The nature of protein glycosylation renders cellular glycomics a very challenging task in having to deal with all the disparate glycans carried on membrane glycoproteins. Rapid mapping by mass spectrometry analysis provides only a coarse sketch of the glycomic complexity based primarily on glycosyl compositions, whereby the missing high-resolution structural details require a combination of multi-mode separations and multi-stages of induced fragmentation to gain sufficiently discriminative precision, often at the expenses of throughput and sensitivity. Given the available technology and foreseeable advances in the near future, homing in on resolving the terminal fucosylated, sialylated and/or sulfated structural units, or glycotopes, maybe a more pragmatic and ultimately more rewarding approach to gain insights into myriad biological processes mediated by these terminal coding units carried on important glycoproteins, to be decoded by a host of endogenous glycan-binding proteins and antibodies. A broad overview of recent technical advances and limitations in cellular glycomics is first provided as a backdrop to the propounded glycotope-centric approach based on advanced nanoLC-MS2/MS3 analysis of permethylated glycans. To prioritize analytical focus on the more tangible glycotopes is akin to first identifying the eye-catching and characteristic-defining flowers and fruits of the glyco-forest, to see the forest for the trees. It has the best prospects of attaining the much-needed balance in sensitivity, structural precision and analytical throughput to match advances in other omics.

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