RARE DISEASE
Alpha-N-acetylgalactosaminidase deficiency type 1
Alpha-N-acetylgalactosaminidase deficiency type 1
Alpha-N-acetylgalactosaminidase deficiency type 1
Synonyms: NAGA deficiency type 1, Schindler disease type 1
Synonyms: NAGA deficiency type 1, Schindler disease type 1
Synonyms: NAGA deficiency type 1, Schindler disease type 1
Drug discovery
0
drugs
With orphan designations
Overview
Alpha-N-acetylgalactosaminidase deficiency type 1 (Schindler disease type I) is a rare autosomal recessive lysosomal storage disorder caused by homozygous mutations in the NAGA gene, leading to deficient α-NAGA enzyme activity and neuroaxonal glycoprotein accumulation [1][3][15]. This infantile-onset neurodegenerative disease presents with developmental regression at 9–15 months, progressive spasticity, cortical blindness, seizures, and severe psychomotor decline, typically resulting in unresponsiveness and early childhood mortality [1][6][14].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders
Research Papers
11 drug discovery papers about Alpha-N-acetylgalactosaminidase deficiency type 1, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
11 drug discovery papers about Alpha-N-acetylgalactosaminidase deficiency type 1, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2022-01-13 | Schistosoma mansoni α-N-acetylgalactosaminidase (SmNAGAL) regulates coordinated parasite movement and egg production
α-galactosidase (α-GAL) and α-N-acetylgalactosaminidase (α-NAGAL) are two glycosyl hydrolases responsible for maintaining cellular homeostasis by regulating glycan substrates on proteins and lipids. Mutations in the human genes encoding either enzyme lead to neurological and neuromuscular impairments seen in both Fabry- and Schindler/Kanzaki- diseases. Here, we investigate whether the parasitic blood fluke Schistosoma mansoni , responsible for the neglected tropical disease schistosomiasis, also contains functionally important α-GAL and α-NAGAL proteins. As infection, parasite maturation and host interactions are all governed by carefully-regulated glycosylation processes, inhibiting S . mansoni’ s α-GAL and α-NAGAL activities could lead to the development of novel chemotherapeutics. Sequence and phylogenetic analyses of putative α-GAL/α-NAGAL protein types showed Smp_089290 to be the only S . mansoni protein to contain the functional amino acid residues necessary for α-GAL/α-NAGAL substrate cleavage. Both α-GAL and α-NAGAL enzymatic activities were higher in females compared to males ( p <0.05; α-NAGAL > α-GAL), which was consistent with smp_089290 ’s female biased expression. Spatial localisation of smp_089290 revealed accumulation in parenchymal cells, neuronal cells, and the vitellaria and mature vitellocytes of the adult schistosome. siRNA-mediated knockdown (>90%) of smp_089290 in adult worms significantly inhibited α-NAGAL activity when compared to control worms ( siLuc treated males, p <0.01; siLuc treated females, p <0.05). No significant reductions in α-GAL activities were observed in the same extracts. Despite this, decreases in α-NAGAL activities correlated with a significant inhibition in adult worm motility as well as in egg production. Programmed CRISPR/Cas9 editing of smp_089290 in adult worms confirmed the egg reduction phenotype. Based on these results, Smp_089290 was determined to act predominantly as an α-NAGAL (hereafter termed SmNAGAL) in schistosome parasites where it participates in coordinating movement and oviposition processes. Further characterisation of SmNAGAL and other functionally important glycosyl hydrolases may lead to the development of a novel anthelmintic class of compounds.
2020-06-25 | Consumption of an Extremely Biodiverse Probiotic and a Supplement based on Microbial Chondroitin Sulfate is Associated with Very Low Serum Alpha-N-acetylgalactosaminidase (Nagalase) Activity and Decrease of C-reactive Protein Values
We describe the case of a 57-years-old male healthy professional who added to his nutritional plan a novel, extremely biodiverse, probiotic and a supplement based on microbial chondroitin sulfate, vitamin D3 and ultrapure phosphatidylcholine to improve his healthy life expectancy. After three months of such a nutritional regimen, serum alpha-N-acetylgalactosaminidase (nagalase) activity was 0.40 that is a value below the minimum level established for adults (normal values: 0.50-0.95 nMol/mL/min). C-reactive Protein (CRP) was less than 1 (normal values: 0.00-5.00 mg/L), a value significantly lower than that recorded before this experience. At the end of the observation period, serum albumin level was 45 g/L, a value very close to the maximum reference value (normal values: 32.00-46.00 g/L). The Prognostic Inflammatory Nutritional Index (PINI) score was 0.05, a value that is close to the minimum calculated value (normal values: 0.00-1.00) and suggests a very low risk of death for all causes. Observation in silico and experiments in vitro demonstrated that both the probiotic and the supplement formed complexes with human nagalase with an efficiency 100 fold higher than that of purified Gc protein-derived Macrophage Activating Factor (GcMAF). The collection of these observations suggests that the combination of this probiotic and this supplement may lead to overall beneficial effects on health as evidenced by positive changes of indicators of immune system function and healthy aging such as nagalase, CRP, albumin and PINI score.
