Mannose-6-phosphate (M6P) is a posttranslational modification on N-linked glycans on lysosomal hydrolases in the Golgi apparatus, which is required for selective transport of lysosomal hydrolases from the Golgi apparatus to lysosomes via M6P receptors. Defects in M6P modification by genetic manipulations or in hereditary genetic disorders result in abnormal extracellular secretion of lysosomal hydrolases and are thus the basis of the pathogenesis of lysosome storage diseases. N-acetylglucosamine (GlcNAc)-1-phosphotransferase, an enzyme catalyzing M6P modification, is synthesized as an inert form that requires proteolytic activation by the Golgi-localized protease, site-1 protease (S1P). S1P, encoded by membrane-bound transcription factor peptidase, site 1 (MBTPS1), is ubiquitously expressed and functions sequentially with the site-2 protease to proteolytically activate unique membrane-bound latent transcription factors in the Golgi apparatus. These transcription factors include sterol regulatory element-binding protein required for inducing lipogenesis, and activating transcription factor 6 required for inducing endoplasmic reticulum stress-related unfolded protein response. Since we reported the first patient with MBTPS1 pathogenic variants who has congenital skeletal dysplasia due to compound endoplasmic reticulum and lysosomal dysfunctions, there have been a few reports regarding novel MBTPS1 variants worldwide. Here we overview genotype-phenotype relationships in so far reported patients with MBTPS1 variants.

Keratan sulfate glycosaminoglycans are negatively charged linear carbohydrate chains consisting of poly-N-acetyllactosamine with sulfate modification. The glycans are found in the extracellular matrix of the cornea, cartilage, and brain of vertebrates, and those function in the cornea has been extensively studied. The biosynthetic pathway of keratan sulfate glycosaminoglycans in the cornea is mainly catalyzed by four enzymes (β1,3-N-acetylglucosaminyltransferase-7, β1,4-galactosyltransferase-4, CHST1, CHST6) in the cooperative manner. In human, genetic mutations in CHST6 cause a hereditary eye disease, macular corneal dystrophy. In this disease, abnormal glycoproteins are synthesized due to impaired sulfation step in keratan sulfate biosynthesis, which may be aggregated and deposited in the corneal stroma, resulting in corneal opacity.

Glycans, which are the carbohydrate moieties in glycoconjugates, tightly regulate biological events. Over decades of studies have demonstrated the relationship between glycans and human health diseases. The altered glycosylation, tumor-associated carbohydrate antigens (TACAs), plays crucial roles in facilitating tumor malignancy in many types of human carcinomas. Such abnormal glycosylation patterns are not solely seen in cancers, but also in congenital disorders of glycosylation (CDGs), neurological diseases, and autoimmune diseases such as IgA nephropathy in human tissues with completely different mechanisms. Here, we discuss focusing on a highly relevant TACA of truncated mucin-type O-GalNAc glycan, the Tn antigen that affects disease courses in both cancers and IgA nephropathy in comprehensive manners.

Fucosylation is one of the most important types of glycosylation in cancer. The expression levels of fucosylated glycans generally increase during cancer development. Consequently, fucosylated molecules have been used as tumor markers. The synthesis of fucosylated glycans occurs through the catalytic activity of fucosyltransferases, which are enzymatic entities that orchestrate the transfer of fucose from GDP-fucose to acceptor substrates. Previously, we reported, for the first time, a deficiency in GDP-mannose 4,6-dehydratase (GMDS), an enzyme crucial for the generation of cellular GDP-fucose, in human cancer cells. This finding was followed by the discovery that fucosylated glycans regulate the susceptibility of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death and natural killer (NK) cell-mediated tumor immune surveillance. In this review, we summarize a series of our studies and discuss the role of fucosylation in the regulation of cancer cell death.

β-L-Arabinofuranosidase (β-Arafase) is an enzyme belonging to the glycoside hydrolase families GH127/137/142/146 that hydrolyze β-L-arabinofuranoside (Araf) from plant polysaccharides and glycoproteins. With the development of functional and structural analyses of β-Arafases from major human intestinal bacteria Bifidobacterium longum ssp. longum and Bacteroides thetaiotaomicron, the importance of β-Arafase to remove modified sugars has been revealed for the efficient degradation of dietary fibers by the intestinal bacteria. This minireview describes the distribution of β-Araf in plant polysaccharides and glycoproteins and the findings revealed by functional and structural studies of β-Arafases from intestinal bacteria.

