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Natural mutations of human XDH promote the nitrite (NO(2)(−))-reductase capacity of xanthine oxidoreductase: A novel mechanism to promote redox health?

Several rare genetic variations of human XDH have been shown to alter xanthine oxidoreductase (XOR) activity leading to impaired purine catabolism. However, XOR is a multi-functional enzyme that depending upon the environmental conditions also expresses oxidase activity leading to both O(2)(·-) and...

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Autores principales: Massimo, G., Khambata, R.S., Chapman, T., Birchall, K., Raimondi, C., Shabbir, A., Dyson, Nicki, Rathod, K.S., Borghi, C., Ahluwalia, A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10511815/
https://www.ncbi.nlm.nih.gov/pubmed/37713777
http://dx.doi.org/10.1016/j.redox.2023.102864
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author Massimo, G.
Khambata, R.S.
Chapman, T.
Birchall, K.
Raimondi, C.
Shabbir, A.
Dyson, Nicki
Rathod, K.S.
Borghi, C.
Ahluwalia, A.
author_facet Massimo, G.
Khambata, R.S.
Chapman, T.
Birchall, K.
Raimondi, C.
Shabbir, A.
Dyson, Nicki
Rathod, K.S.
Borghi, C.
Ahluwalia, A.
author_sort Massimo, G.
collection PubMed
description Several rare genetic variations of human XDH have been shown to alter xanthine oxidoreductase (XOR) activity leading to impaired purine catabolism. However, XOR is a multi-functional enzyme that depending upon the environmental conditions also expresses oxidase activity leading to both O(2)(·-) and H(2)O(2) and nitrite (NO(2)(−)) reductase activity leading to nitric oxide (·NO). Since these products express important, and often diametrically opposite, biological activity, consideration of the impact of XOR mutations in the context of each aspect of the biochemical activity of the enzyme is needed to determine the potential full impact of these variants. Herein, we show that known naturally occurring hXDH mutations do not have a uniform impact upon the biochemical activity of the enzyme in terms of uric acid (UA), reactive oxygen species (ROS) and nitric oxide ·NO formation. We show that the His1221Arg mutant, in the presence of xanthine, increases UA, O(2)(·-) and NO generation compared to the WT, whilst the Ile703Val increases UA and ·NO formation, but not O(2)(·-). We speculate that this change in the balance of activity of the enzyme is likely to endow those carrying these mutations with a harmful or protective influence over health that may explain the current equipoise underlying the perceived importance of XDH mutations. We also show that, in presence of inorganic NO(2)(−), XOR-driven O(2)(·-) production is substantially reduced. We suggest that targeting enzyme activity to enhance the NO(2)(−)-reductase profile in those carrying such mutations may provide novel therapeutic options, particularly in cardiovascular disease.
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spelling pubmed-105118152023-09-22 Natural mutations of human XDH promote the nitrite (NO(2)(−))-reductase capacity of xanthine oxidoreductase: A novel mechanism to promote redox health? Massimo, G. Khambata, R.S. Chapman, T. Birchall, K. Raimondi, C. Shabbir, A. Dyson, Nicki Rathod, K.S. Borghi, C. Ahluwalia, A. Redox Biol Research Paper Several rare genetic variations of human XDH have been shown to alter xanthine oxidoreductase (XOR) activity leading to impaired purine catabolism. However, XOR is a multi-functional enzyme that depending upon the environmental conditions also expresses oxidase activity leading to both O(2)(·-) and H(2)O(2) and nitrite (NO(2)(−)) reductase activity leading to nitric oxide (·NO). Since these products express important, and often diametrically opposite, biological activity, consideration of the impact of XOR mutations in the context of each aspect of the biochemical activity of the enzyme is needed to determine the potential full impact of these variants. Herein, we show that known naturally occurring hXDH mutations do not have a uniform impact upon the biochemical activity of the enzyme in terms of uric acid (UA), reactive oxygen species (ROS) and nitric oxide ·NO formation. We show that the His1221Arg mutant, in the presence of xanthine, increases UA, O(2)(·-) and NO generation compared to the WT, whilst the Ile703Val increases UA and ·NO formation, but not O(2)(·-). We speculate that this change in the balance of activity of the enzyme is likely to endow those carrying these mutations with a harmful or protective influence over health that may explain the current equipoise underlying the perceived importance of XDH mutations. We also show that, in presence of inorganic NO(2)(−), XOR-driven O(2)(·-) production is substantially reduced. We suggest that targeting enzyme activity to enhance the NO(2)(−)-reductase profile in those carrying such mutations may provide novel therapeutic options, particularly in cardiovascular disease. Elsevier 2023-09-04 /pmc/articles/PMC10511815/ /pubmed/37713777 http://dx.doi.org/10.1016/j.redox.2023.102864 Text en © 2023 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Paper
Massimo, G.
Khambata, R.S.
Chapman, T.
Birchall, K.
Raimondi, C.
Shabbir, A.
Dyson, Nicki
Rathod, K.S.
Borghi, C.
Ahluwalia, A.
Natural mutations of human XDH promote the nitrite (NO(2)(−))-reductase capacity of xanthine oxidoreductase: A novel mechanism to promote redox health?
title Natural mutations of human XDH promote the nitrite (NO(2)(−))-reductase capacity of xanthine oxidoreductase: A novel mechanism to promote redox health?
title_full Natural mutations of human XDH promote the nitrite (NO(2)(−))-reductase capacity of xanthine oxidoreductase: A novel mechanism to promote redox health?
title_fullStr Natural mutations of human XDH promote the nitrite (NO(2)(−))-reductase capacity of xanthine oxidoreductase: A novel mechanism to promote redox health?
title_full_unstemmed Natural mutations of human XDH promote the nitrite (NO(2)(−))-reductase capacity of xanthine oxidoreductase: A novel mechanism to promote redox health?
title_short Natural mutations of human XDH promote the nitrite (NO(2)(−))-reductase capacity of xanthine oxidoreductase: A novel mechanism to promote redox health?
title_sort natural mutations of human xdh promote the nitrite (no(2)(−))-reductase capacity of xanthine oxidoreductase: a novel mechanism to promote redox health?
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10511815/
https://www.ncbi.nlm.nih.gov/pubmed/37713777
http://dx.doi.org/10.1016/j.redox.2023.102864
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