2018-05-10 | The Effect of Fucoidan from the Brown Alga Fucus evanescence on the Activity of α-N-Acetylgalactosaminidase of Human Colon Carcinoma Cells
α-N-acetylgalactosaminidase (EC 3.2.1.49) (alpha-NaGalase) catalyzes the hydrolysis of N-acetamido-2-deoxy-α-d-galactoside residues from non-reducing ends of various complex carbohydrates and glycoconjugates. It is known that human cancer cells express an alpha-NaGalase, which accumulates in the blood plasma of patients. The enzyme deglycosylates the Gc protein-derived macrophage activating factor (GcMAF) and inhibits macrophage activity acting as an immunosuppressor. The high specific activity 0.033 ± 0.002 μmol mg−1 min−1 of the enzyme was found in human colon carcinoma cells DLD-1. The alpha-NaGalase of DLD-1 cells was isolated and biochemical characterized. The enzyme exhibits maximum activity at pH 5.2 and temperature 55 °C. The Km is 2.15 mM, Vmax⁻0.021 μmol min−1 mL−1, kcat⁻1.55 min−1 and kcat/Km⁻0.72 min−1 mM−1 at 37 °C, pH 5.2. The effects of fucoidan from the brown alga Fucus evanescence on the activity of alpha-NaGalase in human colon carcinoma DLD-1 cells and on the biosynthesis of this enzyme were investigated. It was shown that fucoidan did not inhibit free alpha-NaGalase, however, it reduced the expression of the enzyme in the DLD-1 cells at IC50 73 ± 4 μg mL−1.
2010-02-24 | Synthesis of 2-acetamido-1,2-dideoxy-d-galacto-nojirimycin [DGJNAc] from d-glucuronolactone: the first sub-micromolar inhibitor of α-N-acetylgalactosaminidases
2-Acetamido-1,2-dideoxy-d-galacto-nojirimycin [DGJNAc], prepared in 20% overall yield from d-glucuronolactone, is the first potent competitive sub-micromolar inhibitor of α-N-acetyl-galactosaminidases (Ki 0.081 μM from chicken liver, Ki 0.136 μM from Charonia lampas). DGJNAc is a good competitive—whereas the enantiomer l-DGJNAc is a very weak but non-competitive—inhibitor of β-hexosaminidases.
small molecules
2022-01-13 | Schistosoma mansoni α-N-acetylgalactosaminidase (SmNAGAL) regulates coordinated parasite movement and egg production
α-galactosidase (α-GAL) and α-N-acetylgalactosaminidase (α-NAGAL) are two glycosyl hydrolases responsible for maintaining cellular homeostasis by regulating glycan substrates on proteins and lipids. Mutations in the human genes encoding either enzyme lead to neurological and neuromuscular impairments seen in both Fabry- and Schindler/Kanzaki- diseases. Here, we investigate whether the parasitic blood fluke Schistosoma mansoni , responsible for the neglected tropical disease schistosomiasis, also contains functionally important α-GAL and α-NAGAL proteins. As infection, parasite maturation and host interactions are all governed by carefully-regulated glycosylation processes, inhibiting S . mansoni’ s α-GAL and α-NAGAL activities could lead to the development of novel chemotherapeutics. Sequence and phylogenetic analyses of putative α-GAL/α-NAGAL protein types showed Smp_089290 to be the only S . mansoni protein to contain the functional amino acid residues necessary for α-GAL/α-NAGAL substrate cleavage. Both α-GAL and α-NAGAL enzymatic activities were higher in females compared to males ( p <0.05; α-NAGAL > α-GAL), which was consistent with smp_089290 ’s female biased expression. Spatial localisation of smp_089290 revealed accumulation in parenchymal cells, neuronal cells, and the vitellaria and mature vitellocytes of the adult schistosome. siRNA-mediated knockdown (>90%) of smp_089290 in adult worms significantly inhibited α-NAGAL activity when compared to control worms ( siLuc treated males, p <0.01; siLuc treated females, p <0.05). No significant reductions in α-GAL activities were observed in the same extracts. Despite this, decreases in α-NAGAL activities correlated with a significant inhibition in adult worm motility as well as in egg production. Programmed CRISPR/Cas9 editing of smp_089290 in adult worms confirmed the egg reduction phenotype. Based on these results, Smp_089290 was determined to act predominantly as an α-NAGAL (hereafter termed SmNAGAL) in schistosome parasites where it participates in coordinating movement and oviposition processes. Further characterisation of SmNAGAL and other functionally important glycosyl hydrolases may lead to the development of a novel anthelmintic class of compounds.
