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Review
. 2021 Sep 24;26(19):5784.
doi: 10.3390/molecules26195784.

The Relationship of Glutathione- S-Transferase and Multi-Drug Resistance-Related Protein 1 in Nitric Oxide (NO) Transport and Storage

Tiffany M Russell  1 , Mahan Gholam Azad  1 , Des R Richardson  1   2
Affiliations
Review

The Relationship of Glutathione- S-Transferase and Multi-Drug Resistance-Related Protein 1 in Nitric Oxide (NO) Transport and Storage

Tiffany M Russell et al. Molecules. .

Abstract

Nitric oxide is a diatomic gas that has traditionally been viewed, particularly in the context of chemical fields, as a toxic, pungent gas that is the product of ammonia oxidation. However, nitric oxide has been associated with many biological roles including cell signaling, macrophage cytotoxicity, and vasodilation. More recently, a model for nitric oxide trafficking has been proposed where nitric oxide is regulated in the form of dinitrosyl-dithiol-iron-complexes, which are much less toxic and have a significantly greater half-life than free nitric oxide. Our laboratory has previously examined this hypothesis in tumor cells and has demonstrated that dinitrosyl-dithiol-iron-complexes are transported and stored by multi-drug resistance-related protein 1 and glutathione-S-transferase P1. A crystal structure of a dinitrosyl-dithiol-iron complex with glutathione-S-transferase P1 has been solved that demonstrates that a tyrosine residue in glutathione-S-transferase P1 is responsible for binding dinitrosyl-dithiol-iron-complexes. Considering the roles of nitric oxide in vasodilation and many other processes, a physiological model of nitric oxide transport and storage would be valuable in understanding nitric oxide physiology and pathophysiology.

Keywords: dinitrosyl–dithiol iron complexes; free radicals; glutathione-S-transferase; multi-drug resistance related protein 1; nitric oxide; nitric oxide synthase; nitrogen monoxide; protein metal ion interactions; vasodilation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(a) NO redox species. NO exists as three different redox species: the NO radical (NO•); the nitrosonium cation (NO+); and the NO anion (NO−), which reversibly transitions between species via the addition or loss of an electron. (b) NO production via l-arginine. NO production occurs endogenously by the conversion of l-arginine to l-citrulline via the intermediate Nω-hydroxy-l-arginine. NADPH serves as an electron donor for both reactions.
Figure 2
Figure 2
iNOS expression and related pathways. The expression of iNOS is regulated by cytokines and other factors. Factors that decrease iNOS expression include those such as the tumor suppressor, p53, as well as proteins (e.g., TGF-β) that inhibit the activity of NF-κB. On the other hand, proteins that activate iNOS such as STAT1, IFNγ, or nuclear factor-κB (NF-κB), increase the production of NO.
Figure 3
Figure 3
eNOS is activated by an increase in Ca2+ levels, which recruits CaM and Hsp90 to the enzyme, prompting caveolae (Cav-1) to dissociate from eNOS [60]. The activity of CaM and Hsp90 is promoted by EGF, which promotes CaM expression and the recruitment of Hsp90 [60]. The eNOS complex can then be activated by the phosphorylation of eNOS, which occurs via PKA (activated by shear stress), VEGF (via Ser/Thr kinase Akt), insulin, and bradykinin, which is regulated by Ca2+/calmodulin-dependent protein kinase II (CaMKII) [60]. These stimuli result in the dissociation of adenylate cyclase (Ac) from eNOS. The eNOS complex can then catalyze the production of l-citrulline and NO from l-arginine, and thus increase NO generation.
Figure 4
Figure 4
Regulation of ferritin and TfR1 by IRP1. In the absence of iron, IRP1 without an [4Fe-4S] cluster binds the 5′-IRE of ferritin mRNA, which sterically blocks the translation of ferritin. However, in the presence of high iron concentrations, IRP1 cannot bind to the 5′ IRE of ferritin mRNA due to the formation of a [4Fe-4S] cluster, and translation is active. On the other hand, when IRPs bind the 3′-IREs of TfR1 mRNA, this interaction stabilizes the mRNA and protects it from endonucleases so that TfR1 translation can occur. Whereas, under high iron concentrations, IRPs cannot bind to the 3′-IREs of the TfR1, and the mRNA is exposed and degraded by endonucleases.
Figure 5
Figure 5
The direct and indirect impact of NO on IRP1 and IRE-binding. In the presence of NO, two mechanisms result in the loss of the [4Fe-4S] cluster: (a) direct attack of NO inducing disassembly of the cluster; and (b) an indirect mechanism where NO binds intracellular iron to induce its release from cells, resulting in iron depletion that therefore prevents [4Fe-4S] cluster biogenesis.
Figure 6
Figure 6
The structure and biological functions of DNICs. R may be either glutathione or cysteine.
Figure 7
Figure 7
Proposed mechanisms involved in inhibiting tumor cell metabolism after co-cultivation of tumor cells with NO-generating activated macrophages. Cytokines and other agents (LPS, IFNγ, STAT1, and TNF-α, etc.) promote the synthesis of iNOS-derived NO in macrophages [16]. NO can then diffuse from the cell or form a DNIC complex and be actively transported out of the cell [132,135]. NO is transported into the target tumor cell via diffusion or actively by protein disulfide isomerase (PDI) through trans-nitrosylation [177]. NO within cells has several physiological effects [178,179] and can react with iron and GSH to create DNICs. MRP1 functions to export DNICS out of the cell to facilitate iron and GSH efflux, which results in iron depletion and inhibition of tumor cell proliferation.
Figure 8
Figure 8
Detoxification mechanism between MRP1 and GST enzymes. GST enzymes conjugate GSH to toxic compounds to target them for export out of the cell by the GSH-conjugate transporter, MRP1.
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