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.
Highlights
Via iNOS has the potential to attack and inhibit the iron-containing active sites of various proteins [1,47]. Examples of these proteins include (1) iron–sulfur cluster-dependent enMolecules 2021, 26, 5784 zymes, such as those found in complexes I and II, which are crucial for mitochondrial electron transport; (2) ribonucleotide reductase, the rate-limiting enzyme of DNA synthesis; and (3) mitochondrial that playsand a critical roleiron-containing in the Krebsactive cyclesites
Nitric oxide (NO)’s biological roles in macrophage cytotoxicity and vasodilation and recent developments in understanding NO regulation and storage indicate a central role for DNICs as a common currency of NO
This proposal leads to a model of NO storage and transport by Multi-Drug Resistance-Related Protein 1 (MRP1) and GST
Summary
Nitric oxide (NO) is a diatomic gas that has traditionally been viewed as a toxic, pungent gas and is a product of ammonia oxidation [1]. NO has a high affinity for iron centers [1], which means that increased generation of NO via iNOS has the potential to attack and inhibit the iron-containing active sites of various proteins [1,47]. Examples of these proteins include (1) iron–sulfur cluster-dependent enMolecules 2021, 26, 5784 zymes, such as those found in complexes I and II, which are crucial for mitochondrial electron transport; (2) ribonucleotide reductase, the rate-limiting enzyme of DNA synthesis; and (3) mitochondrial that playsand a critical roleiron-containing in the Krebsactive cyclesites [18].
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