Abstract
The brain N-glycome is known to be crucial for many biological functions, including its involvement in neuronal diseases. Although large structural studies of brain N-glycans were recently carried out, a comprehensive isomer-specific structural analysis has still not been achieved, as indicated by the recent discovery of novel structures with galactosylated bisecting GlcNAc. Here, we present a detailed, isomer-specific analysis of the human brain N-glycome based on standardized porous graphitic carbon (PGC)-LC-MS/MS. To achieve this goal, we biosynthesized glycans with substitutions typically occurring in the brain N-glycome and acquired their normalized retention times. Comparison of these values with the standardized retention times of neutral and desialylated N-glycan fractions of the human brain led to unambiguous isomer specific assignment of most major peaks. Profound differences in the glycan structures between naturally neutral and desialylated glycans were found. The neutral and sialylated N-glycans derive from diverging biosynthetic pathways and are biosynthetically finished end products, rather than just partially processed intermediates. The focus on structural glycomics defined the structure of human brain N-glycans, amongst these are HNK-1 containing glycans, a bisecting sialyl-lactose and structures with fucose and N-acetylgalactosamine on the same arm, the so-called LDNF epitope often associated with parasitic worms.
Highlights
Received: 14 December 2021N-glycosylation, one of the most common post translational modifications, is known to confer crucial biological functions to its acceptors
Guided by reports that brain N-glycans are highly fucosylated and bisected and contain galactose primarily in β1,4-linkage and, to a smaller extent, in β1,3-linkage [9,11], we bio-synthesized a range of N-glycans containing these structural features in addition to the almost complete set of permutations of glycans with five hexose, four Nacetylhexosamine and one fucose residue (H5N4F1) generated for a recent work [28]
A set of structures comprising biantennary glycans with bisecting GlcNAc was prepared with GnGnF6 bi from pig brain as the starting point (Figure 1)
Summary
N-glycosylation, one of the most common post translational modifications, is known to confer crucial biological functions to its acceptors. Other recent studies have revealed a clear connection between Alzheimer’s disease and aberrant glycosylation [2,3]. It was shown that especially fucosylated and oligomannosidic structures are dysregulated in regard to Alzheimers disease [4]. The importance of brain N-glycosylation was further shown by the finding that sialylated N-glycans can modulate the neurotransmitter release in nerve terminals [5,6]. Because of its obviously important role in the central nervous system, large structural and functional studies regarding the brain N-glycome have been carried out in the last years [7,8]
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