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2. The Fate of Intracellular Metal Ions in Microbes

Author

Loutet, Slade A., primary, Chan, Anson C. K., additional, Kobylarz, Marek J., additional, Verstraete, Meghan M., additional, Pfaffen, Stephanie, additional, Ye, Bin, additional, Arrieta, Angel L., additional, and Murphy, Michael E. P., additional

Published
2015
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3. IruO Uses an FAD Semiquinone Intermediate for Iron-Siderophore Reduction

Author

Kobylarz, Marek J., Heieis, Graham, Loutet, Slade A., and Murphy, Michael E. P.

Abstract

Many pathogenic bacteria including Staphylococcus aureus use iron-chelating siderophores to acquire iron. IruO, an FAD-containing NADPH-dependent reductase from S. aureus, functions as a reductase for IsdG and IsdI, two paralogous heme degrading enzymes. Also, the gene encoding for IruO was shown to be required for growth of S. aureus on hydroxamate siderophores as a sole iron source. Here, we show that IruO binds the hydroxamate-type siderophores desferrioxamine B and ferrichrome A with low micromolar affinity and in the presence of NADPH, Fe(II) was released. Steady-state kinetics of Fe(II) release provides kcat/Km values in the range of 600 to 7000 M-¹s-¹ for these siderophores supporting a role for IruO as a siderophore reductase in iron utilization. Crystal structures of IruO were solved in two distinct conformational states mediated by the formation of an intramolecular disulfide bond. A putative siderophore binding site was identified adjacent to the FAD cofactor. This site is partly occluded in the oxidized IruO structure consistent with this form being less active than reduced IruO. This reduction in activity could have a physiological role to limit iron release under oxidative stress conditions. Visible spectroscopy of anaerobically reduced IruO showed that the reaction proceeds by a single electron transfer mechanism through an FAD semiquinone intermediate. From the data a model for single electron siderophore reduction by IruO using NADPH is described.

Published
2021
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4. An iron-dependent metabolic vulnerability underlies VPS34-dependence in RKO cancer cells

Author

Kobylarz, Marek J., primary, Goodwin, Jonathan M., additional, Kang, Zhao B., additional, Annand, John W., additional, Hevi, Sarah, additional, O’Mahony, Ellen, additional, McAllister, Gregory, additional, Reece-Hoyes, John, additional, Wang, Qiong, additional, Alford, John, additional, Russ, Carsten, additional, Lindeman, Alicia, additional, Beibel, Martin, additional, Roma, Guglielmo, additional, Carbone, Walter, additional, Knehr, Judith, additional, Loureiro, Joseph, additional, Antczak, Christophe, additional, Wiederschain, Dmitri, additional, Murphy, Leon O., additional, Menon, Suchithra, additional, and Nyfeler, Beat, additional

Published
2020
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12. The Fate of Intracellular Metal Ions in Microbes

Author

Loutet SA, Chan ACK, Kobylarz MJ, Verstraete MM, Pfaffen S, Ye B, Arrieta AL, Murphy MEP, Nriagu JO, and Skaar EP

Abstract

Metals are essential for all microorganisms as they are required as cofactors of enzymes that mediate metabolic processes that are indispensable for cellular energy production and growth. Some metals, such as zinc, are readily bound and serve as key structural elements of many macromolecules. Thus, to grow, microorganisms have an essential quota for several metals. The catalytic and other chemical properties of metals that microorganisms value create issues for metal management. Due to their high affinity for amino acids and their reactive nature, uptake, intracellular transport, and storage of metals are mediated by tightly regulated proteins. Protein chaperones function to supply some specific metals to sites of utilization and, in some cases, storage. In particular, iron is difficult to acquire and is stored as a mineral in protein nanocages. Other metals, when present in excess, induce the expression of export systems to maintain a defined intracellular concentration of readily exchangeable metal., (© 2015 Massachusetts Institute of Technology and the Frankfurt Institute for Advanced Studies.)

Published
2015

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