Some Papers
“Nitric oxide inhibition of respiration involves both competitive (heme) and
noncompetitive (copper) binding to cytochrome c oxidase.”
Mason et al
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstr
act&list_uids=16407136&query_hl=10&itool=pubmed_docsum
“The L-Arginine-Nitric Oxide Pathway”
Moncada et. Al
http://content.nejm.org/cgi/content/full/329/27/2002?ijkey=d977aa1a5e9e30634a9b8a265
062bebbdc2101b1&keytype2=tf_ipsecsha
“Thus, nitric oxide released by this inducible enzyme accounts for the vasodilatation and
resistance to vasoconstrictors characteristic of septic shock.”
“Selective inhibition of the generation of nitric oxide will probably find applications in
therapy. This is evident in the case of potential selective inhibitors of the inducible nitric
oxide synthase for the treatment of the hypotension of shock or of cytokine therapy as
well as some acute or chronic inflammatory conditions.”
“Nitric oxide regulates mitochondrial respiration and cell functions by inhibiting
cytochrome oxidase”
Brown
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=pubmed
“Further NO may be a physiological regulator of the affinity of mitochondrial respiration
for oxygen, enabling mitochondria to act as sensors of oxygen over the physiological
range.”
“Nitric oxide (NO) has a number of physiological roles, including: (a) relaxation of
smooth muscle; (b) neurotransmission and neuromodulation; (c) inhibition of platelet
aggregation and adhesion; and (d) killing of pathogens.”
“Endotoxins and/or cytokines can induce the expression of the inducible form of NO
synthase in macrophages and cells within virtually every tissue in the body. This response
has been suggested to act as a kind of primitive immune response, whereby the induced
NO production kills pathogens locally. Activated macrophages can kill bacteria, tumour
cells, and a variety of other pathogens; and one of the cytotoxic agents is thought to be
NO.”
“Structure of Cytochrome a3-Cu{a3} Couple in Cytochrome c Oxidase as Revealed
by Nitric Oxide Binding Studies”
Stevens et. Al
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstr
act&list_uids=226967&query_hl=6&itool=pubmed_docsum
A lot of NO binding oxidized CCO experimental data.
“On the Mechanism of Inhibition of Cytochrome c Oxidase by Nitric Oxide”
Giuffre et Al.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstr
act&list_uids=8969202&query_hl=9&itool=pubmed_docsum
“during cellular stress and depending on the relative concentrations of NO and O2, the
presence of NO may lead in the extreme to serious cellular damage and onset of
pathology.”
“Association between mitochondrial dysfunction and severity and outcome of septic
shock.”
Brealey et al.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstr
act&list_uids=12133657&query_hl=11&itool=pubmed_docsum
“Sepsis-induced multiple organ failure is the major cause of mortality and morbidity in
critically ill patients.”
“We and others have shown raised tissue oxygen tensions in septic animals and human
beings, suggesting reduced ability of the organs to use oxygen. Because ATP production
by mitochondrial oxidative phosphorylation accounts for more than 90% of total oxygen
consumption, we postulated that mitochondrial dysfunction results in organ failure,
possibly due to nitric oxide, which is known to inhibit mitochondrial respiration in vitro
and is produced in excess in sepsis.”
“In septic patients, we found an association between nitric oxide overproduction,
antioxidant depletion, mitochondrial dysfunction, and decreased ATP concentrations that
relate to organ failure and eventual outcome. These data implicate bioenergetic failure as
an important pathophysiological mechanism underlying multiorgan dysfunction.”
“Sepsis is the systemic inflammatory response associated with an infectious insult. It is
the leading cause of death in critically ill patients, and the predominant cause of multiple
organ dysfunction.”
“shown increased tissue oxygen tension in the organs of animals and patients with
sepsis.3 and 4 This finding suggests that the predominant defect might lie in cellular oxygen
use (tissue dysoxia) rather than in oxygen delivery per se.”
“Mitochondrial OXIDATIVE PHOSPHORYLATION is responsible for over 90% of total body
oxygen consumption and ATP generation. The RESPIRATORY CHAIN (electron-transport
chain) includes four individual enzyme complexes (I–IV). These enzyme complexes,
notably NADH-ubiquinone oxidoreductase (complex I) and cytochrome C oxidase
(complex IV), can be inhibited by reactive oxygen and nitrogen species such as nitric
oxide.5, 6 and 7 These reactive species are produced in substantial excess during sepsis and
are also generated by the mitochondria.8”
Figure: Tissue ATP concentrations in patients with sepsis and in controls
“Muscle ATP concentrations were significantly lower in septic non-survivors than in
either septic survivors (p=0·0003) or controls (p=0·05).”
