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Review
. 2024 Nov 7;29(1):137.
doi: 10.1186/s11658-024-00658-7.

Human Gb3/CD77 synthase: a glycosyltransferase at the crossroads of immunohematology, toxicology, and cancer research

Katarzyna Szymczak-Kulus  1 , Marcin Czerwinski  2 , Radoslaw Kaczmarek  2
Affiliations
Review

Human Gb3/CD77 synthase: a glycosyltransferase at the crossroads of immunohematology, toxicology, and cancer research

Katarzyna Szymczak-Kulus et al. Cell Mol Biol Lett. .

Abstract

Human Gb3/CD77 synthase (α1,4-galactosyltransferase, P1/Pk synthase, UDP-galactose: β-D-galactosyl-β1-R 4-α-D-galactosyltransferase, EC 2.4.1.228) forms Galα1 → 4Gal structures on glycosphingolipids and glycoproteins. These glycans are recognized by bacterial adhesins and toxins. Globotriaosylceramide (Gb3), the major product of Gb3/CD77 synthase, is a glycosphingolipid located predominantly in plasma membrane lipid rafts, where it serves as a main receptor for Shiga toxins released by enterohemorrhagic Escherichia coli and Shigella dysenteriae of serotype 1. On the other hand, accumulation of glycans formed by Gb3/CD77 synthase contributes to the symptoms of Anderson-Fabry disease caused by α-galactosidase A deficiency. Moreover, variation in Gb3/CD77 synthase expression and activity underlies the P1PK histo-blood group system. Glycosphingolipids synthesized by the enzyme are overproduced in colorectal, gastric, pancreatic, and ovarian cancer, and elevated Gb3 biosynthesis is associated with cancer cell chemo- and radioresistance. Furthermore, Gb3/CD77 synthase acts as a key glycosyltransferase modulating ovarian cancer cell plasticity. Here, we describe the role of human Gb3/CD77 synthase and its products in the P1PK histo-blood group system, Anderson-Fabry disease, and bacterial infections. Additionally, we provide an overview of emerging evidence that Gb3/CD77 synthase and its glycosphingolipid products are involved in cancer metastasis and chemoresistance.

Keywords: Anderson-Fabry disease; Shiga toxin; blood group; cancer; chemoresistance; glycoprotein; glycosphingolipid; glycosyltransferase.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Structure of Gb3/CD77 synthase. A The 3D structure model predicted by AlphaFold (https://alphafold.ebi.ac.uk/entry/Q9NPC4); amino acid residues 1–22 compose the cytoplasmic tail, 23–43 form the transmembrane domain, and 44–353 encompass the stem and catalytic domain facing Golgi lumen. B A schematic representation of the Gb3/CD77 synthase polypeptide chain with important peptide motifs highlighted
Fig. 2
Fig. 2
A schematic representation of the biosynthesis of GSLs and N-glycans produced by Gb3/CD77 synthase. Galα1 → 4Gal structures are highlighted in green, and Galα1 → 4GalNAc in red. Color coding according to the Symbol Nomenclature for Glycans (SNFG) [120]
Fig. 3
Fig. 3
Schematic representation of the A4GALT gene. The rectangles depict the three exons. The circles indicate the positions of SNPs associated with P1/P2 polymorphism (rs5751348 in red, rs2143918 and rs8138197 in blue), and the yellow circle represents the rs397514502 SNP resulting in p.Q211E substitution
See this image and copyright information in PMC

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