Hemoglobin

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https://en.wikipedia.org/wiki/Hemoglobin 

Structure of human hemoglobin. α and β subunits are in red and blue, respectively, and the iron-containing heme groups in green. From PDB: 1GZX​ Proteopedia Hemoglobin
Protein type	metalloprotein, globulin
Function	oxygen-transport
Cofactor(s)	heme (4)
Subunit name Gene Chromosomal locus Hb-α1 HBA1 Chr. 16 p13.3 Hb-α2 HBA2 Chr. 16 p13.3 Hb-β HBB Chr. 11 p15.5

Hemoglobin, or haemoglobin (spelling differences) (from Greek αἷμα, haîma 'blood' + Latin globus 'ball, sphere' + -in) (/ˈhiːməˌɡloʊbɪn, ˈhɛ-, -moʊ-/), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein in the red blood cells (erythrocytes) of almost all vertebrates (the exception being the fish family Channichthyidae) as well as the tissues of some invertebrates. Hemoglobin in blood carries oxygen from the lungs or gills to the rest of the body (i.e. the tissues). There it releases the oxygen to permit aerobic respiration to provide energy to power the functions of the organism in the process called metabolism. A healthy individual has 12 to 20 grams of hemoglobin in every 100 mL of blood.

In mammals, the protein makes up about 96% of the red blood cells' dry content (by weight), and around 35% of the total content (including water). Hemoglobin has an oxygen-binding capacity of 1.34 mL O₂ per gram, which increases the total blood oxygen capacity seventy-fold compared to dissolved oxygen in blood. The mammalian hemoglobin molecule can bind (carry) up to four oxygen molecules.

Hemoglobin is involved in the transport of other gases: It carries some of the body's respiratory carbon dioxide (about 20–25% of the total) as carbaminohemoglobin, in which CO₂ is bound to the heme protein. The molecule also carries the important regulatory molecule nitric oxide bound to a globin protein thiol group, releasing it at the same time as oxygen.

Hemoglobin is also found outside red blood cells and their progenitor lines. Other cells that contain hemoglobin include the A9 dopaminergic neurons in the substantia nigra, macrophages, alveolar cells, lungs, retinal pigment epithelium, hepatocytes, mesangial cells in the kidney, endometrial cells, cervical cells and vaginal epithelial cells. In these tissues, hemoglobin has a non-oxygen-carrying function as an antioxidant and a regulator of iron metabolism. Excessive glucose in one's blood can attach to hemoglobin and raise the level of hemoglobin A1c.

Hemoglobin and hemoglobin-like molecules are also found in many invertebrates, fungi, and plants. In these organisms, hemoglobins may carry oxygen, or they may act to transport and regulate other small molecules and ions such as carbon dioxide, nitric oxide, hydrogen sulfide and sulfide. A variant of the molecule, called leghemoglobin, is used to scavenge oxygen away from anaerobic systems, such as the nitrogen-fixing nodules of leguminous plants, lest the oxygen poison (deactivate) the system.

Hemoglobinemia is a medical condition in which there is an excess of hemoglobin in the blood plasma. This is an effect of intravascular hemolysis, in which hemoglobin separates from red blood cells, a form of anemia.

Research history

Max Perutz won the Nobel Prize for chemistry for his work determining the molecular structure of hemoglobin and myoglobin

In 1825, Johann Friedrich Engelhart discovered that the ratio of iron to protein is identical in the hemoglobins of several species. From the known atomic mass of iron he calculated the molecular mass of hemoglobin to n × 16000 (n = number of iron atoms per hemoglobin, now known to be 4), the first determination of a protein's molecular mass. This "hasty conclusion" drew a lot of ridicule at the time from scientists who could not believe that any molecule could be that big. Gilbert Smithson Adair confirmed Engelhart's results in 1925 by measuring the osmotic pressure of hemoglobin solutions.

The oxygen-carrying property of hemoglobin was described by Hünefeld in 1840. In 1851, German physiologist Otto Funke published a series of articles in which he described growing hemoglobin crystals by successively diluting red blood cells with a solvent such as pure water, alcohol or ether, followed by slow evaporation of the solvent from the resulting protein solution. Hemoglobin's reversible oxygenation was described a few years later by Felix Hoppe-Seyler.

