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Crystal structure of human persulfide dioxygenase: structural basis of ethylmalonic encephalopathy
The ethylmalonic encephalopathy protein 1 (ETHE1) catalyses the oxygen-dependent oxidation of glutathione persulfide (GSSH) to give persulfite and glutathione. Mutations to the hETHE1 gene compromise sulfide metabolism leading to the genetic disease ethylmalonic encephalopathy. hETHE1 is a mono-iron...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Oxford University Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383860/ https://www.ncbi.nlm.nih.gov/pubmed/25596185 http://dx.doi.org/10.1093/hmg/ddv007 |
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author | Pettinati, Ilaria Brem, Jürgen McDonough, Michael A. Schofield, Christopher J. |
author_facet | Pettinati, Ilaria Brem, Jürgen McDonough, Michael A. Schofield, Christopher J. |
author_sort | Pettinati, Ilaria |
collection | PubMed |
description | The ethylmalonic encephalopathy protein 1 (ETHE1) catalyses the oxygen-dependent oxidation of glutathione persulfide (GSSH) to give persulfite and glutathione. Mutations to the hETHE1 gene compromise sulfide metabolism leading to the genetic disease ethylmalonic encephalopathy. hETHE1 is a mono-iron binding member of the metallo-β-lactamase (MBL) fold superfamily. We report crystallographic analysis of hETHE1 in complex with iron to 2.6 Å resolution. hETHE1 contains an αββα MBL-fold, which supports metal-binding by the side chains of an aspartate and two histidine residues; three water molecules complete octahedral coordination of the iron. The iron binding hETHE1 enzyme is related to the ‘classical’ di-zinc binding MBL hydrolases involved in antibiotic resistance, but has distinctive features. The histidine and aspartate residues involved in iron-binding in ETHE1, occupy similar positions to those observed across both the zinc 1 and zinc 2 binding sites in classical MBLs. The active site of hETHE1 is very similar to an ETHE1-like enzyme from Arabidopsis thaliana (60% sequence identity). A channel leading to the active site is sufficiently large to accommodate a GSSH substrate. Some of the observed hETHE1 clinical mutations cluster in the active site region. The structure will serve as a basis for detailed functional and mechanistic studies on ETHE1 and will be useful in the development of selective MBL inhibitors. |
format | Online Article Text |
id | pubmed-4383860 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-43838602015-04-08 Crystal structure of human persulfide dioxygenase: structural basis of ethylmalonic encephalopathy Pettinati, Ilaria Brem, Jürgen McDonough, Michael A. Schofield, Christopher J. Hum Mol Genet Articles The ethylmalonic encephalopathy protein 1 (ETHE1) catalyses the oxygen-dependent oxidation of glutathione persulfide (GSSH) to give persulfite and glutathione. Mutations to the hETHE1 gene compromise sulfide metabolism leading to the genetic disease ethylmalonic encephalopathy. hETHE1 is a mono-iron binding member of the metallo-β-lactamase (MBL) fold superfamily. We report crystallographic analysis of hETHE1 in complex with iron to 2.6 Å resolution. hETHE1 contains an αββα MBL-fold, which supports metal-binding by the side chains of an aspartate and two histidine residues; three water molecules complete octahedral coordination of the iron. The iron binding hETHE1 enzyme is related to the ‘classical’ di-zinc binding MBL hydrolases involved in antibiotic resistance, but has distinctive features. The histidine and aspartate residues involved in iron-binding in ETHE1, occupy similar positions to those observed across both the zinc 1 and zinc 2 binding sites in classical MBLs. The active site of hETHE1 is very similar to an ETHE1-like enzyme from Arabidopsis thaliana (60% sequence identity). A channel leading to the active site is sufficiently large to accommodate a GSSH substrate. Some of the observed hETHE1 clinical mutations cluster in the active site region. The structure will serve as a basis for detailed functional and mechanistic studies on ETHE1 and will be useful in the development of selective MBL inhibitors. Oxford University Press 2015-05-01 2015-01-16 /pmc/articles/PMC4383860/ /pubmed/25596185 http://dx.doi.org/10.1093/hmg/ddv007 Text en © The Author 2015. Published by Oxford University Press. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Pettinati, Ilaria Brem, Jürgen McDonough, Michael A. Schofield, Christopher J. Crystal structure of human persulfide dioxygenase: structural basis of ethylmalonic encephalopathy |
title | Crystal structure of human persulfide dioxygenase: structural basis of ethylmalonic encephalopathy |
title_full | Crystal structure of human persulfide dioxygenase: structural basis of ethylmalonic encephalopathy |
title_fullStr | Crystal structure of human persulfide dioxygenase: structural basis of ethylmalonic encephalopathy |
title_full_unstemmed | Crystal structure of human persulfide dioxygenase: structural basis of ethylmalonic encephalopathy |
title_short | Crystal structure of human persulfide dioxygenase: structural basis of ethylmalonic encephalopathy |
title_sort | crystal structure of human persulfide dioxygenase: structural basis of ethylmalonic encephalopathy |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383860/ https://www.ncbi.nlm.nih.gov/pubmed/25596185 http://dx.doi.org/10.1093/hmg/ddv007 |
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