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Essentiality, Biosynthesis, and Prediction of Glycosylation: A genetic and metabolic encoding of intercellular communication augmentation

  • Author(s): Kellman, Benjamin P.
  • Advisor(s): Lewis, Nathan E
  • Carter, Hannah
  • et al.
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Abstract

Glycans, polysaccharides generalizable to a colored graph with colored edges, 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. We begin with a discussion of 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.

With mechanistic and abstract models of glycan biosynthesis, glycosylation remains unpredictable. While DNA, RNA, and proteins undergo templated synthesis, wherein request (i.e., base-pairing or codon) is made and fulfillment (i.e., nucleotide or amino acid addition), glycan biosynthesis is principally non-templated; metabolically constrained. The premise of the final chapter is that glycoconjugates and glycan-biosynthetic enzymes exist in physical space, have physical and chemical attributes, and therefore interact, attract, and repel each other. Because the glycoconjugate is the point of reference for a glycan and it displays the most variation in the system of glycan biosynthesis, we hypothesize that the glycoconjugate surface is the template-request of the glycan biosynthesis while metabolite availability is the context-dependent, and therefore confounding, fulfillment of that request. Towards expanding our understanding of glycan biosynthesis, we explore site-specific glycosylation databases, amino-acid substitution matrixes, pathogenic mutations and empirical observations of sequence-dependent glycosylation to support the separation of templated biosynthesis into two parts: the request (e.g., codon, or nucleotide) and the request fulfillment (e.g., addition of the corresponding amino acid or paired nucleotide).

Here we explore multiple modes of glycomic analysis including glycan-level, flux-level, and substructure-level analysis. Each resolution provides varying degrees of accuracy and insight but none provided clear and global generalizability. In the final chapter, we establish a genetic encoding for glycosylation providing support for genetic and metabolic encoding. A templated encoding for glycan biosynthesis will make glycans predictable and broadly accessible beyond direct empirical observation.

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This item is under embargo until September 18, 2022.