It is hemoglobin with heme group with iron in the ferric state, Fe (III) (that is, oxidized).
Four different species of hemoglobin are commonly recognized: oxyhemoglobin , deoxyhemoglobin, methemoglobin, and hemicromes .
Methemoglobin is an altered state of hemoglobin created in the presence of oxidative stress.
This process occurs naturally in the body at low levels, and endogenous systems exist to reduce the iron state of iron to the ferrous state.
This abnormal state of hemoglobin or change in the rest of iron impairs its ability to bind and release oxygen and these effects lead to tissue hypoxia and functional anemia .
This renders hemoglobin unable to carry oxygen, leading to decreased oxygen supply to the tissues.
When an abnormal rise in the methemoglobin level occurs and exceeds the body’s ability to reduce methemoglobin, clinically significant methemoglobinemia occurs.
Untreated severe methemoglobinemia can lead to severe hypoxic symptoms and death.
Methemoglobinemia should be suspected in a cyanotic patient with no apparent cardiovascular cause.
The heme group consists of an iron ion, which is surrounded by a heterocyclic porphyrin ring.
The iron center has 6 potential coordination sites, four of which are occupied by porphyrin nitrogens.
The fifth coordination site (below the plane of the ring) covalently binds with a histidine residue from the F8 position of its respective globin chain.
The sixth coordination site (on the plane of the ring) is where all the “action” occurs.
This is the place where oxygen and other small molecules temporarily bind to the iron atom, affecting its electronic structure and magnetic properties.
Red blood cells are red due to the presence of hemoglobin, the conglomerate macromolecule responsible for oxygen transport.
The main function of the hemoglobin protein contained in red blood cells is the transport of oxygen in the inspired air from the lungs to the cells of the tissues.
The adult hemoglobin molecule is composed of four folded polypeptide chains or subunits (two alpha and two beta), each consisting of a non-protein heme group surrounded by a coiled protein (globin).
At the center of each of the four heme groups is an iron atom in the ferrous state (Fe 2+).
These four iron atoms are the functional centers of the hemoglobin molecule because it is here that oxygen reversibly binds to form oxyhemoglobin.
When oxygen is discharged from oxyhemoglobin in tissues, the temporarily shared electron is recaptured by the iron atom, returning to its ferrous state (Fe 2+).
Whatever the precise detail of oxygen binding to hemoglobin, it is clear that for binding to occur, the iron atoms present in each of the four heme groups must be in the ferrous state.
Physiological mechanisms for the conversion of hemoglobin to methemoglobin
The effect of free radical-mediated oxidation is not limited to the hemoglobin molecule, many molecular species in cells throughout the body are affected.
If left unchecked, these oxidative molecular changes can affect function and ultimately cause cell breakdown and injury.
The conversion of iron from the ferrous to the ferric state represents the loss of an electron, that is, it is an oxidative process.
Red blood cells and their contents (including hemoglobin) are considered particularly susceptible to this oxidative stress due to the relatively high concentration of oxygen present and the resulting production of oxygen free radicals.
In this chemical state of hemoglobin, the deoxygenated iron of the divalent state (Fe 2+) of heme, loses an electron and oxidizes to form the trivalent form of hemoglobin, ferrous irons (Fe 3+).
Methemoglobin irons are unable to reversibly bind oxygen. Furthermore, the iron oxygen affinity of any remaining globin in the hemoglobin tetramer is increased.
Thus the formation of methemoglobin from hemoglobin within red blood cells is an ongoing oxidative process that results from the exposure of hemoglobin to a variety of highly reactive molecules (oxygen free radicals), produced during normal cellular metabolism.
The only difference between hemoglobin and methemoglobin is that one or more of the four iron atoms in the methemoglobin molecule are in the ferric state (Fe 3+) rather than the ferrous state (Fe 2+) and therefore they are unable to bind to oxygen.
Methemoglobin is also formed during oxygen discharge from deoxyhemoglobin in tissues if, as sometimes happens, the temporarily donated electron is not recaptured by the iron atom, this process is called auto-oxidation.
It has been estimated that about 3% of hemoglobin is converted to methemoglobin daily by these two oxidative mechanisms.
Physiological mechanisms for the conversion of methemoglobin to hemoglobin
Fortunately, in view of the potential threat to oxygen supply posed by methemoglobin, there are protective mechanisms that ensure that most of this methemoglobin is converted back to hemoglobin.
Protective mechanisms ensure that the amount of methemoglobin in the blood does not normally constitute more than 1 to 2% of total hemoglobin.
For methemoglobin to be converted to iron hemoglobin in the ferric state (Fe 3+) in any or all of the four heme groups, they must be reduced to the ferrous state (Fe 2+); in other words, they must gain an electron.
Due to the loading and unloading of oxygen from hemoglobin and the interactions of oxidizing agents, the body has a low level of methemoglobin that is spontaneously reduced to ferrous hemoglobin (Fe 2+) through the action of methemoglobin reductase. and the electron donor of the nicotinamide adenine dinucleotide.
The system comprises three elements: nicotinamide adenine dinucleotide, the heme-containing protein, cytochrome b5, and the enzyme, cytochrome b5 reductase. The electron donor is nicotinamide adenine dinucleotide, a product of glucose oxidation (glycolysis).
Under physiological conditions, this system represents about 99% of the daily reduction of methemoglobin to hemoglobin.
When exposed to a large amount of an oxidizing agent, these endogenous systems are overwhelmed and the result is an elevated level of methemoglobin (acquired methemoglobinemia).
The reducing pathway, which is dependent on the enzyme NADPH-MHb reductase, is also capable of converting methemoglobin to hemoglobin, but under normal physiological conditions this is of very little importance.
However, this alternative pathway is significant in cases of cytochrome-b5-reductase deficiency and is essential for the therapeutic action of methylene blue, the drug used to treat acquired methemoglobinemia.
Finally, several species of general antioxidants, that is, electron donors, present in red blood cells, such as the reduction of glutathione and ascorbic acid, may play a minor role in reducing methemoglobin to hemoglobin.