Glycosylation is a highly complex process to produce a diverse repertoire of cellular glycans that are frequently attached to proteins and lipids. Glycans participate in fundamental biological processes  including protein folding and clearance, cell proliferation and apoptosis, development, immune response , and pathogenesis. As one of the major types of glycans, N-linked glycans are formed by sequential attachments of monosaccharides into proteins with the help of a limited number of enzymes. Many of these enzymes can accept multiple N-linked glycans as substrates, thus generating a large number of glycan intermediates and their intermingled pathways. Motivated by the quantitative methods developed in complex network research, we investigated the URLanization of such N-linked glycosylation pathways in mammalian cells. The N-linked glycosylation pathways were found to be extremely modular, while composed of cohesive topological modules all directly branched from the common upstream pathway of glycan synthesis. This unique structural property allows the glycan production between modules to be controlled in that upstream region. Although the enzymes involved in multiple glycan substrates indicate cross-talk between modules, the impact of the cross-talk on the module-specific enhancement of glycan synthesis could be confined within a moderate range by transcriptional-level control. Our findings give the experimentally-testable predictions for glycosylation processes, and can be potentially applied to the engineering of therapeutic glycoproteins .
Glycosylation is a highly complex process to produce a diverse repertoire of cellular glycans that are attached to proteins and lipids. Glycans are involved in fundamental biological processes , including protein folding and clearance, cell proliferation and apoptosis, development, immune responses , and pathogenesis. One of the major types of glycans, N-linked glycans , is formed by sequential attachments of monosaccharides to proteins by a limited number of enzymes. Many of these enzymes can accept multiple N-linked glycans as substrates, thereby generating a large number of glycan intermediates and their intermingled pathways. Motivated by the quantitative methods developed in complex network research, we investigated the URLanization of such N-linked glycosylation pathways in mammalian cells. The N-linked glycosylation pathways are extremely modular, and are composed of cohesive topological modules that directly branch from a common upstream pathway of glycan synthesis. This unique structural property allows the glycan production between modules to be controlled by the upstream region. Although the enzymes act on multiple glycan substrates , indicating cross-talk between modules, the impact of the cross-talk on the module-specific enhancement of glycan synthesis may be confined within a moderate range by transcription-level control. The findings of the present study provide experimentally-testable predictions for glycosylation processes, and may be applicable to therapeutic glycoprotein engineering .
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