Application of our mathematical model of hemoglobin Zock, shows that this model can account for the above-mentioned phenomena in a straightforward way. Unable to display preview. Download preview PDF. Skip to main content. This service is more advanced with JavaScript available.
Advertisement Hide. Authors Authors and affiliations Jacob P. This process is experimental and the keywords may be updated as the learning algorithm improves. This is a preview of subscription content, log in to check access. Bishop, G. Di Cera, E. Douglas, C. London There is evidence that CO is also derived from non-heme sources, e. The biological effect of endogenous CO is due largely to the high affinity that heme has for CO and the resulting binding of CO by heme-containing proteins.
By a curious quirk of nature then, heme is both the source of CO and the mediator of its biological effect. The modulation in function of some heme-containing proteins that results from CO binding has important physiological effects. Thus endogenously produced carbon monoxide is not, as was once supposed, simply a potentially toxic waste product of metabolism but is involved in many physiological functions, including regulation of respiration [5], neuronal signaling [6], regulation of blood pressure [7] and uterine contraction during pregnancy [8].
Of all heme-containing proteins, Hb is not only the most abundant but also exhibits the highest affinity for carbon monoxide, so that most CO in blood is bound to Hb. Reversible binding occurs at the same iron atom on the heme site where oxygen binds; the product of this binding is carboxyhemoglobin COHb. This provides the means by which endogenous carbon monoxide can be transported, prior to elimination from the body by the lungs in expired air.
A minimum of 0. In addition to the CO produced endogenously, the air we breathe contains CO, partly the result of natural processes but mostly from the incomplete combustion of hydrocarbons. The most significant unnatural source of environmental CO is motor-vehicle exhaust. Although normally present at concentrations of less than 10 parts per million ppm [10], carbon monoxide in inspired air has an important additive effect on the amount of COHb in blood due to the high affinity that Hb exhibits for CO.
Cigarette smoke contains a high concentration of CO and smokers are exposed to an estimated ppm CO while smoking and consequently have much higher COHb. The source of the CO in blood is both endogenous heme catabolism and environmental CO content of inspired air so that the causes of raised COHb can be addressed under two main headings:. Increased endogenous production of CO is a feature of any condition associated with increased heme catabolism. The hemolytic anemias are a group of conditions of variable etiology whose common pathological feature is increased rate of red-cell destruction hemolysis.
Increased red-cell destruction results in increased heme catabolism and therefore increased production of CO. The normal neonatal COHb range determined for this study was 0.
Slight increase in COHb — so slight to be of little clinical significance per se — is often a feature of severe inflammatory disease, e. It is thus a relatively common finding in critically ill patients [16].
The mechanism of this increase is thought to be increased expression of heme oxygenase the enzyme responsible for CO production induced by inflammatory cytokines [17]. Increased endogenous production of CO can arise independently of heme catabolism. Methylene chloride dichloromethane is a toxic organic solvent with wide application, including paint remover, degreaser and aerosol propellant.
The toxicity of methylene chloride is due in part to its in vivo metabolism in the liver to CO. Subjects who inhale toxic amounts of methylene chloride vapor, usually a result of working in poorly ventilated conditions, have raised COHb caused by increased production of CO.
COHb levels, which can be severe enough to threaten life, correlates well with methylene chloride exposure levels [18]. This is clinically the most significant cause of increased COHb for two reasons. Most clinical requests for measurement of COHb are made in the context of known or suspected acute or chronic carbon-monoxide poisoning. Deliberate or accidental poisoning by carbon monoxide remains a significant problem.
In the US, it accounts for an estimated 40, emergency room attendances and between 5, and 6, deaths each year [19]. Most of these are suicides, usually the result of deliberate exposure to motor-vehicle exhaust, but still deaths a year result from accidental exposure to carbon monoxide from a wide variety of sources. In the UK, CO is responsible for 50 deaths and serious injuries every year [20].
Internationally, CO may be responsible for more than half of all fatal poisonings worldwide [21]. Low-grade chronic CO poisoning is associated with non-specific symptoms and requires a high degree of suspicion for diagnosis, and most authorities believe many cases remain undiagnosed or misdiagnosed [22].
Carbon monoxide is a ubiquitous product of incomplete combustion of hydrocarbons. Common sources of CO in cases of poisoning include house fire, motor-vehicle exhaust and faulty domestic heating systems.
Less commonly, gas ovens, paraffin kerosene heaters and even charcoal briquettes, e. Clearly a closed or poorly ventilated environment is an important contributory factor in most cases, but it remains possible to suffer severe, even fatal, CO poisoning in the outdoors if close enough to a rich source of CO, e. The amount of COHb in blood is a function of both inspired CO concentration parts per million, ppm and duration of exposure. During exposure to a fixed CO concentration, COHb levels increase rapidly over the first 2 hours, then begin to plateau at around 3 hours, reaching an equilibrium steady state at hours.
To maintain COHb below 2. CO concentration in specific environments:. The toxicity of CO is due in part to the effect that hemoglobin binding of CO has on the oxygen-carrying capacity of blood.