In 1959, Max Perutz determined the molecular structure of hemoglobin by X-ray crystallography. This work resulted in his sharing with John Kendrew the 1962 Nobel Prize in Chemistry for their studies of the structures of globular proteins.

The role of hemoglobin in the blood was elucidated by French physiologist Claude Bernard. The name hemoglobin is derived from the words heme and globin, reflecting the fact that each subunit of hemoglobin is a globular protein with an embedded heme group. Each heme group contains one iron atom, that can bind one oxygen molecule through ion-induced dipole forces. The most common type of hemoglobin in mammals contains four such subunits.

Genetics

Hemoglobin consists of protein subunits (the globin molecules), and these proteins, in turn, are folded chains of a large number of different amino acids called polypeptides. The amino acid sequence of any polypeptide created by a cell is in turn determined by the stretches of DNA called genes. In all proteins, it is the amino acid sequence that determines the protein's chemical properties and function.

There is more than one hemoglobin gene: in humans, hemoglobin A (the main form of hemoglobin present in adult) is coded for by the genes, HBA1, HBA2, and HBB. The hemoglobin subunit alpha 1 and alpha 2 are coded by the genes HBA1 and HBA2, respectively, which are both on chromosome 16 and are close to each other. The hemoglobin subunit beta is coded by HBB gene which is on chromosome 11 . The amino acid sequences of the globin proteins in hemoglobins usually differ between species. These differences grow with evolutionary distance between species. For example, the most common hemoglobin sequences in humans, bonobos and chimpanzees are completely identical, without even a single amino acid difference in either the alpha or the beta globin protein chains. Whereas the human and gorilla hemoglobin differ in one amino acid in both alpha and beta chains, these differences grow larger between less closely related species.

Even within a species, variants of hemoglobin exist, although one sequence is usually "most common" in each species. Mutations in the genes for the hemoglobin protein in a species result in hemoglobin variants. Many of these mutant forms of hemoglobin cause no disease. Some of these mutant forms of hemoglobin, however, cause a group of hereditary diseases termed the hemoglobinopathies. The best known hemoglobinopathy is sickle-cell disease, which was the first human disease whose mechanism was understood at the molecular level. A (mostly) separate set of diseases called thalassemias involves underproduction of normal and sometimes abnormal hemoglobins, through problems and mutations in globin gene regulation. All these diseases produce anemia.

Protein alignment of human hemoglobin proteins, alpha, beta, and delta subunits respectively. The alignments were created using UniProt's alignment tool available online.

Variations in hemoglobin amino acid sequences, as with other proteins, may be adaptive. For example, hemoglobin has been found to adapt in different ways to high altitudes. Organisms living at high elevations experience lower partial pressures of oxygen compared to those at sea level. This presents a challenge to the organisms that inhabit such environments because hemoglobin, which normally binds oxygen at high partial pressures of oxygen, must be able to bind oxygen when it is present at a lower pressure. Different organisms have adapted to such a challenge. For example, recent studies have suggested genetic variants in deer mice that help explain how deer mice that live in the mountains are able to survive in the thin air that accompanies high altitudes. A researcher from the University of Nebraska-Lincoln found mutations in four different genes that can account for differences between deer mice that live in lowland prairies versus the mountains. After examining wild mice captured from both highlands and lowlands, it was found that: the genes of the two breeds are "virtually identical—except for those that govern the oxygen-carrying capacity of their hemoglobin". "The genetic difference enables highland mice to make more efficient use of their oxygen", since less is available at higher altitudes, such as those in the mountains. Mammoth hemoglobin featured mutations that allowed for oxygen delivery at lower temperatures, thus enabling mammoths to migrate to higher latitudes during the Pleistocene. This was also found in hummingbirds that inhabit the Andes. Hummingbirds already expend a lot of energy and thus have high oxygen demands and yet Andean hummingbirds have been found to thrive in high altitudes. Non-synonymous mutations in the hemoglobin gene of multiple species living at high elevations (Oreotrochilus, A. castelnaudii, C. violifer, P. gigas, and A. viridicuada) have caused the protein to have less of an affinity for inositol hexaphosphate (IHP), a molecule found in birds that has a similar role as 2,3-BPG in humans; this results in the ability to bind oxygen in lower partial pressures.