“The respiratory chain is located in the mitochondrial inner membrane and consists of the
four complexes plus specialised electron carriers. Passage of electrons down the chain
creates a proton gradient across the inner membrane sufficient to drive ATP synthase
(complex V) to phosphorylate ADP to ATP. These complexes can be inhibited by nitric
oxide and its congeners,5, 6 and 7 which are produced in excess during sepsis.23”
“Cytochrome c oxidase rapidly metabolises nitric oxide to nitrite”
Torres et al
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=pubmed
“Electrons enter the enzyme at the CuA site which is in rapid redox equilibrium with one
of the haem irons, Fea. From here, electrons are transferred to the binuclear centre,
comprising the magnetically coupled CuBand Fea3 metals, where oxygen is reduced and
water formed.”
“CCO is known to be reversibly inhibited by nitric oxide (NO), the ¢nal inhibited species
being a ferrous nitrosyl complex formed between NO and ferrous Fea3 [2^5]. However, a
primary role in inhibition has also been attributed to the other metal in the binuclear
centre, CuB. From an analysis of data obtained by optical spectroscopy, we have
suggested that NO rapidly (in the ms time range) reduces CuB forming nitrite within the
binuclear centre [6] (Fig. 1)”
“The scheme depicted in Fig. 1 predicts that on reaction with NO, one nitrite ion (or
molecule of nitrous acid) is formed per enzyme molecule.”
“Finally, NO, although synthesised by a speci¢c enzyme, seems to have multiple means
of destruction in vivo [16]. Mitochondria have been demonstrated to be a major
metaboliser of NO in the cell [17]. A signi¢cant fraction of this metabolism is cyanide
sensitive and therefore likely to be associated with cytochrome oxidase. As shown in this
paper, the oxidation of NO to nitrite by this enzyme results in a rapid means of
metabolism of NO with a safe end-product.”
“Competitive, Reversible, Physiological? Inhibition of Mitochondrial Cytochrome
Oxidase by Nitric Oxide”
Cooper et al
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstr
act&list_uids=14711004&query_hl=17&itool=pubmed_docsum
“Being a free radical, the reactivity of nitric oxide is dominated by its interactions with
compounds containing other unpaired electrons. In biology the principle reactants
are transition metals, in particular iron (1). Originally considered an environmental
toxin in mammalian systems, nitric oxide is now known to be an intercellular messenger
(2, 3), produced in a reaction catalysed by the flavohaem enzyme nitric oxide synthase
(4)”
“The essential hypothesis was that NO bound to the ferrous haem a3 site of the enzyme
(the same site where O2 binds).”
“This resulted in a high a3nity reversible inhibition compe- titive with oxygen
concentration, that could play a role in physiological control or pathophysiological
damage, depen- dent on the levels of NO produced.”
“There is no doubt that lowering the oxygen tension increases the ability of
nanomolar levels of nitric oxide to inhibit cellular oxygen consumption in vitro.”
“The reaction of NO with reduced (ferrous) haem a3 has been well characterized (17, 18),
but that with the oxidised (cupric) CuB is less well known (19, 20).”
“demonstrating in particular that at low rates of enzyme turnover the NO/copper
interaction predo- minates over that of NO and haem iron (22).”
“As the NO/CuB interactions are not at the oxygen reduction site (heme a3), there is not
a direct competition with oxygen.”
“The hypothesis that nitric oxide reversibly and competi- tively inhibits mitochondrial
oxygen consumption in vivo by competing for oxygen at the level of cytochrome
oxidase has advanced considerably since it was first proposed in 1994.”
“relative roles of the NO/copper and the NO/haem interactions, and the impor- tance (if
any) of irreversible e3ects exhibited at higher NO levels to disease pathology, remain to
be elucidated.”
“Figure 1. Possible interactions of nitric oxide with cytochrome oxidase active site. Three
possible modes of binding of NO to the binuclear haem/copper oxygen reduction site of
cytochrome oxidase. Note in the mammalian enzyme two molecules of NO are unlikely
to bind simultaneously under conceivable physiological conditions.”
“Ligand-protein interactions in nitric oxide synthase.”
Rousseau et al
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstr
act&list_uids=15598509&query_hl=19&itool=pubmed_docsum
Really good NOS paper
“Structure and function of a molecular machine: cytochrome c oxidase.”
Malatesta et al
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstr
act&list_uids=7703349&query_hl=12&itool=pubmed_DocSum
“Cytochrome c is responsible for over 90% of the dioxygen consumption in the living
cell and contributes to the build-up of a proton electrochemical gradient derived by the
vectorial transfer of electrons between cytochrome c and molecular oxygen. The metal
ions found in cytochrome oxidases play a crucial role in these processes and have been
extensively studied.”
Websites
Nitric Oxide Synthase
http://metallo.scripps.edu/PROMISE/NOS.html
Electron Transport Chain
http://en.wikipedia.org/wiki/Electron_transfer_chain