2020-06-25 | Consumption of an Extremely Biodiverse Probiotic and a Supplement based on Microbial Chondroitin Sulfate is Associated with Very Low Serum Alpha-N-acetylgalactosaminidase (Nagalase) Activity and Decrease of C-reactive Protein Values
We describe the case of a 57-years-old male healthy professional who added to his nutritional plan a novel, extremely biodiverse, probiotic and a supplement based on microbial chondroitin sulfate, vitamin D3 and ultrapure phosphatidylcholine to improve his healthy life expectancy. After three months of such a nutritional regimen, serum alpha-N-acetylgalactosaminidase (nagalase) activity was 0.40 that is a value below the minimum level established for adults (normal values: 0.50-0.95 nMol/mL/min). C-reactive Protein (CRP) was less than 1 (normal values: 0.00-5.00 mg/L), a value significantly lower than that recorded before this experience. At the end of the observation period, serum albumin level was 45 g/L, a value very close to the maximum reference value (normal values: 32.00-46.00 g/L). The Prognostic Inflammatory Nutritional Index (PINI) score was 0.05, a value that is close to the minimum calculated value (normal values: 0.00-1.00) and suggests a very low risk of death for all causes. Observation in silico and experiments in vitro demonstrated that both the probiotic and the supplement formed complexes with human nagalase with an efficiency 100 fold higher than that of purified Gc protein-derived Macrophage Activating Factor (GcMAF). The collection of these observations suggests that the combination of this probiotic and this supplement may lead to overall beneficial effects on health as evidenced by positive changes of indicators of immune system function and healthy aging such as nagalase, CRP, albumin and PINI score.
2018-05-10 | The Effect of Fucoidan from the Brown Alga Fucus evanescence on the Activity of α-N-Acetylgalactosaminidase of Human Colon Carcinoma Cells
α-N-acetylgalactosaminidase (EC 3.2.1.49) (alpha-NaGalase) catalyzes the hydrolysis of N-acetamido-2-deoxy-α-d-galactoside residues from non-reducing ends of various complex carbohydrates and glycoconjugates. It is known that human cancer cells express an alpha-NaGalase, which accumulates in the blood plasma of patients. The enzyme deglycosylates the Gc protein-derived macrophage activating factor (GcMAF) and inhibits macrophage activity acting as an immunosuppressor. The high specific activity 0.033 ± 0.002 μmol mg−1 min−1 of the enzyme was found in human colon carcinoma cells DLD-1. The alpha-NaGalase of DLD-1 cells was isolated and biochemical characterized. The enzyme exhibits maximum activity at pH 5.2 and temperature 55 °C. The Km is 2.15 mM, Vmax⁻0.021 μmol min−1 mL−1, kcat⁻1.55 min−1 and kcat/Km⁻0.72 min−1 mM−1 at 37 °C, pH 5.2. The effects of fucoidan from the brown alga Fucus evanescence on the activity of alpha-NaGalase in human colon carcinoma DLD-1 cells and on the biosynthesis of this enzyme were investigated. It was shown that fucoidan did not inhibit free alpha-NaGalase, however, it reduced the expression of the enzyme in the DLD-1 cells at IC50 73 ± 4 μg mL−1.
2010-02-24 | Synthesis of 2-acetamido-1,2-dideoxy-d-galacto-nojirimycin [DGJNAc] from d-glucuronolactone: the first sub-micromolar inhibitor of α-N-acetylgalactosaminidases
2-Acetamido-1,2-dideoxy-d-galacto-nojirimycin [DGJNAc], prepared in 20% overall yield from d-glucuronolactone, is the first potent competitive sub-micromolar inhibitor of α-N-acetyl-galactosaminidases (Ki 0.081 μM from chicken liver, Ki 0.136 μM from Charonia lampas). DGJNAc is a good competitive—whereas the enantiomer l-DGJNAc is a very weak but non-competitive—inhibitor of β-hexosaminidases.
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Drug Discovery Landscape
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