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

Abstract 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 ti...

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Autores principales:	Andrea Bernini, Elena Petricci, Andrea Atrei, Maria Camilla Baratto, Fabrizio Manetti, Annalisa Santucci
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/67404596870e443d8436200fe91b2752
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spelling	oai:doaj.org-article:67404596870e443d8436200fe91b27522021-11-21T12:20:03ZA molecular spectroscopy approach for the investigation of early phase ochronotic pigment development in Alkaptonuria10.1038/s41598-021-01670-z2045-2322https://doaj.org/article/67404596870e443d8436200fe91b27522021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-01670-zhttps://doaj.org/toc/2045-2322Abstract 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.Andrea BerniniElena PetricciAndrea AtreiMaria Camilla BarattoFabrizio ManettiAnnalisa SantucciNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Andrea Bernini Elena Petricci Andrea Atrei Maria Camilla Baratto Fabrizio Manetti Annalisa Santucci A molecular spectroscopy approach for the investigation of early phase ochronotic pigment development in Alkaptonuria
description	Abstract 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.
format	article
author	Andrea Bernini Elena Petricci Andrea Atrei Maria Camilla Baratto Fabrizio Manetti Annalisa Santucci
author_facet	Andrea Bernini Elena Petricci Andrea Atrei Maria Camilla Baratto Fabrizio Manetti Annalisa Santucci
author_sort	Andrea Bernini
title	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_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_sort	molecular spectroscopy approach for the investigation of early phase ochronotic pigment development in alkaptonuria
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/67404596870e443d8436200fe91b2752
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A molecular spectroscopy approach for the investigation of early phase ochronotic pigment development in Alkaptonuria

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