Cells are covered by a dense layer of carbohydrates, known as cell glycocalyx. Cell surface glycans are attached to the cell membrane in forms of glycoconjugates, among which glycolipids are ubiquitous. The most common glycolipids are glycosphingolipids (GSLs) and glycosylphosphatidylinositols (GPIs), which play a critical role in various physiological and pathological processes. However, due to the complex and diverse structures of GSLs and GPIs, they are difficult to obtain from natural sources. Our research aims at developing practical methods for the synthesis of natural and functionalized GSLs and GPIs, as well as GPI-anchored peptides and proteins, and use the synthetic molecules to investigate related biological problems. In this context, we have developed a diversity-oriented strategy for the synthesis of GSLs and their derivatives, using a simple lactoside as the universal starting material, through stepwise chemical or enzymatic elongation of the glycan and on-site chemoselective lipid remodeling after each glycosylation step. This strategy has enabled two-way diversification of the glycan and lipid to afford a large variety of GSLs and GSL analogs or derivatives conveniently. Using commercial and synthetic GSLs as standards, we have established an MS/MS-based method for GSL characterization and glycolipidomics analysis via two-stage matching of experimental and reference spectra. First, the highly conserved glycan fragments are matched to yield GSL species identification; next, glycolipid fragments of the matched species are treated according to a lipid rule-based method to characterize lipid form. This enables the identification of diverse lipid forms of GSLs using a database containing the MS/MS spectrum of only one lipid form for each GSL species. We have also developed multiple chemical and chemoenzymatic methods for the synthesis of GPIs containing different lipids, glycans and/or functional groups useful for biological studies and for the synthesis of GPI-anchored peptides and proteins. These synthetic GPIs and GPI conjugates have been employed to probe GPI-bacterial toxin interactions, the structure-activity relationships of GPIs, GPI-cell membrane interactions, and GPI-anchored proteomics.

Synthesis and biological studies of glycolipids

ACS Spring 2022

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