8ZWR

Structure-Based Mechanism and Specificity of Human Galactosyltransferase B3GalT5

Summary for 8ZWR

• Entry DOI: 10.2210/pdb8zwr/pdb
• Descriptor: Beta-1,3-galactosyltransferase 5, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: globo-series glycosphingolipid biosynthesis, oxocarbenium, sn2-like, inverting galactosyltransferase, michaelis complex, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 69185.35

Authors

Lo, J.M.,Ma, C. (deposition date: 2024-06-13, release date: 2025-04-09, Last modification date: 2025-04-16)

Primary citation

Lo, J.M.,Kung, C.C.,Cheng, T.R.,Wong, C.H.,Ma, C.
Structure-Based Mechanism and Specificity of Human Galactosyltransferase beta 3GalT5.
J.Am.Chem.Soc., 147:10875-10885, 2025

PubMed Abstract: Human β1,3-galactosyltransferase 5 (β3GalT5) is a key enzyme involved in the synthesis of glycans on glycoproteins and glycolipids that are associated with various important biological functions, especially tumor malignancy and cancer progression, and has been considered as a promising target for development of anticancer agents. In this study, we determined the X-ray structures of β3GalT5 in complex with the stable donor analogue UDP-2-fluorogalactose or the native donor substrate UDP-galactose (UDP-Gal) and several glycan acceptors at different reaction steps. Based on the structures obtained from our experiments, β3GalT5 catalyzes the transfer of galactose from UDP-Gal to a broad spectrum of glycan acceptors with an S2-like mechanism; however, in the absence of a glycan acceptor, UDP-Gal is slowly converted to UDP and two other products, one is galactose through an S2-like mechanism with water as an acceptor and the other is an oxocarbenium-like product, presumably through an S1-like mechanisms. The structure, mechanism, and specificity of β3GalT5 presented in this study advance our understanding of enzymatic glycosylation and provide valuable insights for application to glycan synthesis and drug design targeting β3GalT5-associated cancer.

PubMed: 40130308
DOI: 10.1021/jacs.4c11724

Experimental method

X-RAY DIFFRACTION (1.94 Å)