The Selenoprotein Glutathione Peroxidase 4: From Molecular Mechanisms to Novel Therapeutic Opportunities
Abstract
:1. Introduction
2. Glutathione Peroxidase Family
2.1. The Origins of Glutathione Peroxidase
2.2. The Role of Elemental Selenium in Selenoproteins
2.3. The Biochemical Structure of Glutathione Peroxidase
2.4. General Mechanism of Glutathione Peroxidase
2.5. Substrate Specificity
2.6. Role of Oxidative Stress in Biology
2.7. Glutathione Peroxidase in Health and Diseases
3. Glutathione Peroxidase 4 in Biochemistry and Molecular Biology
3.1. The Origins of Glutathione Peroxidase 4
3.2. Clinical Relevance of Glutathione Peroxidase 4
3.3. Structure and Genetics of Glutathione Peroxidase 4
3.4. Enzymology and Kinetics of Glutathione Peroxidase 4 and GSH
3.5. Synthesis, Degradation, and Regulation of Glutathione Peroxidase 4
4. Glutathione Peroxidase 4 as a Chief Regulator of Ferroptosis
4.1. Overview of Ferroptosis
4.2. Molecular Mechanisms of Ferroptosis
4.3. Regulation of Ferroptosis through GPX4
4.4. Modulation of GPX4 to Probe Ferroptosis
4.5. GPX4, Ferroptosis, and Mitochondria
5. Conclusions and Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Mammalian GPX Type | Tissue Distribution | Cellular Localization | Primary Function | Biological Relevance/References |
---|---|---|---|---|
GPX-1 | Most abundant and ubiquitously expressed GPx. Highly distributed in the lungs, kidney, red blood cells, and liver. | Cytosol and mitochondria. | Reduces hydrogen peroxides in the cytoplasm at the expense of GSH. | Dampens phosphorylation of phosphatases [13], modulator of the insulin signaling pathway [14], acts in an antiapoptotic manner which can support tumor cell survival [15] |
GPX-2 | Gastrointestinal tract, endothelial cells (particularly malignant tissues and pluripotent stem cells). | Cytosol | Reduces hydrogen peroxide. | Inhibits inflammation-induced carcinogenesis in the gut [13], but also promotes the growth of some cancers including bladder cancer [16,17,18] |
GPX-3 | Kidney, lung, heart, muscle. | Plasma | Reduces hydrogen peroxide using GSH, Trx, or Grx. | Deficiency facilitates platelet aggregation and is a risk factor for stroke [13]. Acts as a tumor suppressor in many cancers including lung cancer [19,20] |
GPX-4 | Widespread. Especially testis and spermatozoa kidney, followed by the liver, spleen, pancreas, heart, and brain. | Cytosol, Mitochondria, Plasma. | Reduces hydroperoxides from phospholipids and cholesterol. | Key regulator of ferroptosis [21,22]. Deficiency facilitates male infertility [23,24], Modulator of a rare genetic disorder called SSMD [25]. Implicated in several cancers including CCC and TNBC [26] |
GPX-5 | Testis, spermatozoa, liver, kidney. | Epididymis | Protects the membranes of spermatozoa from lipid peroxidation. | Deficiency, together with GPX4, decreases male fertility [27] |
GPX-6 | Embryos and adult olfactory epithelium. | n.d. | n.d. | Reduces the motor defects found in Huntington’s disease [28] |
GPX-7 | Endoplasmic reticulum | n.d. | Mild glutathione peroxidase activity. Senses ROS levels and transmits redox signals to other thiols. | Contributes to oxidative protein folding in the ER. [29,30] |
GPX-8 | Endoplasmic reticulum | n.d. | Mild glutathione peroxidase activity. Prevents endoplasmic reticulum oxidation and stress. | Contributes to oxidative protein folding in the ER. [29,30] |
Mammalian GPX Type | Peroxidic Residue | Uniprot Molecular Weight (kDa) | Structure Type | Human Wild-Type Crystal Structure (PDB Code) | Human Mutant Crystal Structure (PDB Code) | Reference (Uniprot Code) |
---|---|---|---|---|---|---|
GPX-1 | Selenocysteine | 22 | Homotetramer | n.d. | U46G (2F8A) | P07203 |
GPX-2 | Selenocysteine | 21.9 | Homotetramer | n.d. | U46C (2HE3) | P18283 |
