Glycosyltransferases are a class of enzymes that catalyze the biosynthesis of oligosaccharides, polysaccharides, and glycoconjugates. The sugar portion is transferred from an activated sugar donor to a specific acceptor molecule through the formation of a glycosidic bond. Other sugars, nucleic acids, lipids, and proteins can act as acceptor molecules. Glycosyltransferases are mainly found in the Golgi apparatus of eukaryotes as type II transmembrane proteins. Sequence alignment tools can be used to predict glycosyltransferase function. However, even closely related sequences show different catalytic activities. Glycosyltransferases are classified as "retention" or "conversion" enzymes depending on whether the end-group heterodimeric bond in the donor substrate is retained or reversed during the sugar transfer process.
Changes in glycosyltransferase expression levels are closely associated with neurodegeneration, but it is difficult to determine whether these effects are upstream of neurotoxicity. Two distinct glycosyltransferase-related mechanisms are prominent: ganglioside synthesis and the addition of O-linked β-N-acetylglucosamine (O-GlcNAcylation) to proteins. The major gangliosides are sialic acid-containing sphingolipids. In the mammalian brain, they are synthesized in the endoplasmic reticulum from lactosyl ceramide precursors and then translocated from the cis-Golgi network to the trans-Golgi network for remodeling by a series of glycosyltransferases. Mature gangliosides are expressed in the plasma membrane and soma of most vertebrate cells. They are particularly abundant in neurons and glial cells within the CNS, and they are thought to play an important role in cell signaling. O-GlcNAcylation occurs primarily in the brain and is regulated by the glycosyltransferases O-linked N-acetylglucosaminyltransferase (OGT) and EGF structural domain-specific O-linked N-acetylglucosaminyltransferase (EOGT), which partially attach O-GlcNAc to receptor proteins via O-linked glycosidic bonds at specific serine/threonine residues. OGT acts intracellularly, while EOGT acts extracellularly on secreted and membrane proteins. O-GlcNAcylation of CNS proteins important for an axonal and synaptic function is significantly reduced in animal models of neurodegenerative diseases and in tissues from patients with Parkinson's disease, Huntington's chorea, and Alzheimer's disease.
Fig.1 Golgi homeostasis defects. (Lefeber, et al., 2020)
β-1,4-Galactosyltransferase 1 (B4GalT1; EC 2.4.1.38) is a trans-Golgi-resident family 7 glycosyltransferase. In the presence of manganese, it transfers a galactose group (Gal) from UDP-galactose (UDP-Gal) to an N-acetylglucosamine (GlcNAc) residue, forming a β1-4 linkage. B4GalT1 can interact with α-lactalbumin to form a lactose synthase complex (EC 2.4.1.22), in which case the specificity of its sugar acceptor is altered, and the acceptor can be a single glucose residue (Glc) instead of GlcNAc, thereby synthesizing the disaccharide lactose. B4GalT1 has a type II membrane protein topology with a short N-terminal cytoplasmic tail and an alpha-helical transmembrane domain responsible for Golgi localization, a stalk domain believed to be largely disordered and whose function is unclear (amino acids 45-125), and a globular catalytic domain (amino acids 126-398) carrying sugar transfer activity.
The genetic variants that contribute to impaired mental performance are highly diverse. ST3GAL3 encodes the Golgi enzyme β-galactoside-α2,3- sialyltransferase- iii, an enzyme that in humans predominantly forms sialyl Lewis epitopes on proteins. ST3GAL3 is located on chromosome 1 at the MRT4 locus and is associated with nonsyndromic autosomal recessive mental retardation.
Here we describe one of the disorders in the Disorders of Multiple Glycosylation and Other Pathways. CD BioGlyco provides comprehensive and deep insights into disorders of glycosyltransferases. We offer advanced glycomedicine development service, including but not limited to Glycoengineered Protein-based Glycomedicine Development, Glycosides-based Glycomedicine Development, Custom Sialyl Tn Antigen Production Service, and Custom Sialyl Lewis x Antigen Production Service. If you are interested in our services, please contact us for more details without any hesitation.
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