Mannose-6-phosphate (M6P) is a posttranslational modification on N-linked glycans on lysosomal hydrolases in the Golgi apparatus, which is required for selective transport of lysosomal hydrolases from the Golgi apparatus to lysosomes via M6P receptors. Defects in M6P modification by genetic manipulations or in hereditary genetic disorders result in abnormal extracellular secretion of lysosomal hydrolases and are thus the basis of the pathogenesis of lysosome storage diseases. N-acetylglucosamine (GlcNAc)-1-phosphotransferase, an enzyme catalyzing M6P modification, is synthesized as an inert form that requires proteolytic activation by the Golgi-localized protease, site-1 protease (S1P). S1P, encoded by membrane-bound transcription factor peptidase, site 1 (MBTPS1), is ubiquitously expressed and functions sequentially with the site-2 protease to proteolytically activate unique membrane-bound latent transcription factors in the Golgi apparatus. These transcription factors include sterol regulatory element-binding protein required for inducing lipogenesis, and activating transcription factor 6 required for inducing endoplasmic reticulum stress-related unfolded protein response. Since we reported the first patient with MBTPS1 pathogenic variants who has congenital skeletal dysplasia due to compound endoplasmic reticulum and lysosomal dysfunctions, there have been a few reports regarding novel MBTPS1 variants worldwide. Here we overview genotype-phenotype relationships in so far reported patients with MBTPS1 variants.

Keratan sulfate glycosaminoglycans are negatively charged linear carbohydrate chains consisting of poly-N-acetyllactosamine with sulfate modification. The glycans are found in the extracellular matrix of the cornea, cartilage, and brain of vertebrates, and those function in the cornea has been extensively studied. The biosynthetic pathway of keratan sulfate glycosaminoglycans in the cornea is mainly catalyzed by four enzymes (β1,3-N-acetylglucosaminyltransferase-7, β1,4-galactosyltransferase-4, CHST1, CHST6) in the cooperative manner. In human, genetic mutations in CHST6 cause a hereditary eye disease, macular corneal dystrophy. In this disease, abnormal glycoproteins are synthesized due to impaired sulfation step in keratan sulfate biosynthesis, which may be aggregated and deposited in the corneal stroma, resulting in corneal opacity.

Glycans, which are the carbohydrate moieties in glycoconjugates, tightly regulate biological events. Over decades of studies have demonstrated the relationship between glycans and human health diseases. The altered glycosylation, tumor-associated carbohydrate antigens (TACAs), plays crucial roles in facilitating tumor malignancy in many types of human carcinomas. Such abnormal glycosylation patterns are not solely seen in cancers, but also in congenital disorders of glycosylation (CDGs), neurological diseases, and autoimmune diseases such as IgA nephropathy in human tissues with completely different mechanisms. Here, we discuss focusing on a highly relevant TACA of truncated mucin-type O-GalNAc glycan, the Tn antigen that affects disease courses in both cancers and IgA nephropathy in comprehensive manners.

Fucosylation is one of the most important types of glycosylation in cancer. The expression levels of fucosylated glycans generally increase during cancer development. Consequently, fucosylated molecules have been used as tumor markers. The synthesis of fucosylated glycans occurs through the catalytic activity of fucosyltransferases, which are enzymatic entities that orchestrate the transfer of fucose from GDP-fucose to acceptor substrates. Previously, we reported, for the first time, a deficiency in GDP-mannose 4,6-dehydratase (GMDS), an enzyme crucial for the generation of cellular GDP-fucose, in human cancer cells. This finding was followed by the discovery that fucosylated glycans regulate the susceptibility of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death and natural killer (NK) cell-mediated tumor immune surveillance. In this review, we summarize a series of our studies and discuss the role of fucosylation in the regulation of cancer cell death.

β-L-Arabinofuranosidase (β-Arafase) is an enzyme belonging to the glycoside hydrolase families GH127/137/142/146 that hydrolyze β-L-arabinofuranoside (Araf) from plant polysaccharides and glycoproteins. With the development of functional and structural analyses of β-Arafases from major human intestinal bacteria Bifidobacterium longum ssp. longum and Bacteroides thetaiotaomicron, the importance of β-Arafase to remove modified sugars has been revealed for the efficient degradation of dietary fibers by the intestinal bacteria. This minireview describes the distribution of β-Araf in plant polysaccharides and glycoproteins and the findings revealed by functional and structural studies of β-Arafases from intestinal bacteria.