The plasma membrane-localized protein α-dystroglycan (α-DG) is modified by the core M3-type glycan, a characteristic O-mannosyl glycan, on particular Thr residues. Defects in the core M3-type glycan synthesis cause a group of congenital muscular dystrophies with neuronal abnormalities. In 2016, the complete structure of the core M3-type glycan was clarified and ribitol phosphate (RboP) or glycerol phosphate (GroP) were identified as novel glycan constituents in mammals. However, the mechanisms that regulate the biosynthesis of this unique glycan remain unclear. This review summarizes our recent progress in understanding the regulatory mechanisms of core M3-type glycan biosynthesis, with a special focus on the molecular machinery of RboP and GroP modifications.
Glycoconjugates, such as glycolipids and glycoproteins, are widely distributed from microorganisms to plants and animals and are involved in many basic biological events. However, their scarcity and diversity make it difficult to obtain pure samples, thereby hampering their elucidation. Supplying structurally defined molecules based on organic synthesis is a powerful tool for clarifying their functions at the molecular level. In this review, several synthetic approaches that the author has been engaged are introduced. The efficient synthesis of gangliosides was achieved by the development of an intramolecular ceramide introduction reaction. A combination of appropriate deprotection and glycosylation reactions enabled rapid glycan synthesis, and a high-mannose-type glycan library was constructed using chemo-enzymatic approaches. Structure-activity relationship studies of the bacterial glycolipid MPIase have uncovered the mechanism of membrane protein integration in Escherichia coli.
Cytosolic peptide:N-glycanase (PNGase, NGLY1) is a hydrolase that catalyzes the removal of N-glycans from misfolded glycoproteins. NGLY1 contributes to cytosolic glycan degradation (non-lysosomal degradation) and one of the protein quality control systems, endoplasmic reticulum-associated degradation. NGLY1 also is responsible for full activation of a transcription factor, nuclear factor erythroid-2 like 1 (NFE2L1). NGLY1 deficiency is caused by mutations in the human NGLY1 gene. The physiological function of NGLY1 has since attracted a great deal of attention, and researchers have made great progress in terms of its elucidation. Several of these studies have used model organisms of mice, Drosophila and Caenorhabditis elegans. The focus of the present minireview is the physiological function of NGLY1, which was revealed via analyses using mouse models, and those revelations are described here.
Site-selective functionalization of saccharides has been actively studied in recent years because it offers the possibility of simplifying synthetic schemes of sugar-related compounds by reducing the steps for protection and deprotection. Since molecular catalysts were able to promote various functional group transformations that cannot be catalyzed by enzymes, a variety of catalytic reaction systems using molecular catalysts have been developed. In this minireview, some examples of site-selective silylation of sugar derivatives were described briefly.
The plasma membrane-localized protein α-dystroglycan (α-DG) is modified by the core M3-type glycan, a characteristic O-mannosyl glycan, on particular Thr residues. Defects in the core M3-type glycan synthesis cause a group of congenital muscular dystrophies with neuronal abnormalities. In 2016, the complete structure of the core M3-type glycan was clarified and ribitol phosphate (RboP) or glycerol phosphate (GroP) were identified as novel glycan constituents in mammals. However, the mechanisms that regulate the biosynthesis of this unique glycan remain unclear. This review summarizes our recent progress in understanding the regulatory mechanisms of core M3-type glycan biosynthesis, with a special focus on the molecular machinery of RboP and GroP modifications.
Glycoconjugates, such as glycolipids and glycoproteins, are widely distributed from microorganisms to plants and animals and are involved in many basic biological events. However, their scarcity and diversity make it difficult to obtain pure samples, thereby hampering their elucidation. Supplying structurally defined molecules based on organic synthesis is a powerful tool for clarifying their functions at the molecular level. In this review, several synthetic approaches that the author has been engaged are introduced. The efficient synthesis of gangliosides was achieved by the development of an intramolecular ceramide introduction reaction. A combination of appropriate deprotection and glycosylation reactions enabled rapid glycan synthesis, and a high-mannose-type glycan library was constructed using chemo-enzymatic approaches. Structure-activity relationship studies of the bacterial glycolipid MPIase have uncovered the mechanism of membrane protein integration in Escherichia coli.
Cytosolic peptide:N-glycanase (PNGase, NGLY1) is a hydrolase that catalyzes the removal of N-glycans from misfolded glycoproteins. NGLY1 contributes to cytosolic glycan degradation (non-lysosomal degradation) and one of the protein quality control systems, endoplasmic reticulum-associated degradation. NGLY1 also is responsible for full activation of a transcription factor, nuclear factor erythroid-2 like 1 (NFE2L1). NGLY1 deficiency is caused by mutations in the human NGLY1 gene. The physiological function of NGLY1 has since attracted a great deal of attention, and researchers have made great progress in terms of its elucidation. Several of these studies have used model organisms of mice, Drosophila and Caenorhabditis elegans. The focus of the present minireview is the physiological function of NGLY1, which was revealed via analyses using mouse models, and those revelations are described here.
Site-selective functionalization of saccharides has been actively studied in recent years because it offers the possibility of simplifying synthetic schemes of sugar-related compounds by reducing the steps for protection and deprotection. Since molecular catalysts were able to promote various functional group transformations that cannot be catalyzed by enzymes, a variety of catalytic reaction systems using molecular catalysts have been developed. In this minireview, some examples of site-selective silylation of sugar derivatives were described briefly.