Disorders of O-Man Glycosylation

Structure and Function of O-Man Glycan

The addition of carbohydrates or glycans to extracellular and membrane proteins is an important post-translational modification in biological processes. O-Mannose (O-Man) glycans are initiated by the covalent attachment of Man to the hydroxyl oxygen of serine (Ser) or threonine (Thr) residues via α-bond. O-Man linked to protein was first discovered in yeast in the 1950s. It was not until 1979 that O-Man modification was first detected in mammals. In mammalian tissues, O-Man glycans account for 30% of all O-linked glycans and can be divided into three core categories. Core M1 is biologically essential by extension of the separate β1-2-linked N-acetylglucosamine (GlcNAc). Core M2 is initiated by two GlcNAc extensions in β1-2 and β1-6 linkages and is mainly found in brain and prostate tissue. The core M3 glycans are initiated by β1,4-linked GlcNAc stretches and constitute a highly heterogeneous part of the O-glycan group. O-Man is extended to form various glycans by adding galactose (Gal), N-acetylgalactosamine (GalNAc), Sialic Acid (SA), sulfated glucuronic acid, etc. to the O-Man core structure.

Core structures of O-Man glycans.Fig.1 Core structures of O-Man glycans. (Praissman & Wells, 2014)

The study found that O-Man glycans are essential for normal nervous system development that relies on neuronal migration and axonal pathway discovery. In addition, O-Man glycans have been implicated in muscle structure and function. For example, disorders in the O-Man biosynthetic pathway lead to congenital muscular dystrophy (CMD). O-Glycan Analysis is a useful method for laboratory detection of CMD.

Biosynthetic Pathway of O-Man Glycan

Protein-O-mannosyltransferases 1 and 2 (POMT1/2) are used to initiate all O-Man glycans on Ser or Thr of acceptor proteins. Man connects β1-2GlcNAc to form core M1 or connects β1-4GlcNAc to form core M3. In this process, mutations in protein O-linked mannose β-1,4-N-acetylglucosaminyltransferase 1 and 2 (POMGNT1/2) can both lead to muscular dystrophy. If the branch β1-6GlcNAc is added on M1, the core M2 is formed. The core M1 and M2 are then extended by Gal and terminated with fucose (Fuc), SA, and glucuronic acid (GlcA) terminal forms. The study found that the gene responsible for the addition of the end group is not associated with dystrophic glycoproteinopathy. The core M3 is elongated by GalNAc after adding β1-4GlcNAc, and then Man is 6-O-phosphorylated by protein O-mannose kinase (POMK). Fukutin (FKTN) and fukutin-related protein (FKRP) add ribitol-5-phosphate to the GalNAc residue of core M3, which is then extended by transmembrane protein 5 (TMEM5) and β1,4-glucuronyltransferase 1 (B4GAT1) with xylose (Xyl) and GlcA residues.

Biosynthetic pathway of O-Man glycan.Fig.2 Biosynthetic pathway of O-Man glycan. (Praissman & Wells, 2014)

Features of CMD

CMD is a family of recessive genetic disorders characterized by continuous skeletal muscle weakness and wasting. CMD is associated with Abnormal O-Glycosylation of Man, primarily α-dystroglycan (α-DG). Matrix glycans generated by O-mannosylation are required for laminin binding in the extracellular matrix to α-DG. Mutations of α-DG disrupt this interaction and alter the properties of cell membranes, leading to the development of muscular dystrophy. Disruption of α-DG association with other ligands in the eye and brain also leads to clinically widespread muscular dystrophy. Genetic analysis of patients is essential for discovering α-DG's functional glycan and its biosynthesis. Known and putative genes associated with α-DG mutations during biosynthesis include POMT1, POMT2, POMGNT1, Like-glycosyltransferase (LARGE), FKRP, FKTN, and isoprenoid synthase domain-containing protein (ISPD).

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  1. Praissman, J.L.; Wells, L. Mammalian O-mannosylation pathway: glycan structures, enzymes, and protein substrates. Biochemistry. 2014, 53(19): 3066-3078.
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