Research results featured in Nature Chemical
Biology.
A team of researchers from Wake Forest University, the National
Institutes of Health and other institutions has discovered a previously
undetected chemical process within the oxygen-carrying molecule
hemoglobin that could have far-reaching implications for the treatment
of cardiovascular diseases.
In a paper published online Nov. 4 (2007) in
the journal Nature Chemical Biology, senior authors Daniel Kim-Shapiro,
professor of physics at Wake Forest, and Mark Gladwin, chief of the
Vascular Medicine Branch of the National Heart, Lung and Blood
Institute of the NIH, describe how hemoglobin, through a catalytic
reaction that does not change its own chemical properties, converts
nitrite salt to the vasodilator nitric oxide. The paper further
documents how the nitric oxide activity harnessed by hemoglobin
escapes the red blood cell to regulate blood flow and how the process,
surprisingly, relies on the oxidized, or rusted, form of hemoglobin,
previously associated only with diseased states.
Daniel Kim-Shapiro, professor of physics at Wake
Forest University, is the senior co-author of a scientific paper
published online Nov. 4 by the journal Nature Chemical Biology, in
which he, Mark Gladwin, chief of the vascular medicine branch of
the National Heart, Lung and Blood Institute of the NIH, and a team of researchers announced the discovery of a previously
undetected chemical process in hemoglobin.
Photo � by Ken Bennett
�We believe we have solved the paradox of how
hemoglobin mediates the conversion of nitrite to nitric oxide in a way
that it is not immediately destroyed in the red cell and so it can be
effective biologically,� Kim-Shapiro says.
In the bloodstream, iron-rich hemoglobin consumes, on contact, any
free nitric oxide released by the blood vessels, so the idea that
hemoglobin participates in forming nitric oxide had seemed implausible
until recently.
In 2003, Gladwin and collaborators at the NIH, Wake Forest and the
University of Alabama discovered that nitrite salt, the same substance
used to cure meat and previously thought to be biologically inert,
serves in the cell as a storage pool for nitric oxide. Since then,
nitrite has been the object of intense study by researchers worldwide
in pursuit of new treatments for such conditions as sickle cell
disease, myocardial infarction, pulmonary hypertension, stroke and
atherosclerosis.
In the most recent study, the researchers conclude that the
nitrite-hemoglobin reaction generates dinitrogen trioxide (N2O3),
which takes one of several pathways from the red blood cell and later
separates into nitric oxide (NO) and nitrogen dioxide (NO2).
The newly discovered chemistry in hemoglobin has eluded scientists for
a century because the intermediate molecule, nitrite-methemoglobin,
formed during the process cannot be observed by electron paramagnetic
resonance spectroscopy, the most sophisticated analysis technique
currently available. That has rendered the reaction �invisible� by
direct observation, but indirect measurement of the process is
possible.
�Using a variety of biophysical techniques and by careful examination
of the rates of reactions and the products that are made when
experimenting with hemoglobin and nitrite, we were able to discover
this reaction mechanism,� Kim-Shapiro explains.
The research was funded by grants from the NIH.
Further Information and Source:
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Swati Basu, Rozalina Grubina, Jinming Huang, Jeanet Conradie5,6, Zhi
Huang, Anne Jeffers, Alice Jiang, Xiaojun He, Ivan Azarov, Ryan
Seibert, Atul Mehta, Rakesh Patel, Stephen Bruce King, Neil Hogg,
Abhik Ghosh, Mark T Gladwin & Daniel B Kim-Shapiro: Catalytic generation of N2O3 by the
concerted nitrite reductase and anhydrase activity of hemoglobin.
In: Natural Chemical Biology;
published online: 4 November 2007; doi 10.1038/nchembio.2007.46
