The strength with which oxygen binds to hemoglobin is affected by several factors. These factors shift or reshape the oxyhemoglobin dissociation curve. A shift to the right indicates that the hemoglobin under study has a decreased affinity for oxygen. This makes it more difficult for hemoglobin to bind to oxygen (requiring a higher partial pressure of oxygen to achieve the same oxygen saturation), but it makes it easier for the hemoglobin to release oxygen bound to it. The effect of this shift of the curve increases the partial pressure of oxygen in the tissues when it is most needed, such as during exercise, or hemorrhagic shock. In contrast, the curve is shifted to the left by the opposite of these conditions. This shift indicates that the hemoglobin under study has an increased affinity for oxygen, so that hemoglobin binds oxygen more easily, but unloads it more reluctantly. Left shift of the curve is a sign of hemoglobin's increased affinity for oxygen (e.g. at the lungs). Similarly, right shift shows decreased affinity, as would appear with an increase in either body temperature, hydrogen ions,
2,3-bisphosphoglycerate (2,3-BPG) concentration or carbon dioxide concentration. Note: • Left shift: higher O2 affinity • Right shift: lower O2 affinity • fetal hemoglobin has higher O2 affinity than adult hemoglobin; primarily due to much-reduced affinity to
2,3-bisphosphoglycerate. The causes of the shift to the right can be remembered using the
mnemonic, "
CADET, face Right!" for
CO2,
Acid, 2,3-
DPG,
Exercise and
Temperature. Factors that move the oxygen dissociation curve to the right are those physiological states where tissues need more oxygen. For example, during exercise, muscles have a higher metabolic rate, and consequently need more oxygen, produce more carbon dioxide and lactic acid, and their temperature rises.
pH A decrease in pH (increase in ion concentration) shifts the standard curve to the right, while an increase shifts it to the left. This occurs because at greater ion concentration, various amino acid residues, such as Histidine 146 exist predominantly in their protonated form allowing them to form ion pairs that stabilize deoxyhemoglobin in the T state. The T state has a lower affinity for oxygen than the R state, so with increased acidity, the hemoglobin binds less O2 for a given PO2 (and more H+). This is known as the
Bohr effect. A reduction in the total binding capacity of hemoglobin to oxygen (i.e. shifting the curve down, not just to the right) due to reduced pH is called the
root effect. This is seen in bony fish. The binding affinity of hemoglobin to O2 is greatest under a relatively high pH.
Carbon dioxide Carbon dioxide affects the curve in two ways. First, CO2 accumulation causes
carbamino compounds to be generated through chemical interactions, which bind to hemoglobin forming
carbaminohemoglobin. CO2 is considered an
Allosteric regulation as the inhibition happens not at the binding site of hemoglobin. Second, it influences
intracellular pH due to the formation of bicarbonate ions. Formation of carbaminohemoglobin stabilizes T state hemoglobin by forming ion pairs.
2,3-BPG 2,3-Bisphosphoglycerate or 2,3-BPG (formerly named 2,3-diphosphoglycerate or 2,3-DPG) is an
organophosphate formed in
red blood cells during
glycolysis and is the
conjugate base of
2,3-bisphosphoglyceric acid. The production of 2,3-BPG is likely an important adaptive mechanism, because the production increases for several conditions in the presence of diminished peripheral tissue O2 availability, such as
hypoxemia, chronic lung disease,
anemia, and
congestive heart failure, among others, which necessitate easier oxygen unloading in the peripheral tissue. High levels of 2,3-BPG shift the curve to the right (as in childhood), while low levels of 2,3-BPG cause a leftward shift, seen in states such as
septic shock, and
hypophosphataemia.
Carbon monoxide Hemoglobin binds with
carbon monoxide 210 times more readily than with oxygen. With an increased level of carbon monoxide, a person can suffer from severe tissue
hypoxia while maintaining a normal pO2 because carboxyhemoglobin does not carry oxygen to the tissues.
Effects of methemoglobinaemia Methemoglobinaemia is a form of abnormal hemoglobin where the iron centre has been oxidised from the
ferrous +2 oxidation state (the normal form, which on binding with oxygen changes to the ferric state) to the
ferric +3 state. This causes a leftward shift in the oxygen hemoglobin dissociation curve, as any residual heme with oxygenated ferrous iron (+2 state) is unable to unload its bound oxygen into tissues (because 3+ iron impairs hemoglobin's cooperativity), thereby increasing its affinity with oxygen. However, methemoglobin has increased affinity for
cyanide, and is therefore useful in the treatment of
cyanide poisoning. In cases of accidental ingestion, administration of a
nitrite (such as
amyl nitrite) can be used to deliberately oxidise hemoglobin and raise methemoglobin levels, restoring the functioning of
cytochrome oxidase. The nitrite also acts as a
vasodilator, promoting the cellular supply of oxygen, and the addition of an iron salt provides for competitive binding of the free cyanide as the biochemically inert
hexacyanoferrate(III) ion, [Fe(CN)6]3−. An alternative approach involves administering
thiosulfate, thereby converting cyanide to
thiocyanate, SCN−, which is excreted
via the kidneys. Methemoglobin is also formed in small quantities when the dissociation of oxyhemoglobin results in the formation of methemoglobin and
superoxide, O2−, instead of the usual products. Superoxide is a
free radical and causes biochemical damage, but is neutralised by the action of the enzyme
superoxide dismutase.
Effects of ITPP Myo-inositol trispyrophosphate (ITPP), also known as OXY111A, is an
inositol phosphate that causes a rightward shift in the oxygen hemoglobin dissociation curve through
allosteric modulation of hemoglobin within red blood cells. It is an experimental drug intended to reduce tissue
hypoxia. The effects appear to last roughly as long as the affected red blood cells remain in circulation. == Fetal hemoglobin ==