Structure, function, and implications of fucosyltransferases in health and disease.

Fucosylation is a ubiquitous glycosylation event that shapes cellular communication and immunity. Catalyzed by fucosyltransferases (FUTs), this reaction encompasses diverse substrates, mechanisms, and biologic consequences. In this Review, we explore the structural and functional landscape of FUTs primarily from higher eukaryotes, with focus on the mechanistic determinants of regioselectivity, donor/acceptor coordination, and domain modularity. We highlight advances in structural biology, modeling, and enzyme engineering that clarify how FUTs decode glycan topology and specificity. Phylogenetic and structural analyses reveal two major clades of human FUTs that differ in GDP-Fuc recognition and conformational flexibility, providing a molecular rationale for their mechanistic divergence. Drawing from mammalian FUT studies, we propose a conceptual framework in which distinct family members exploit strategies including donor-induced conformational changes, exosite interactions, or local peptide cues to achieve specificity and catalytic efficiency. We also examine their roles in physiology, inflammation, immune regulation, and cancer, and summarize current FUT inhibitors and enzyme-based therapeutic strategies.