Major "Missed" Biochemical Pathway Emerges As Important in Virtually All Cells
DURHAM, N.C. -- A new study by Duke University researchers
provides more evidence that the nitric oxide (NO) system in the
life of a cell plays a key role in disease, and the findings
point to ways to improve treatment of illnesses such as heart
disease and cancer.
The nitric oxide system in cells is "a major biological
signaling pathway that has been missed with regard to the way
it controls proteins," and it is linked to cancer and other
diseases when the system goes awry, said Jonathan Stamler,
M.D., a professor of medicine and biochemistry at Duke
University Medical Center who worked on the study.
In the body, nitric oxide plays a role in the transport of
oxygen to tissues and physiological activities such as the
transmission of nerve impulses, and the beating of the heart.
When things go awry with the nitric oxide system, bad things
can happen in bodies, according to recent studies. For
instance, there may be too little nitric oxide in
atherosclerosis and there may be too much in Parkinson's
disease; there may not be enough nitric oxide in sickle cell
disease and there may be too much in some types of diabetes,
The new findings, which Stamler said change understanding of
how the nitric oxide system is controlled, appear in the May 23
issue of the journal Science.
"What we see now for the first time in the Science paper is
that there are enzymes that are removing NO from proteins to
control protein activity," Stamler said. "This action has a
broad-based effect, frankly, and probably happens in virtually
all cells and across all protein classes. Nitric oxide is
implicated in many disease processes. Sepsis, asthma, cystic
fibrosis, Parkinson's disease, heart failure, malignant
hyperthermia -- all of these diseases are linked to aberrant
An important factor that previously wasn't appreciated, he
said, is that the target of nitric oxide in disease is
different in every case. The finding of how nitric oxide
binding to proteins is regulated opens the field for new
refinement in biochemical research, said Stamler, who has been
studying nitric oxide in cells for 15 years.
"Now we will need to study whether the aberrant cell signals
are a matter of too much NO being produced and added to
proteins or not enough being removed from proteins," he said.
"It is not simply a matter of too much or too little NO being
in cells, but rather how much is being added or taken away from
specific proteins, which is quite a different thing."
First author on the paper, Moran Benhar, Ph.D., and
co-author Douglas Hess, Ph.D., are both in the Duke Department
of Medicine. Co-author Michael Forrester is a graduate student
in the Duke Department of Biochemistry.
The research explains that the enzymes thioredoxin 1 and
thioredoxin 2 remove nitric oxide from the amino acid cysteine
within mammalian cells, thereby regulating several different
actions in cells. One result of this removal is the activation
of molecules that begin apoptosis, which is the normal
programmed death of a cell. This process has potential
importance for many diseases, including inflammatory diseases,
heart failure and cancer. Because thioredoxins are established
targets of drug therapy for arthritis, the research suggests
potential therapeutic applications of the process.
The nitric oxide system is analogous to the much more
studied phosphorylation system, in which phosphates are added
and removed from proteins, the paper said. Changes in
phosphorylation are among the most common causes of disease,
and proteins that regulate phosphorylation are major drug
targets, Stamler said.
"Aberrant dephosphosphorylation causes disease. Expect the
same for denitrosylation," Stamler said.
Similar research at Duke that was published in the journal
Nature on March 16 supports Stamler's findings. Christopher
Counter, an associate professor in the Duke Department of
Pharmacology and Cancer Biology, and colleagues found that eNOS
(endothelial nitric oxide synthase), an enzyme that enhances
the creation of nitric oxide, promoted tumor development and
tumor maintenance in mice.
"The Chris Counter work is especially exciting because he
shows that a nitric oxide synthase is linked to cancer, and he
specifically identifies the protein that is the target of the
nitric oxide, the protein that gets turned on through
S-nitrosylation," Stamler said. Blocking S-nitrosylation of
this protein prevented cancer.
The steady stream of new papers on nitric oxide seems to
underscore Stamler's long-held belief that nitric oxide affects
cells in bigger ways than many had appreciated. "When we began
our studies two decades ago, we hypothesized that nitric oxide
was part of a significant, broad-based system," Stamler said.
"Our hypothesis never changed."