CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase (ST3GAL3) mediates the transfer of sialic acid from CMP-sialic acid to galactose-containing glycoproteins and forms the sialyl Lewis, an epitope on proteins which are required for attaining and/or maintaining higher cognitive functions. Some defects in ST3GAL3 result in mental retardation, autosomal recessive 12 (MRT12; MIM:611090), a disorder characterised by below average general intellectual function and impaired adaptative behaviour. Another defect of ST3GAL3 can cause early infantile epileptic encephalopathy-15 (EIEE15: MIM:615006), resulting in severe mental retardation.
In two ST3GAL3 homozygous mutations causing MRT12, A13D and D370Y, most of the mutant protein was improperly localized to the endoplasmic reticulum. This prevented the protein from interacting with its substrates in the Golgi, resulting in a loss of function and loss of the sialyl Lewis, an epitope important for higher cognative functions (Najmabadi et al. 2007, Hu et al. 2011). Another homozygous mutation, A320P, causing EIEE15, functional expression studies showed a 75% reduction in the secretion of the mutant protein and no detectable enzymatic activity (Edvardson et al. 2012). This mutation affects the highly conserved sialyl motif S, which is crucial for binding both donor and acceptor substrates.
CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase (ST3GAL3), located on the Golgi membrane, mediates the transfer of sialic acid (Neu5Ac, N-acetylneuraminic acid) in an α2,3 linkage to the terminal galactose of Gal-beta-1,3-GlcNAc- and Gal-beta-1,4-GalNAc- sequences found on glycoproteins and glycolipids (Kitagawa & Paulson 1993). The product, Type 1 monosialylgalactosylgloboside (Type 1 MSGG) is the precursor to sialyl Lewis a (sLeA) (also known as the CA19-9 antigen), a tumour marker that is used primarily in the management of pancreatic cancer. Increased sialylation has been observed to be associated with malignant transformation and metastasis.
The alpha-2,3-sialyltransferases ST3GAL3,4 and 6 (Kitagawa & Paulson 1993, Okajima et al. 1999, Kitagawa & Paulson 1994) located on the Golgi membrane, mediate the transfer of sialic acid (Neu5Ac, N-acetylneuraminic acid) in an α2,3 linkage to the terminal galactose of Gal-beta-1,4-GlcNAc- sequences found on glycoproteins and glycolipids to form Type 2 monosialylgalactosylgloboside (Type 2 MSGG).
Increased sialylation has been associated with malignant transformation and metastasis. ST3GAL6 is highly expressed in patients with multiple myeloma (MM). Knockdown of ST3GAL6 has been shown to prolong survival in mice (Glavey et al. 2014).
The alpha-2,3-sialyltransferases 2 and 3 (ST3GAL2,3) transfer a sialic acid (Neu5Ac) moiety to the terminal galactosyl (Gal-R) residue of gangliosides GM1, GA1, and GD1b to produce GD1a, GM1b, and GT1a. Neu5Ac is added to Gal-R via an alpha-2,3 linkage (Kim et al., 1996; Grahn et al., 2002; Sturgill et al., 2012). Gangliosides localize to the plasma membrane via vesicle transport, endocytosis, and exocytosis. Defects in ST3GAL3 cause an intellectual developmental disorder (MRT12, MIM:611090; reviewed by Khamirani et al., 2021).
Mature fringe-modified NOTCH usually has a tetrasaccharide attached to conserved fucosylated serine and threonine residues in EGF repeats. The chemical structure of these tetrasaccharides is Sia-alpha2,3-Gal-beta1,4-GlcNAc-beta1,3-fucitol (Moloney et al. 2000). The identity of sialyltransferase(s) that add sialic acid to galactose remains unknown in this context. Based on the type of chemical bonds in the tetrasaccharide, there are three known Golgi membrane sialyltransferases that could perform this function: ST3GAL3, ST3GAL4, ST3GAL6 (Harduin-Lepers et al. 2001).