Cardwell, P. A., Del Moro, C., Murphy, M. P., Lapthorn, A. J. and Hartley, R. C. (2024) Human mitochondrial glutathione transferases: Kinetic parameters and accommodation of a mitochondria-targeting group in substrates. Bioorganic and Medicinal Chemistry, (doi: 10.1016/j.bmc.2024.117712) (In Press)
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Abstract
Glutathione-S-transferases are key to the cellular detoxification of xenobiotics and products of oxidative damage. GSTs catalyse the reaction of glutathione (GSH) with electrophiles to form stable thioether adducts. GSTK1-1 is the main GST isoform in the mitochondrial matrix, but the GSTA1-1 and GSTA4-4 isoforms are also thought to be in the mitochondria with their distribution altering in transformed cells, thus potentially providing a cancer specific target. A mitochondria-targeted version of the GST substrate 1-chloro-2,4-dinitrobenzene (CDNB), MitoCDNB, has been used to manipulate the mitochondrial GSH pool. To finesse this approach to target particular GST isoforms in the context of cancer, here we have determined the kcat/Km for the human isoforms of GSTK1-1, GSTA1-1 and GSTA4-4 with respect to GSH and CDNB. We show how the rate of the GST-catalysed reaction between GSH and CDNB analogues can be modified by both the electron withdrawing substituents, and by the position of the mitochondria-targeting triphenylphosphonium on the chlorobenzene ring to tune the activity of mitochondria-targeted substrates. These findings can now be exploited to selectively disrupt the mitochondrial GSH pools of cancer cells expressing particular GST isoforms.
| Item Type: | Articles |
|---|---|
| Additional Information: | This research was funded in part by a Wellcome Trust Investigator award to RCH (220257/B/20/Z). Work in the MPM lab is supported by the Medical Research Council UK (MC_UU_00028/4) and by a Wellcome Trust Investigator award (220257/Z/20/Z). PAC's PhD studentship was supported by the Engineering and Physical Sciences Research Council (EP/R513222/1). |
| Keywords: | Glutathione-S-transferase, glutathione, mitochondria, oxidative stress, cancer. |
| Status: | In Press |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Lapthorn, Dr Adrian and Cardwell, Patrick and Hartley, Professor Richard and del moro, carlo |
| Authors: | Cardwell, P. A., Del Moro, C., Murphy, M. P., Lapthorn, A. J., and Hartley, R. C. |
| College/School: | College of Science and Engineering > School of Chemistry |
| Journal Name: | Bioorganic and Medicinal Chemistry |
| Publisher: | Elsevier |
| ISSN: | 0968-0896 |
| ISSN (Online): | 1464-3391 |
| Published Online: | 03 April 2024 |
| Copyright Holders: | Copyright © 2024 The Authors |
| First Published: | First published in Bioorganic and Medicinal Chemistry 2024 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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