Fabry Disease: Molecular Basis, Pathophysiology, Diagnostics and Potential Therapeutic Directions

Biomolecules, Journal Year: 2021, Volume and Issue: 11(2), P. 271 - 271

Published: Feb. 12, 2021

Fabry disease (FD) is a lysosomal storage disorder (LSD) characterized by the deficiency of α-galactosidase A (α-GalA) and consequent accumulation toxic metabolites such as globotriaosylceramide (Gb3) globotriaosylsphingosine (lysoGb3). Early diagnosis appropriate timely treatment FD patients are crucial to prevent tissue damage organ failure which no can reverse. LSDs might profit from four main therapeutic strategies, but hitherto there cure. Among possibilities intravenous administered enzyme replacement therapy (ERT), oral pharmacological chaperone (PCT) or stabilizers, substrate reduction (SRT) more recent gene/RNA therapy. Unfortunately, only benefit ERT and, since 2016, PCT, both always combined with supportive adjunctive preventive therapies clinically manage FD-related chronic renal, cardiac neurological complications. Gene for currently studied further strategies novel PCTs under investigation. In this review, we discuss molecular basis FD, pathophysiology diagnostic procedures, together current treatments potential avenues that could in future.

Language: Английский

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Fabry disease: Mechanism and therapeutics strategies

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: Oct. 26, 2022

Fabry disease is a monogenic characterized by deficiency or loss of the α-galactosidase A (GLA). The resulting impairment in lysosomal GLA enzymatic activity leads to pathogenic accumulation substrate and, consequently, progressive appearance clinical symptoms target organs, including heart, kidney, and brain. However, mechanisms involved disease-mediated organ damage are largely ambiguous poorly understood, which hinders development therapeutic strategies for treatment this disorder. Although currently available approaches have shown some efficiency disease, they all exhibit limitations that need be overcome. In review, we first introduce current mechanistic knowledge discuss potential its treatment. We then systemically summarize advances research on approaches, enzyme replacement therapy (ERT), gene therapy, chaperone as well targeting subcellular compartments, such lysosomes, endoplasmic reticulum, nucleus. Finally, future discussed based results studies associated with these approaches.

Language: Английский

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1,6-epi-Cyclophellitol Cyclosulfamidate Is a Bona Fide Lysosomal α-Glucosidase Stabilizer for the Treatment of Pompe Disease

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(32), P. 14819 - 14827

Published: Aug. 2, 2022

α-Glucosidase inhibitors are potential therapeutics for the treatment of diabetes, viral infections, and Pompe disease. Herein, we report a 1,6-epi-cyclophellitol cyclosulfamidate as new class reversible α-glucosidase that displays enzyme inhibitory activity by virtue its conformational mimicry substrate when bound in Michaelis complex. The α-d-glc-configured cyclophellitol 4 binds competitive manner human lysosomal acid (GAA), ER α-glucosidases, and, at higher concentrations, intestinal displaying an excellent selectivity over β-glucosidases GBA GBA2 glucosylceramide synthase (GCS). Cyclosulfamidate stabilizes recombinant GAA (rhGAA, alglucosidase alfa, Myozyme) cell medium plasma facilitates trafficking to lysosomes. It rhGAA more effectively than existing small-molecule chaperones does so vitro, cellulo, vivo zebrafish, thus representing promising therapeutic alternative Miglustat

Language: Английский

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The Catalytic Reaction Mechanism of the β-Galactocerebrosidase Enzyme Deficient in Krabbe Disease

ACS Catalysis, Journal Year: 2020, Volume and Issue: 10(20), P. 12091 - 12097

Published: Aug. 31, 2020

Krabbe disease is a neurodegenerative disorder related to misfunction of β-galactocerebrosidase (GALC), glycosidase that catalyzes the cleavage β-galactosidic bonds in glycosphingolipids. Here we uncover catalytic molecular mechanism GALC using quantum mechanics/molecular mechanics methods. Our results clarify unusual chair conformation substrate observed crystal structure and show catalysis can take place via two distinct conformational pathways (1S3 → [4H3]‡ 4C1 4C1) with similar free energy barriers because leaving group flexibility. This mechanistic insight will aid design diagnosis probes chaperones.