Affinity of hemoglobin for CO is times greater than that for oxygen [9, 20, 23, 24]. CO displaces oxygen from hemoglobin and thus COHb effectively reduces the oxygen-carrying capacity in a dose-dependant manner.
In addition, binding of CO by Hb at the first of the four heme sites has an effect on its quaternary structure that results in decreased affinity for oxygen at the remaining three sites. This effect is evident in a shift of the hemoglobin dissociation curve to the left Figure I and results in reduced release of oxygen from hemoglobin at the tissues. The combined effect of a reduced oxygen-carrying capacity and reduced release of oxygen to tissue leaves tissues effectively starved of oxygen hypoxic.
Organs like the brain and heart, whose normal oxygen consumption is by comparison with other organs relatively high, are particularly sensitive to the relative anoxia induced by increased COHb.
Fetal Hb exhibits an even higher affinity for CO than adult Hb, so that since CO diffuses readily across the placental membrane, the developing fetus is particularly vulnerable to tissue anoxia in cases of maternal CO exposure [26]. If increased production of COHb were, as was once supposed, the only mechanism involved in CO toxicity, then the severity of symptoms would be accurately predicted by the level of COHb, but this is not always the case. It is now clear that "free" CO dissolved in blood plasma enters tissues and competes with oxygen for sites on tissue-cell heme proteins such as myoglobin, peroxidase and the cytochrome enzymes with a variety of pathological effects independent of hemoglobin CO binding [20].
A high index of suspicion is required to entertain a diagnosis of carbon-monoxide poisoning unless CO exposure is certain, because all symptoms of mild-to-moderate poisoning are non-specific.
The classic "cherry-red" skin color of carbon-monoxide poisoning is in fact not usually evident. The most common symptoms: headache, dizziness and confusion reflect the marked sensitivity of the brain to relative anoxia. Nausea and vomiting are also common. Affected patients may be breathless, particularly on exertion, and have clinical signs tachycardia, tachypnea indicating compensation for the oxygen deficit.
In more severe cases there are frank signs and symptoms of cardiac involvement, including palpitations, hypotension, ischemic chest pain angina and even myocardial infarction. Convulsions and coma occur in severe toxicity. A raised COHb in the absence of a disease process associated with the hemolytic process is diagnostic of carbon-monoxide poisoning; the actual level correlates with the severity of symptoms in the majority of cases Table II.
This case [27] concerns a year-old boy who started his motorbike in the family garage. Before he could get to the garage door he was overcome by the exhaust fumes and collapsed. He was found unconscious around 9 hours after he was last seen, wedged between the family car and the unopened garage door. Although by now there was no evidence of CO exposure, e. After initial assessment at the local hospital, his respiration, already "rapid and labored" on admission, deteriorated and he was intubated and transferred to a tertiary referral center, some 13 hours after he was found.
The cause of his continuing unconscious state remained a mystery at this time. On admission to the second hospital, blood was sampled for COHb estimation. The laboratory reported a COHb of 4. The boy remained deeply comatose for 10 days and was dependent on mechanical ventilation for 11 days. Asked 6 years, 4 months ago. Active 2 years, 6 months ago. Viewed k times. I have two main related questions: Why is the carboxyhemoglobin bond stronger relative to that of oxygenated hemoglobin?
Why is carbon monoxide highly attracted to hemoglobin? Improve this question. Add a comment. Active Oldest Votes. Comparison of the oxygen and carbon monoxide binding modes The simpler picture I drew above for carbon monoxide is not correct. Summary Carbon monoxide is generally a good ligand that can bind to metal centres well. Oxygen is generally a poor ligand. Nature did everything to make oxygen a comfortable home in haemoglobin. Improve this answer. David 2 2 silver badges 11 11 bronze badges.
Jan Jan Here it is: Proc. And yes, the debate about Fe II vs. Fe III in oxyHb is not yet settled. This recent article on Hb is a really nice read, summarising a lot of the work that has been done in the area: Proc. Feel free to include in your answer if you wish. You might find the MO scheme in there quite useful for your first part. I'd say a job well done, you deserve more attention for this!
How it does this is related to CO's molecular orbitals, which look like: Note that the 4, 5, and 6 sigma orbitals, as well as the 2 pi orbital, are all antibonding. Mithoron 4, 12 12 gold badges 36 36 silver badges 55 55 bronze badges. Breaking Bioinformatics Breaking Bioinformatics 2, 1 1 gold badge 13 13 silver badges 29 29 bronze badges.
I will search on that. Although the images are appreciated, more importantly, as mentioned in my question, can you write the equations for Fe and CO reactions in Hemoglobin including the hybridization and oxidation states? Give me a second to put the picture together of how it fits in with the overall molecule.
Maybe the first sentence, it goes steep downhill from there. CO has a formal negative charge at carbon only in one possible resonance structure. It has a positive charge, because oxygen is so much more electronegative. Relieve stress? What does that even mean? According to this the BO would be one, not 3 as you stated. The BO is not 3. It's somewhere between , but it's not that easy to determine.
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