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A molecular spectroscopy approach for the investigation of early phase ochronotic pigment development in Alkaptonuria

Alkaptonuria (AKU), a rare genetic disorder, is characterized by the accumulation of homogentisic acid (HGA) in organs due to a deficiency in functional levels of the enzyme homogentisate 1,2-dioxygenase (HGD), required for the breakdown of HGA, because of mutations in the HGD gene. Over time, HGA a...

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Autores principales: Bernini, Andrea, Petricci, Elena, Atrei, Andrea, Baratto, Maria Camilla, Manetti, Fabrizio, Santucci, Annalisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8605014/
https://www.ncbi.nlm.nih.gov/pubmed/34799606
http://dx.doi.org/10.1038/s41598-021-01670-z
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author Bernini, Andrea
Petricci, Elena
Atrei, Andrea
Baratto, Maria Camilla
Manetti, Fabrizio
Santucci, Annalisa
author_facet Bernini, Andrea
Petricci, Elena
Atrei, Andrea
Baratto, Maria Camilla
Manetti, Fabrizio
Santucci, Annalisa
author_sort Bernini, Andrea
collection PubMed
description Alkaptonuria (AKU), a rare genetic disorder, is characterized by the accumulation of homogentisic acid (HGA) in organs due to a deficiency in functional levels of the enzyme homogentisate 1,2-dioxygenase (HGD), required for the breakdown of HGA, because of mutations in the HGD gene. Over time, HGA accumulation causes the formation of the ochronotic pigment, a dark deposit that leads to tissue degeneration and organ malfunction. Such behaviour can be observed also in vitro for HGA solutions or HGA-containing biofluids (e.g. urine from AKU patients) upon alkalinisation, although a comparison at the molecular level between the laboratory and the physiological conditions is lacking. Indeed, independently from the conditions, such process is usually explained with the formation of 1,4-benzoquinone acetic acid (BQA) as the product of HGA chemical oxidation, mostly based on structural similarity between HGA and hydroquinone that is known to be oxidized to the corresponding para-benzoquinone. To test such correlation, a comprehensive, comparative investigation on HGA and BQA chemical behaviours was carried out by a combined approach of spectroscopic techniques (UV spectrometry, Nuclear Magnetic Resonance, Electron Paramagnetic Resonance, Dynamic Light Scattering) under acid/base titration both in solution and in biofluids. New insights on the process leading from HGA to ochronotic pigment have been obtained, spotting out the central role of radical species as intermediates not reported so far. Such evidence opens the way for molecular investigation of HGA fate in cells and tissue aiming to find new targets for Alkaptonuria therapy.
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spelling pubmed-86050142021-11-22 A molecular spectroscopy approach for the investigation of early phase ochronotic pigment development in Alkaptonuria Bernini, Andrea Petricci, Elena Atrei, Andrea Baratto, Maria Camilla Manetti, Fabrizio Santucci, Annalisa Sci Rep Article Alkaptonuria (AKU), a rare genetic disorder, is characterized by the accumulation of homogentisic acid (HGA) in organs due to a deficiency in functional levels of the enzyme homogentisate 1,2-dioxygenase (HGD), required for the breakdown of HGA, because of mutations in the HGD gene. Over time, HGA accumulation causes the formation of the ochronotic pigment, a dark deposit that leads to tissue degeneration and organ malfunction. Such behaviour can be observed also in vitro for HGA solutions or HGA-containing biofluids (e.g. urine from AKU patients) upon alkalinisation, although a comparison at the molecular level between the laboratory and the physiological conditions is lacking. Indeed, independently from the conditions, such process is usually explained with the formation of 1,4-benzoquinone acetic acid (BQA) as the product of HGA chemical oxidation, mostly based on structural similarity between HGA and hydroquinone that is known to be oxidized to the corresponding para-benzoquinone. To test such correlation, a comprehensive, comparative investigation on HGA and BQA chemical behaviours was carried out by a combined approach of spectroscopic techniques (UV spectrometry, Nuclear Magnetic Resonance, Electron Paramagnetic Resonance, Dynamic Light Scattering) under acid/base titration both in solution and in biofluids. New insights on the process leading from HGA to ochronotic pigment have been obtained, spotting out the central role of radical species as intermediates not reported so far. Such evidence opens the way for molecular investigation of HGA fate in cells and tissue aiming to find new targets for Alkaptonuria therapy. Nature Publishing Group UK 2021-11-19 /pmc/articles/PMC8605014/ /pubmed/34799606 http://dx.doi.org/10.1038/s41598-021-01670-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Bernini, Andrea
Petricci, Elena
Atrei, Andrea
Baratto, Maria Camilla
Manetti, Fabrizio
Santucci, Annalisa
A molecular spectroscopy approach for the investigation of early phase ochronotic pigment development in Alkaptonuria
title A molecular spectroscopy approach for the investigation of early phase ochronotic pigment development in Alkaptonuria
title_full A molecular spectroscopy approach for the investigation of early phase ochronotic pigment development in Alkaptonuria
title_fullStr A molecular spectroscopy approach for the investigation of early phase ochronotic pigment development in Alkaptonuria
title_full_unstemmed A molecular spectroscopy approach for the investigation of early phase ochronotic pigment development in Alkaptonuria
title_short A molecular spectroscopy approach for the investigation of early phase ochronotic pigment development in Alkaptonuria
title_sort molecular spectroscopy approach for the investigation of early phase ochronotic pigment development in alkaptonuria
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8605014/
https://www.ncbi.nlm.nih.gov/pubmed/34799606
http://dx.doi.org/10.1038/s41598-021-01670-z
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