Lars; Lewis, Nathan E.

doi:10.1101/2020.09.02.278663

Cited by 4 publications

(1 citation statement)

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“…The low parameterization and scalability of these models accommodate diverse approaches to compute fluxes, such as flux balance modeling, probabilistic learning [58,59], multiomic comparison, and other linearized approaches [61]. The reduced complexity of linearized glycan biosynthesis models allows for the simulation of multiple glycogene knockouts [62], tolerance of glycan structure and reaction uncertainty [60], and analysis of many types of glycosylation including human milk oligosaccharide biosynthesis [60,63], O-linked glycans [50,64], GAGs [58], and glycolipids [65]. The simplicity of these models makes otherwise computationally taxing questions feasible.…”

Section: Mechanistic Models Of Glycan Biosynthesismentioning

confidence: 99%

Big-Data Glycomics: Tools to Connect Glycan Biosynthesis to Extracellular Communication

Kellman

Lewis

2021

Trends in Biochemical Sciences

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Characteristically, cells must sense and respond to environmental cues. Despite the importance of cell-cell communication, our understanding remains limited and often lacks glycans. Glycans decorate proteins and cell membranes at the cell-environment interface, and modulate intercellular communication, from development to pathogenesis. Providing further challenges, glycan biosynthesis and cellular behavior are co-regulating systems. Here, we discuss how glycosylation contributes to extracellular responses and signaling. We further organize approaches for disentangling the roles of glycans in multicellular interactions using newly available datasets and tools, including glycan biosynthesis models, omics datasets, and systems-level analyses. Thus, emerging tools in big data analytics and systems biology are facilitating novel insights on glycans and their relationship with multicellular behavior. Extracellular Glycans Influence Intercellular BehaviorEvery cell and many viruses are wrapped in a sugar-coating of functional glycans (see Glossary) and glycoconjugates that helps modulate cell-cell communication, the glycocalyx. Glycans are bound to peptide or lipid glycoconjugates and matured in the endomembrane system. They then reside on the cell surface or diffuse into the extracellular matrix (ECM). The emergence, recycling, and dispersion of glycans is often slow, variable, and glycoconjugate dependent (2-1000 h); therefore, environmentally responsive nascent glycans do not transform the cell surface immediately [1,2]. Instead, the glycocalyx constitutes a composite memory of recent and current responses to intercellular exchanges. Together, the glycocalyx, the communication-modulating glycans and glycoconjugates between conversing cells form a rich resource that can be leveraged to improve our understanding of how cells communicate (Figure 1, Key Figure ).ECM glycans are voluminous, ubiquitous, and diverse, extending to 2-3 times the cell diameter [3]. With 4549 of 20 365 reviewed human proteins (UniProtKB) corresponding to~250 000 proteoforms per cell type [4], there are~50 glycoforms for every glycoprotein. Glycan metabolism uses 342 documented [5] human glycosyltransferases and glycosidases, each performing interdependent and distinct monosaccharide additions and removals. Borrowing from epigenetics, lectins, glycosyltransferases, and glycosidases have been described as the readers, writers, and erasers of the glycocalyx [6,7]. These encapsulating carbohydrates moderate many cellular responses, including development, growth, differentiation, migration, signaling, and morphogenesis (Table 1) making few biological discussions complete outside the glycan context (Figure 2) [8].Today, we are seeing glycan essentiality and neglect in the study of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the COVID-19 causative agent (Figure 2C). Because cells and viruses are wrapped in glycans, glycans moderate the first host-pathogen interactions, including immune evasion through viral glycosylation [9,10] and h...

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