Abstract
Background: The N-glycan structure and composition of the spike (S) protein of SARS-CoV-2 are pertinent to vaccine development and efficacy. Methods: We reconstructed the glycosylation network based on previously published mass spectrometry data using GNAT, a glycosylation network analysis tool. Our compilation of the network tool had 26 glycosyltransferase and glucosidase enzymes and could infer the pathway of glycosylation machinery based on glycans in the virus spike protein. Once the glycan biosynthesis pathway was generated, we simulated the effect of blocking specific enzymes—swainsonine or deoxynojirimycin for blocking mannosidase-II and indolizidine for blocking alpha-1,6-fucosyltransferase—to see how they would affect the biosynthesis network and the glycans that were synthesized. Results: The N-glycan biosynthesis network of SARS-CoV-2 spike protein shows an elaborate enzymatic pathway with several intermediate glycans, along with the ones identified by mass spectrometric studies. Of the 26 enzymes, the following were involved—Man-Ia, MGAT1, MGAT2, MGAT4, MGAT5, B3GalT, B4GalT, Man-II, SiaT, ST3GalI, ST3GalVI, and FucT8. Blocking specific enzymes resulted in a substantially modified glycan profile of SARS-CoV-2. Conclusion: Variations in the final N-glycan profile of the virus, given its site-specific microheterogeneity, are factors in the host response to the infection, vaccines, and antibodies. Heterogeneity in the N-glycan profile of the spike (S) protein and its potential effect on vaccine efficacy or adverse reactions to the vaccines remain unexplored. Here, we provide all the resources we generated—the glycans in the glycoCT xml format and the biosynthesis network for future work.
Highlights
Glycosylation is a very common and complex post-translational modification process of proteins (Shental-Bechor and Levy, 2008)
We examined the effect of blocking two different glycosylation enzymes, to see if we can modify the network of glycans developed as part of the virus spike glycoprotein
Simulated N-glycan biosynthetic network generation: We used the list of the most representative N-glycans per glycosite detected by Zhang et al (Zhang et al, 2021) and the N-glycan profile of SARS-CoV-2 as reported by Shajahan et al (Shajahan et al, 2020) to generate our primary glycosylation biosynthesis networks
Summary
Glycosylation is a very common and complex post-translational modification process of proteins (Shental-Bechor and Levy, 2008). About 70% of human proteins are likely glycosylated (An et al, 2009). N-glycosylation is one of the main types of glycosylation in humans (Reily et al, 2019). N-glycosylation has been shown to have an impact on protein folding and function in several cases (Parodi, 2000; Mitra et al, 2006). The site of glycosylation and the type of the glycan—mannose-rich, hybrid, or complex—likely influence protein function and folding. Virus replication involves the host glycosylation machinery for post-translational modifications. It can be useful to understand which enzymes are critical to this process. The N-glycan structure and composition of the spike (S) protein of SARSCoV-2 are pertinent to vaccine development and efficacy
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