Birds' unique circulatory lungs also promote efficient use of oxygen at low partial pressures of O₂. These two adaptations reinforce each other and account for birds' remarkable high-altitude performance.

Hemoglobin adaptation extends to humans, as well. There is a higher offspring survival rate among Tibetan women with high oxygen saturation genotypes residing at 4,000 m. Natural selection seems to be the main force working on this gene because the mortality rate of offspring is significantly lower for women with higher hemoglobin-oxygen affinity when compared to the mortality rate of offspring from women with low hemoglobin-oxygen affinity. While the exact genotype and mechanism by which this occurs is not yet clear, selection is acting on these women's ability to bind oxygen in low partial pressures, which overall allows them to better sustain crucial metabolic processes.

Synthesis

Hemoglobin (Hb) is synthesized in a complex series of steps. The heme part is synthesized in a series of steps in the mitochondria and the cytosol of immature red blood cells, while the globin protein parts are synthesized by ribosomes in the cytosol. Production of Hb continues in the cell throughout its early development from the proerythroblast to the reticulocyte in the bone marrow. At this point, the nucleus is lost in mammalian red blood cells, but not in birds and many other species. Even after the loss of the nucleus in mammals, residual ribosomal RNA allows further synthesis of Hb until the reticulocyte loses its RNA soon after entering the vasculature (this hemoglobin-synthetic RNA in fact gives the reticulocyte its reticulated appearance and name).

Structure of heme

Heme b group

Hemoglobin has a quaternary structure characteristic of many multi-subunit globular proteins. Most of the amino acids in hemoglobin form alpha helices, and these helices are connected by short non-helical segments. Hydrogen bonds stabilize the helical sections inside this protein, causing attractions within the molecule, which then causes each polypeptide chain to fold into a specific shape. Hemoglobin's quaternary structure comes from its four subunits in roughly a tetrahedral arrangement.

In most vertebrates, the hemoglobin molecule is an assembly of four globular protein subunits. Each subunit is composed of a protein chain tightly associated with a non-protein prosthetic heme group. Each protein chain arranges into a set of alpha-helix structural segments connected together in a globin fold arrangement. Such a name is given because this arrangement is the same folding motif used in other heme/globin proteins such as myoglobin. This folding pattern contains a pocket that strongly binds the heme group.

A heme group consists of an iron (Fe) ion held in a heterocyclic ring, known as a porphyrin. This porphyrin ring consists of four pyrrole molecules cyclically linked together (by methine bridges) with the iron ion bound in the center. The iron ion, which is the site of oxygen binding, coordinates with the four nitrogen atoms in the center of the ring, which all lie in one plane. The iron is bound strongly (covalently) to the globular protein via the N atoms of the imidazole ring of F8 histidine residue (also known as the proximal histidine) below the porphyrin ring. A sixth position can reversibly bind oxygen by a coordinate covalent bond, completing the octahedral group of six ligands. This reversible bonding with oxygen is why hemoglobin is so useful for transporting oxygen around the body. Oxygen binds in an "end-on bent" geometry where one oxygen atom binds to Fe and the other protrudes at an angle. When oxygen is not bound, a very weakly bonded water molecule fills the site, forming a distorted octahedron.

Even though carbon dioxide is carried by hemoglobin, it does not compete with oxygen for the iron-binding positions but is bound to the amine groups of the protein chains attached to the heme groups.

The iron ion may be either in the ferrous Fe²⁺ or in the ferric Fe³⁺ state, but ferrihemoglobin (methemoglobin) (Fe³⁺) cannot bind oxygen. In binding, oxygen temporarily and reversibly oxidizes (Fe²⁺) to (Fe³⁺) while oxygen temporarily turns into the superoxide ion, thus iron must exist in the +2 oxidation state to bind oxygen. If superoxide ion associated to Fe³⁺ is protonated, the hemoglobin iron will remain oxidized and incapable of binding oxygen. In such cases, the enzyme methemoglobin reductase will be able to eventually reactivate methemoglobin by reducing the iron center.

