Asn215Ser, Ala143Thr, and Arg112Cys variants in α-galactosidase A protein confer stability loss in Fabry’s disease

Sudhan, M.; Janakiraman, V.; Patil, Rajesh B.; Oyouni, Atif Abdulwahab A.; Mufti, Ahmad H.; Ahmed, Shiek S. S. J.

doi:10.1080/07391102.2022.2148001

Cited by 2 publications

(2 citation statements)

References 40 publications

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“…In the same way, QMEAN evaluates the quality of a structure based on its physical and chemical properties. It then assigns the structure an overall quality score and compares it to the estimated QMEAN-scores of high-resolution experimental structures [ 22 ].…”

Section: Methodsmentioning

confidence: 99%

Effects of Bacterial Metabolites on the Wnt4 Protein in Dental-Pulp-Stem-Cells-Based Endodontic Pulpitis Treatment

et al. 2023

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Porphyromonas gingivalis is associated with endodontic pulpitis, causing damage to the dental pulp, leading to severe pain and a decline in quality of life. Regenerative pulp treatments using dental pulp stem cells (DPSCs) can be hindered by interactions between DPSCs and the infecting bacteria. The protein WNT family member 4 (Wnt4) plays a critical role in the differentiation of DPSCs and the regeneration of odontogenic tissue. However, the specific influence of P. gingivalis on Wnt4 remains unclear. In this study, we employed a computational approach to investigate the underlying mechanisms through which P. gingivalis-produced metabolites inhibit the Wnt4 protein, thereby diminishing the regenerative potential and therapeutic efficacy of odontogenic tissue. Among the metabolites examined, C29H46N7O18P3S−4 exhibited the strongest inhibitory effect on the Wnt4 protein, as evidenced by the lowest binding energy score of −6782 kcal/mol. Molecular dynamic simulation trajectories revealed that the binding of C29H46N7O18P3S−4 significantly altered the structural dynamics and stability of the Wnt4 protein. These alterations in protein trajectories may have implications for the molecular function of Wnt4 and its associated pathways. Overall, our findings shed light on the inhibitory impact of P. gingivalis-produced metabolites on the Wnt4 protein. Further in vitro, in vivo, and clinical studies are necessary to validate and expand upon our findings.

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Section: Methodsmentioning

confidence: 99%

Effects of Bacterial Metabolites on the Wnt4 Protein in Dental-Pulp-Stem-Cells-Based Endodontic Pulpitis Treatment

et al. 2023

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“…Unfortunately, this is often not done for subjects born with this variant [13][14][15] . The cause of the large individual variability in residual enzyme activity of some GLA variants has not yet been established.…”

Section: Phenotypic Categorization Of Gla Variantsmentioning

confidence: 99%

Investigating Fabry disease - some lessons learned

Schiffmann

2024

Rare Dis Orphan Drugs J

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Despite recent advances, there is still much to be learned about the pathogenesis of Fabry disease. The categorization of GLA gene missense mutations has been complicated by the fact that some missense variants may fall into more than one category. For instance, the A143T variant may cause late-onset Fabry disease in some subjects and not result in Fabry disease in others (pseudo-deficient). Efforts to mitigate the pathobiology of α-galactosidase A deficiency should differentiate between damaging (maladaptive) consequences and compensatory (adaptive) changes. Current therapy leaves a significant unmet need, especially concerning cardiovascular complications and cardiological clinical outcomes. Non-Fabry-specific therapy is necessary and quite beneficial and must be utilized. Its contribution should be considered when trying to assess the net effect of Fabry-specific therapy. Enzyme replacement therapy (ERT) can be administered to patients independently of their GLA genotype, as it slows the decline of kidney function in most patients if initiated sufficiently early in the disease course. Migalastat has better tissue penetration than ERT, but its usefulness is restricted to patients with amenable missense GLA variants. However, it is important to realize that in a substantial proportion of common amenable mutations, migalastat increases α-galactosidase A activity level beyond the disease threshold and thus eliminates the metabolic disturbance that is at the center of Fabry disease. Substrate reduction therapy and gene therapy approaches are being developed, but these therapeutic modalities have their own limitations and difficulties.

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Asn215Ser, Ala143Thr, and Arg112Cys variants in α-galactosidase A protein confer stability loss in Fabry’s disease

Cited by 2 publications

References 40 publications

Effects of Bacterial Metabolites on the Wnt4 Protein in Dental-Pulp-Stem-Cells-Based Endodontic Pulpitis Treatment

Effects of Bacterial Metabolites on the Wnt4 Protein in Dental-Pulp-Stem-Cells-Based Endodontic Pulpitis Treatment

Investigating Fabry disease - some lessons learned

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