Glutathione and the intracellular labile heme pool
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Glutathione and the intracellular labile heme pool Rosemary O’Keeffe . Gladys Oluyemisi Latunde-Dada . Yu-Lin Chen . Xiaole L. Kong . Agostino Cilibrizzi . Robert C. Hider
Received: 3 July 2020 / Accepted: 24 November 2020 Ó The Author(s) 2020
Abstract One candidate for the cytosolic labile iron pool is iron(II)glutathione. There is also a widely held opinion that an equivalent cytosolic labile heme pool exists and that this pool is important for the intracellular transfer of heme. Here we describe a study designed to characterise conjugates that form between heme and glutathione. In contrast to hydrated iron(II), heme reacts with glutathione, under aerobic conditions, to form the stable hematin–glutathione complex, which contains iron(III). Thus, glutathione is clearly not the cytosolic ligand for heme, indeed we demonstrate that the rate of heme degradation is enhanced in the presence of glutathione. We suggest that the concentration of heme in the cytosol is extremely low and that intracellular heme transfer occurs via intracellular membrane structures. Should any heme inadvertently escape into the cytosol, it would be rapidly R. O’Keeffe Y.-L. Chen X. L. Kong A. Cilibrizzi (&) R. C. Hider (&) Institute of Pharmaceutical Science, King’s College London, London, UK e-mail: [email protected] R. C. Hider e-mail: [email protected] R. O’Keeffe DMPK/ADME Research, Oncology R & D, Astrazenca, Cambridge, UK G. O. Latunde-Dada Department of Nutrition, King’s College London, London, UK
conjugated to glutathione thereby protecting the cell from the toxic effects of heme. Keywords
Heme Hematin Glutathione
Introduction The labile iron pool, first proposed by Greenberg and Wintrope (1946) plays an essential role in supplying iron to iron–dependent enzymes and to mitochondria for heme and iron–sulfur cluster synthesis (Hider and Kong 2011). On the basis of a range of biochemical and thermodynamic arguments, Williams (1982) suggested that the oxidation state of cytosolic iron is iron(II) and that its concentration falls in the range 10-7–10-6 M, a proposal supported by fluorescence studies (Breuer et al 1995). Evidence has been presented for the nature of this labile iron pool as being iron(II)glutathione (Hider and Kong 2011), GSH acting as a buffer for iron(II), maintaining iron in the reduced state. An iron chaperone (PCBP–1) has been demonstrated to only donate iron for cytosolic [2Fe–2S] cluster assembly as a PCBP–1–Fe–GSH complex, no transfer of iron occurring in the absence of GSH. PCBP–1 apparently requires GSH to bind iron (Patel et al 2019). A labile heme cytosolic pool is also reported to exist in mammalian cells (Shviro and Shaklai 1987;
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Biometals
Sahini et al 1996) and as the axial iron coordination sites of heme are unoccupied, it is conceivable that GSH coordinates iron at one of these sites. Directly relating to this suggestion is the finding of Shviro and Shaklai (1987) that hematin binds GSH and that the 1:1 species is the do
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