GPX-3 | Selenocystine | 22.5 | Homotetramer | n.d. | U46G (2R37) | P22352 |
GPX-4 | Selenocysteine | 22 | Monomer | 6ElW | Many mutants (e.g., 7L81, 6HN3, 7L8K, etc.) | P36969 |
GPX-5 | Cysteine | 25.2 | Homotetramer | 213Y | n.d. | O75715 |
GPX-6 | Selenocysteine in Humans. Cysteine in rodents | 24.9 | Homotetramer | n.d. | n.d. | P59796 |
GPX-7 | Cysteine | 20.9 | Monomer | 2P31 | n.d. | Q96SL4 |
GPX-8 | Cysteine | 23.8 | Monomer | 3CYN | n.d. | Q8TED1 |
Compound | Mode of Action | PubChem CID |
---|---|---|
(1S,3R)-RSL3 | Covalently and irreversibly inhibits GPX4. RSL3 is potent but has poor ADME properties [123] | 1750826 |
DP12--DP19 | Not well characterized. Exhibits potency and ferroptosis hallmarks [22] | 5728915 |
Altretamine | GPX4 inhibitor [22] | 2123 26186195 |
DPI10 & ML210 | Nitroisoxazole moiety generates a nitrile oxide electrophile that may react with GPX4 [117] | 15945537 |
ML162 | Shares the same chloroacetamide moiety as RSL3 but is otherwise very structurally different. Likely to have different off-target effects [22] | 3689413 |
DPI17 & DPI18 | Exhibits potency and ferroptosis hallmarks. Likely to be a covalent GPX4 inhibitor [22] | 932617 |
JKE-1674, JKE-1716 & BSC144988 | Identical function as DPI10. Nitroisozazole moiety leads to a nitrile oxide electrophilic reaction with GPX4 [117] | 145865941 |
Withaferin A | Acts as a GPX4 inhibitor likely through its electrophilic groups [117] | 265237 |
Compound | Possible Mode of Action | PubChem CID |
---|---|---|
Erastin | Directly inhibits system Xc causing depletion of intracellular GSH, which normally works alongside GPX4 to suppress phospholipid hydroperoxide accumulation [120] | 11214940 |
Erastin Derivatives (Piperazine & Imidazole Ketone Erastin) | Same proposed mode of action as Erasin. These derivatives have improved ADME properties [22] | 72710858 & 91824786 |
RSL5 | Displays similar effects as Erastin and may have identical mechanisms, but this has not been experimentally verified [123] | 2863472 |
Sulfasalazine (FDA-approved drug) | Inhibits system Xc, which causes GSH depletion. Low potency and metabolically unstable in vivo [117] | 5339 |
Glutamate | Inhibits system Xc likely by inhibiting one of its kinase targets. May induce necrotic cell death at high concentrations [99] | 23672308 |
Diaryl-isoxazole | Non-competitive System Xc-inhibitor [117,124] | n.a |
Engineered human cyst(e)inase | Systemic Depletion of Cysteine [117,124] | n.a |
Tac-beclin1 | System Xc-inhibitor [117,124] | n.a |
Lanperisone (FDA-approved drug) | Inhibits cystine uptake, Causes GSH depletion [117,124] | 198707 |
Sorafenib | Inhibits system Xc, Causes GSH depletion. It also activates NRF2 against ferroptosis [22,121] | 216239 |
FINO2 and FIN56 | Does not directly target GPX4, system Xc, or CoQ10. Rather, it oxidizes iron which leads to the subsequent inactivation of GPX4 activity [124] | n.a |
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Weaver, K.; Skouta, R. The Selenoprotein Glutathione Peroxidase 4: From Molecular Mechanisms to Novel Therapeutic Opportunities. Biomedicines 2022, 10, 891. https://doi.org/10.3390/biomedicines10040891
Weaver K, Skouta R. The Selenoprotein Glutathione Peroxidase 4: From Molecular Mechanisms to Novel Therapeutic Opportunities. Biomedicines. 2022; 10(4):891. https://doi.org/10.3390/biomedicines10040891
Chicago/Turabian StyleWeaver, Kamari, and Rachid Skouta. 2022. "The Selenoprotein Glutathione Peroxidase 4: From Molecular Mechanisms to Novel Therapeutic Opportunities" Biomedicines 10, no. 4: 891. https://doi.org/10.3390/biomedicines10040891
APA StyleWeaver, K., & Skouta, R. (2022). The Selenoprotein Glutathione Peroxidase 4: From Molecular Mechanisms to Novel Therapeutic Opportunities. Biomedicines, 10(4), 891. https://doi.org/10.3390/biomedicines10040891