Alkaptonuria (AKU), a rare genetic disorder, is characterized by the accumulation of homogentisic acid (HGA) in organs, which occurs because the homogentisate 1,2-dioxygenase (HGD) enzyme is not functional due to gene variants. Over time, HGA oxidation and accumulation cause the formation of the ochronotic pigment, a deposit that provokes tissue degeneration and organ malfunction. Here, we report a comprehensive review of the variants so far reported, the structural studies on the molecular consequences of protein stability and interaction, and molecular simulations for pharmacological chaperones as protein rescuers. Moreover, evidence accumulated so far in alkaptonuria research will be re-proposed as the bases for a precision medicine approach in a rare disease.

Bernini, A., Spiga, O., Santucci, A. (2023). Structure-function relationship of homogentisate 1,2-dioxygenase: understanding the genotype-phenotype correlations in the rare genetic disease Alkaptonuria. CURRENT PROTEIN & PEPTIDE SCIENCE, 24(5), 380-392 [10.2174/1389203724666230307104135].

Structure-function relationship of homogentisate 1,2-dioxygenase: understanding the genotype-phenotype correlations in the rare genetic disease Alkaptonuria

Andrea Bernini;Ottavia Spiga;Annalisa Santucci
2023-01-01

Abstract

Alkaptonuria (AKU), a rare genetic disorder, is characterized by the accumulation of homogentisic acid (HGA) in organs, which occurs because the homogentisate 1,2-dioxygenase (HGD) enzyme is not functional due to gene variants. Over time, HGA oxidation and accumulation cause the formation of the ochronotic pigment, a deposit that provokes tissue degeneration and organ malfunction. Here, we report a comprehensive review of the variants so far reported, the structural studies on the molecular consequences of protein stability and interaction, and molecular simulations for pharmacological chaperones as protein rescuers. Moreover, evidence accumulated so far in alkaptonuria research will be re-proposed as the bases for a precision medicine approach in a rare disease.
2023
Bernini, A., Spiga, O., Santucci, A. (2023). Structure-function relationship of homogentisate 1,2-dioxygenase: understanding the genotype-phenotype correlations in the rare genetic disease Alkaptonuria. CURRENT PROTEIN & PEPTIDE SCIENCE, 24(5), 380-392 [10.2174/1389203724666230307104135].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/1261123