Staphylococcus aureus haem biosynthesis and acquisition pathways are linked through haem monooxygenase IsdG

Videira, Marco A. M., Lobo, Susana A. L., Silva, Liliana S. O., Palmer, David J., Warren, Martin J. ORCID:, Prieto, Manuel, Coutinho, Ana, Sousa, Filipa L., Fernandes, Fábio and Saraiva, Lígia M. (2018) Staphylococcus aureus haem biosynthesis and acquisition pathways are linked through haem monooxygenase IsdG. Molecular Microbiology, 109 (3). pp. 385-400. ISSN 0950-382X

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Haem is an essential cofactor in central metabolic pathways in the vast majority of living systems. Prokaryotes acquire haem via haem biosynthesis pathways, and some also utilize haem uptake systems, yet it remains unclear how they balance haem requirements with the paradox that free haem is toxic. Here, using the model pathogen Staphylococcus aureus, we report that IsdG, one of two haem oxygenase enzymes in the haem uptake system, inhibits the formation of haem via the internal haem biosynthesis route. More specifically, we show that IsdG decreases the activity of ferrochelatase and that the two proteins interact both in vitro and in vivo. Further, a bioinformatics analysis reveals that a significant number of haem biosynthesis pathway containing organisms possess an IsdG-homologue and that those with both biosynthesis and uptake systems have at least two haem oxygenases. We conclude that IsdG-like proteins control intracellular haem levels by coupling the two pathways. IsdG is thus a target for the treatment of S. aureusinfections.

Item Type: Article
Additional Information: Funding Information: We are grateful to Mark O’Brian (University of Buffalo), Mariana Pinho (Instituto Tecnologia Química e Biológica António Xavier) and Simon Foster (University of Sheffield) for their generous gift of the ΔvisA strain, pBCB and pWhiteWalker plamids, respectively. We also thank Patrícia Ferreira for technical support. This work was financially supported by: Project LISBOA-01-0145-FEDER-007660 (Microbiologia Molecular, Estrutural e Celular) (LMS) funded by FEDER funds through COMPETE2020 - Programa Operacional Competitividade e Internacionalização (POCI), PPBI-POCI-01-0145-FEDER-022122 (FF) and by national funds through FCT - Fundação para a Ciência e a Tecnologia- for project PTDC/BBB-BQB/5069/2014 and grants SFRH/BD/95912/2013 (MAMV) and SFRH/BD/118545/2016 (LSOS). Grant WWTF (VRG15-007) (FS) is also acknowledged. Publisher Copyright: © 2018 John Wiley & Sons Ltd
Uncontrolled Keywords: microbiology,molecular biology ,/dk/atira/pure/subjectarea/asjc/2400/2404
Faculty \ School: Faculty of Science
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Depositing User: LivePure Connector
Date Deposited: 20 Sep 2022 14:30
Last Modified: 24 Oct 2022 06:52
DOI: 10.1111/mmi.14060

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