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Molecular analysis and essentiality of Aro1 shikimate biosynthesis multi-enzyme in Candida albicans

In the human fungal pathogen Candida albicans, ARO1 encodes an essential multi-enzyme that catalyses consecutive steps in the shikimate pathway for biosynthesis of chorismate, a precursor to folate and the aromatic amino acids. We obtained the first molecular image of C. albicans Aro1 that reveals t...

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Autores principales: Stogios, Peter J, Liston, Sean D, Semper, Cameron, Quade, Bradley, Michalska, Karolina, Evdokimova, Elena, Ram, Shane, Otwinowski, Zbyszek, Borek, Dominika, Cowen, Leah E, Savchenko, Alexei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Life Science Alliance LLC 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9074039/
https://www.ncbi.nlm.nih.gov/pubmed/35512834
http://dx.doi.org/10.26508/lsa.202101358
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author Stogios, Peter J
Liston, Sean D
Semper, Cameron
Quade, Bradley
Michalska, Karolina
Evdokimova, Elena
Ram, Shane
Otwinowski, Zbyszek
Borek, Dominika
Cowen, Leah E
Savchenko, Alexei
author_facet Stogios, Peter J
Liston, Sean D
Semper, Cameron
Quade, Bradley
Michalska, Karolina
Evdokimova, Elena
Ram, Shane
Otwinowski, Zbyszek
Borek, Dominika
Cowen, Leah E
Savchenko, Alexei
author_sort Stogios, Peter J
collection PubMed
description In the human fungal pathogen Candida albicans, ARO1 encodes an essential multi-enzyme that catalyses consecutive steps in the shikimate pathway for biosynthesis of chorismate, a precursor to folate and the aromatic amino acids. We obtained the first molecular image of C. albicans Aro1 that reveals the architecture of all five enzymatic domains and their arrangement in the context of the full-length protein. Aro1 forms a flexible dimer allowing relative autonomy of enzymatic function of the individual domains. Our activity and in cellulo data suggest that only four of Aro1’s enzymatic domains are functional and essential for viability of C. albicans, whereas the 3-dehydroquinate dehydratase (DHQase) domain is inactive because of active site substitutions. We further demonstrate that in C. albicans, the type II DHQase Dqd1 can compensate for the inactive DHQase domain of Aro1, suggesting an unrecognized essential role for this enzyme in shikimate biosynthesis. In contrast, in Candida glabrata and Candida parapsilosis, which do not encode a Dqd1 homolog, Aro1 DHQase domains are enzymatically active, highlighting diversity across Candida species.
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spelling pubmed-90740392022-05-21 Molecular analysis and essentiality of Aro1 shikimate biosynthesis multi-enzyme in Candida albicans Stogios, Peter J Liston, Sean D Semper, Cameron Quade, Bradley Michalska, Karolina Evdokimova, Elena Ram, Shane Otwinowski, Zbyszek Borek, Dominika Cowen, Leah E Savchenko, Alexei Life Sci Alliance Research Articles In the human fungal pathogen Candida albicans, ARO1 encodes an essential multi-enzyme that catalyses consecutive steps in the shikimate pathway for biosynthesis of chorismate, a precursor to folate and the aromatic amino acids. We obtained the first molecular image of C. albicans Aro1 that reveals the architecture of all five enzymatic domains and their arrangement in the context of the full-length protein. Aro1 forms a flexible dimer allowing relative autonomy of enzymatic function of the individual domains. Our activity and in cellulo data suggest that only four of Aro1’s enzymatic domains are functional and essential for viability of C. albicans, whereas the 3-dehydroquinate dehydratase (DHQase) domain is inactive because of active site substitutions. We further demonstrate that in C. albicans, the type II DHQase Dqd1 can compensate for the inactive DHQase domain of Aro1, suggesting an unrecognized essential role for this enzyme in shikimate biosynthesis. In contrast, in Candida glabrata and Candida parapsilosis, which do not encode a Dqd1 homolog, Aro1 DHQase domains are enzymatically active, highlighting diversity across Candida species. Life Science Alliance LLC 2022-05-05 /pmc/articles/PMC9074039/ /pubmed/35512834 http://dx.doi.org/10.26508/lsa.202101358 Text en © 2022 Stogios et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Articles
Stogios, Peter J
Liston, Sean D
Semper, Cameron
Quade, Bradley
Michalska, Karolina
Evdokimova, Elena
Ram, Shane
Otwinowski, Zbyszek
Borek, Dominika
Cowen, Leah E
Savchenko, Alexei
Molecular analysis and essentiality of Aro1 shikimate biosynthesis multi-enzyme in Candida albicans
title Molecular analysis and essentiality of Aro1 shikimate biosynthesis multi-enzyme in Candida albicans
title_full Molecular analysis and essentiality of Aro1 shikimate biosynthesis multi-enzyme in Candida albicans
title_fullStr Molecular analysis and essentiality of Aro1 shikimate biosynthesis multi-enzyme in Candida albicans
title_full_unstemmed Molecular analysis and essentiality of Aro1 shikimate biosynthesis multi-enzyme in Candida albicans
title_short Molecular analysis and essentiality of Aro1 shikimate biosynthesis multi-enzyme in Candida albicans
title_sort molecular analysis and essentiality of aro1 shikimate biosynthesis multi-enzyme in candida albicans
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9074039/
https://www.ncbi.nlm.nih.gov/pubmed/35512834
http://dx.doi.org/10.26508/lsa.202101358
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