Orthodox vs. Paradox: Supporting the Central Dogma With Sugar Code.

The central dogma of molecular biology, traditionally focused on nucleic acids and proteins, has historically overlooked the crucial involvement of carbohydrates (sugars/glycans) in cellular processes. Carbohydrates combine with lipids, proteins, and RNA to form glycoconjugates-glycolipids, glycoproteins, and glycoRNAs-that mediate signaling, recognition, and dynamic cellular responses. A glycomics-centered perspective within the paracentral dogma extends the central dogma by incorporating additional biomacromolecular modifications, illustrating how glycans function as context-dependent molecular signals synthesized through non-template enzymatic processes that are partly genetically constrained yet structurally unpredictable. Recognized as the "third alphabet of life" after nucleic acids (the first) and amino acids (the second), the glycan encodes rich information that regulates cellular communication, immunity, and disease processes.Glycoconjugates with the recently discovered glycoRNAs demonstrate how glycan modifications integrate with nucleic acids, while O-GlcNAcylation in DNA synthesis and DNA damage response, exemplified by O-GlcNAc transferase and O-GlcNAcase, modulates genome stability and cellular homeostasis. Advances in glycomics, framed within the concept of paracentral dogma, provide deep insights into glycoconjugates and their sugar-encoded information, offering novel avenues for vaccination, targeted interventions and glycomedicine.