Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Mar 2;287(10):6960-8.
doi: 10.1074/jbc.R111.329847. Epub 2012 Jan 19.

Nitrogen monoxide (NO) storage and transport by dinitrosyl-dithiol-iron complexes: long-lived NO that is trafficked by interacting proteins

Yohan Suryo Rahmanto  1 , Danuta S Kalinowski, Darius J R Lane, Hiu Chuen Lok, Vera Richardson, Des R Richardson
Affiliations

Nitrogen monoxide (NO) storage and transport by dinitrosyl-dithiol-iron complexes: long-lived NO that is trafficked by interacting proteins

Yohan Suryo Rahmanto et al. J Biol Chem. .

Abstract

Nitrogen monoxide (NO) markedly affects intracellular iron metabolism, and recent studies have shown that molecules traditionally involved in drug resistance, namely GST and MRP1 (multidrug resistance-associated protein 1), are critical molecular players in this process. This is mediated by interaction of these proteins with dinitrosyl-dithiol-iron complexes (Watts, R. N., Hawkins, C., Ponka, P., and Richardson, D. R. (2006) Proc. Natl. Acad. Sci. U.S.A. 103, 7670-7675; Lok, H. C., Suryo Rahmanto, Y., Hawkins, C. L., Kalinowski, D. S., Morrow, C. S., Townsend, A. J., Ponka, P., and Richardson, D. R. (2012) J. Biol. Chem. 287, 607-618). These complexes are bioavailable, have a markedly longer half-life compared with free NO, and form in cells after an interaction between iron, NO, and glutathione. The generation of dinitrosyl-dithiol-iron complexes acts as a common currency for NO transport and storage by MRP1 and GST P1-1, respectively. Understanding the biological trafficking mechanisms involved in the metabolism of NO is vital for elucidating its many roles in cellular signaling and cytotoxicity and for development of new therapeutic targets.

PubMed Disclaimer

Figures

FIGURE 1.
FIGURE 1.
A, schematic showing the basic processes of cellular iron metabolism. Iron is transported in the blood bound to Tf. Tf binds to TfR1 on the cell surface and is internalized by receptor-mediated endocytosis. Iron is released from Tf by a decrease in pH and transported across the endosomal membrane by DMT1. Once in the cytosol, iron becomes part of the poorly characterized intracellular iron pool, which has been suggested to be bound by low-Mr ligands, e.g. citrate or chaperone molecules such as PCBP1 and PCBP2. Iron can be stored within the protein ferritin. In the absence of NO, iron can be released from cells by the trans-plasma membrane protein Fpn1. B, line drawings of the structures of physiologically relevant DNICs. These include DNDGIC and DNDCIC. Coordinating water molecules have been omitted for clarity in each case.
FIGURE 2.
FIGURE 2.
A, hypothetical model of d-glucose-dependent NO-mediated iron mobilization from cells. Studies using a variety of metabolizable and non-metabolizable sugars demonstrated that NO-mediated iron mobilization from cells is dependent on the transport of d-glucose into cells and its metabolism (39). Glucose is used by the tricarboxylic acid cycle for the production of ATP and by the pentose phosphate pathway (PPP) for the generation of NADPH, which is involved in the synthesis of GSH (39). NO either diffuses or is transported into cells by protein-disulfide isomerase (PDI) (100). Once within cells, NO intercepts and binds iron bound to proteins or iron that is en route to ferritin. The high affinity of NO for iron results in the formation of DNICs (represented here as GS-Fe-NO). GSH may either be involved as a reductant to remove iron from endogenous ligands and/or complete the iron coordination shell along with NO in the DNIC. This complex as an intact entity or its separate components can be released from the cell by an active process requiring MRP1. This model has been modified from Ref. . G-6-P, glucose 6-phosphate. B, schematic illustrating the respective roles of GST P1-1 and MRP1 in NO storage and transport. NO can diffuse through the membrane or may be actively transported into cells by protein-disulfide isomerase (100). Because of the ability of NO to act as a ligand, it can bind iron transported into cells and released from Tf. GSH completes the coordination sphere of the NO-iron complex to form a DNIC. DNICs can be bound by GST P1-1 or effluxed out of cells via MRP1 (37, 38).
FIGURE 3.
FIGURE 3.
Schematic illustration of the interdependence of iron, NO, GSH, and MRP1 and the hypothetical consequences of DNIC efflux. A, endothelial cells. The efficient efflux of DNICs (represented here as GS-Fe-NO) by active transport by MRP1 may be crucial where NO is produced in small quantities, e.g. in blood vessels, in which eNOS generates NO to effect smooth muscle relaxation. B, activated macrophages targeting tumor cells. When NO is generated in large amounts, e.g. by iNOS of Mφs, it could lead to substantial iron and GSH efflux from tumor cells as DNICs and induce cytotoxicity. The schemes have been modified from Ref. .
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Stamler J. S., Singel D. J., Loscalzo J. (1992) Biochemistry of nitric oxide and its redox-activated forms. Science 258, 1898–1902 - PubMed
    1. Richardson D. R., Ponka P. (1997) The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells. Biochim. Biophys. Acta 1331, 1–40 - PubMed
    1. Watts R. N., Ponka P., Richardson D. R. (2003) Effects of nitrogen monoxide and carbon monoxide on molecular and cellular iron metabolism: mirror-image effector molecules that target iron. Biochem. J. 369, 429–440 - PMC - PubMed
    1. Hibbs J. B., Jr., Taintor R. R., Vavrin Z. (1984) Iron depletion: possible cause of tumor cell cytotoxicity induced by activated macrophages. Biochem. Biophys. Res. Commun. 123, 716–723 - PubMed
    1. Henry Y., Ducrocq C., Drapier J. C., Servent D., Pellat C., Guissani A. (1991) Nitric oxide, a biological effector. Electron paramagnetic resonance detection of nitrosyl-iron-protein complexes in whole cells. Eur. Biophys. J. 20, 1–15 - PubMed

Publication types

MeSH terms