Language: Английский

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Synthesis of multimeric pyrrolidine iminosugar inhibitors of human β-glucocerebrosidase and α-galactosidase A: First example of a multivalent enzyme activity enhancer for Fabry disease

European Journal of Medicinal Chemistry, Journal Year: 2020, Volume and Issue: 192, P. 112173 - 112173

Published: Feb. 20, 2020

Language: Английский

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Trans-cyclosulfamidate mannose-configured cyclitol allows isoform-dependent inhibition of GH47 α-d-mannosidases through a bump–hole strategy

Chemical Science, Journal Year: 2023, Volume and Issue: 14(46), P. 13581 - 13586

Published: Jan. 1, 2023

1,6- Trans -manno-cyclosulfamidate 6 inhibits selectively an L310S mutant of Caulobacter GH47 α- d -mannosidase by virtue its 1 C 4 conformation and bump-and-hole strategy, enabling allele-specific inhibition within the α-mannosidase family.

Language: Английский

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Unraveling the effect of A143T, P205T and D244N mutations in α-galactosidase A on its catalytic activity and susceptibility to globotriaosylceramide and iminosugar 1-deoxygalactonojirimycin chaperone

Journal of Molecular Liquids, Journal Year: 2022, Volume and Issue: 353, P. 118790 - 118790

Published: Feb. 19, 2022

Language: Английский

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New α-galactosidase-inhibiting aminohydroxycyclopentanes

RSC Advances, Journal Year: 2021, Volume and Issue: 11(26), P. 15943 - 15951

Published: Jan. 1, 2021

A concise and robust synthesis of new cyclopentanoid competitive inhibitors α-galactosidases related to Fabry's disease other α-galactosidase disorders.

Language: Английский

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A theoretical study on binding and stabilization of galactose and novel galactose analogues to the human α-galactosidase A variant causing Fabry disease

Biophysical Chemistry, Journal Year: 2022, Volume and Issue: 292, P. 106915 - 106915

Published: Oct. 27, 2022

Language: Английский

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Nucleotide binding as an allosteric regulatory mechanism for Akkermansia muciniphila β- N -acetylhexosaminidase Am2136

Gut Microbes, Journal Year: 2022, Volume and Issue: 14(1)

Published: Nov. 17, 2022

β-N-acetylhexosaminidases (EC3.2.1.52), which belong to the glycosyl hydrolase family GH20, are important enzymes for oligosaccharides modification. Numerous microbial have been investigated applications in biology, biomedicine and biotechnology. Akkermansia muciniphila is an anaerobic intestinal commensal bacterium possesses specific gut mucosal layer colonization mucin degradation. In this study, we assessed vitro glycan cleavage activity of A. β-N-acetylhexosaminidase Am2136 demonstrated its ability that hydrolyzing β-linkages joining N-acetylglucosamine a wide variety aglycone residues, indicated may be generalist β-N-acetylhexosaminidase. Structural enzyme assay experiments allowed us probe essential function inter-domain interactions β23-β33. Importantly, revealed hydrolysis was enhanced by nucleotides. We further speculated activation mechanism might associated with conformational motions between domain III IV. To our knowledge, first report nucleotide effector regulated β-N-acetylhexosaminidase, reveal novel biological functions. These findings contribute understanding distinct properties within GH20 lay certain foundation develop controllable catalysts.Abbreviations: OD600 - optical cell densities at 600 nm; LB Luria–Bertani; IPTG isopropyl β-D-1-thiogalactopyranoside; PMSF phenylmethanesulfonyl fluoride; rmsd root mean square deviation; GlcNAc N-acetyl-β-D-glucosamine; GalNAc N-acetyl-β-D-galactosamine; Gal galactose

Language: Английский

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