In adult humans, the most common hemoglobin type is a tetramer (which contains four subunit proteins) called hemoglobin A, consisting of two α and two β subunits non-covalently bound, each made of 141 and 146 amino acid residues, respectively. This is denoted as α₂β₂. The subunits are structurally similar and about the same size. Each subunit has a molecular weight of about 16,000 daltons, for a total molecular weight of the tetramer of about 64,000 daltons (64,458 g/mol). Thus, 1 g/dL = 0.1551 mmol/L. Hemoglobin A is the most intensively studied of the hemoglobin molecules.

In human infants, the hemoglobin molecule is made up of 2 α chains and 2 γ chains. The gamma chains are gradually replaced by β chains as the infant grows.

The four polypeptide chains are bound to each other by salt bridges, hydrogen bonds, and the hydrophobic effect.

Oxygen saturation

In general, hemoglobin can be saturated with oxygen molecules (oxyhemoglobin), or desaturated with oxygen molecules (deoxyhemoglobin).

Oxyhemoglobin

Oxyhemoglobin is formed during physiological respiration when oxygen binds to the heme component of the protein hemoglobin in red blood cells. This process occurs in the pulmonary capillaries adjacent to the alveoli of the lungs. The oxygen then travels through the blood stream to be dropped off at cells where it is utilized as a terminal electron acceptor in the production of ATP by the process of oxidative phosphorylation. It does not, however, help to counteract a decrease in blood pH. Ventilation, or breathing, may reverse this condition by removal of carbon dioxide, thus causing a shift up in pH.

Hemoglobin exists in two forms, a taut (tense) form (T) and a relaxed form (R). Various factors such as low pH, high CO₂ and high 2,3 BPG at the level of the tissues favor the taut form, which has low oxygen affinity and releases oxygen in the tissues. Conversely, a high pH, low CO₂, or low 2,3 BPG favors the relaxed form, which can better bind oxygen. The partial pressure of the system also affects O₂ affinity where, at high partial pressures of oxygen (such as those present in the alveoli), the relaxed (high affinity, R) state is favoured. Inversely, at low partial pressures (such as those present in respiring tissues), the (low affinity, T) tense state is favoured. Additionally, the binding of oxygen to the iron(II) heme pulls the iron into the plane of the porphyrin ring, causing a slight conformational shift. The shift encourages oxygen to bind to the three remaining heme units within hemoglobin (thus, oxygen binding is cooperative).

Deoxygenated hemoglobin

Deoxygenated hemoglobin is the form of hemoglobin without the bound oxygen. The absorption spectra of oxyhemoglobin and deoxyhemoglobin differ. The oxyhemoglobin has significantly lower absorption of the 660 nm wavelength than deoxyhemoglobin, while at 940 nm its absorption is slightly higher. This difference is used for the measurement of the amount of oxygen in a patient's blood by an instrument called a pulse oximeter. This difference also accounts for the presentation of cyanosis, the blue to purplish color that tissues develop during hypoxia.

Deoxygenated hemoglobin is paramagnetic; it is weakly attracted to magnetic fields. In contrast, oxygenated hemoglobin exhibits diamagnetism, a weak repulsion from a magnetic field.

Evolution of vertebrate hemoglobin

Scientists agree that the event that separated myoglobin from hemoglobin occurred after lampreys diverged from jawed vertebrates. This separation of myoglobin and hemoglobin allowed for the different functions of the two molecules to arise and develop: myoglobin has more to do with oxygen storage while hemoglobin is tasked with oxygen transport. The α- and β-like globin genes encode the individual subunits of the protein. The predecessors of these genes arose through another duplication event also after the gnathosome common ancestor derived from jawless fish, approximately 450–500 million years ago. Ancestral reconstruction studies suggest that the preduplication ancestor of the α and β genes was a dimer made up of identical globin subunits, which then evolved to assemble into a tetrameric architecture after the duplication. The development of α and β genes created the potential for hemoglobin to be composed of multiple distinct subunits, a physical composition central to hemoglobin's ability to transport oxygen. Having multiple subunits contributes to hemoglobin's ability to bind oxygen cooperatively as well as be regulated allosterically. Subsequently, the α gene also underwent a duplication event to form the HBA1 and HBA2 genes. These further duplications and divergences have created a diverse range of α- and β-like globin genes that are regulated so that certain forms occur at different stages of development.

Most ice fish of the family Channichthyidae have lost their hemoglobin genes as an adaptation to cold water.

