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Most GTs show high specificity toward donor and acceptor molecules, but some can recognize several donor or acceptor molecules and\/or create novel glycosidic linkage types. This promiscuity has profound implications for cellular processes, influencing signaling pathways, protein stability, and disease progression. GT promiscuity may result from the structural peculiarities of the enzyme and acceptor, modulation by a ligand, oligomerization with other enzymes, or its subcellular localization. In this review, current insights into GT promiscuity are discussed, highlighting its biological significance and potential associations with human diseases. 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