Iron's oxidation state in oxyhemoglobin

Assigning oxygenated hemoglobin's oxidation state is difficult because oxyhemoglobin (Hb-O₂), by experimental measurement, is diamagnetic (no net unpaired electrons), yet the lowest-energy (ground-state) electron configurations in both oxygen and iron are paramagnetic (suggesting at least one unpaired electron in the complex). The lowest-energy form of oxygen, and the lowest energy forms of the relevant oxidation states of iron, are these:

• Triplet oxygen, the lowest-energy molecular oxygen species, has two unpaired electrons in antibonding π* molecular orbitals.
• Iron(II) tends to exist in a high-spin 3d⁶ configuration with four unpaired electrons.
• Iron(III) (3d⁵) has an odd number of electrons, and thus must have one or more unpaired electrons, in any energy state.

All of these structures are paramagnetic (have unpaired electrons), not diamagnetic. Thus, a non-intuitive (e.g., a higher-energy for at least one species) distribution of electrons in the combination of iron and oxygen must exist, in order to explain the observed diamagnetism and no unpaired electrons.

The two logical possibilities to produce diamagnetic (no net spin) Hb-O₂ are:

1. Low-spin Fe²⁺ binds to singlet oxygen. Both low-spin iron and singlet oxygen are diamagnetic. However, the singlet form of oxygen is the higher-energy form of the molecule.
2. Low-spin Fe³⁺ binds to O₂^•− (the superoxide ion) and the two unpaired electrons couple antiferromagnetically, giving observed diamagnetic properties. Here, the iron has been oxidized (has lost one electron), and the oxygen has been reduced (has gained one electron).

Another possible model in which low-spin Fe⁴⁺ binds to peroxide, O₂²⁻, can be ruled out by itself, because the iron is paramagnetic (although the peroxide ion is diamagnetic). Here, the iron has been oxidized by two electrons, and the oxygen reduced by two electrons.

Direct experimental data:

• X-ray photoelectron spectroscopy suggests iron has an oxidation state of approximately 3.2.
• Infrared vibrational frequencies of the O-O bond suggests a bond length fitting with superoxide (a bond order of about 1.6, with superoxide being 1.5).
• X-ray Absorption Near Edge Structures at the iron K-edge. The energy shift of 5 eV between deoxyhemoglobin and oxyhemoglobin, as for all the methemoglobin species, strongly suggests an actual local charge closer to Fe³⁺ than Fe²⁺.

Thus, the nearest formal oxidation state of iron in Hb-O₂ is the +3 state, with oxygen in the −1 state (as superoxide .O₂⁻). The diamagnetism in this configuration arises from the single unpaired electron on superoxide aligning antiferromagnetically with the single unpaired electron on iron (in a low-spin d⁵ state), to give no net spin to the entire configuration, in accordance with diamagnetic oxyhemoglobin from experiment.

The second choice of the logical possibilities above for diamagnetic oxyhemoglobin being found correct by experiment, is not surprising: singlet oxygen (possibility #1) is an unrealistically high energy state. Model 3 leads to unfavorable separation of charge (and does not agree with the magnetic data), although it could make a minor contribution as a resonance form. Iron's shift to a higher oxidation state in Hb-O₂ decreases the atom's size, and allows it into the plane of the porphyrin ring, pulling on the coordinated histidine residue and initiating the allosteric changes seen in the globulins.

Early postulates by bio-inorganic chemists claimed that possibility #1 (above) was correct and that iron should exist in oxidation state II. This conclusion seemed likely, since the iron oxidation state III as methemoglobin, when not accompanied by superoxide .O₂⁻ to "hold" the oxidation electron, was known to render hemoglobin incapable of binding normal triplet O₂ as it occurs in the air. It was thus assumed that iron remained as Fe(II) when oxygen gas was bound in the lungs. The iron chemistry in this previous classical model was elegant, but the required presence of the diamagnetic, high-energy, singlet oxygen molecule was never explained. It was classically argued that the binding of an oxygen molecule placed high-spin iron(II) in an octahedral field of strong-field ligands; this change in field would increase the crystal field splitting energy, causing iron's electrons to pair into the low-spin configuration, which would be diamagnetic in Fe(II). This forced low-spin pairing is indeed thought to happen in iron when oxygen binds, but is not enough to explain iron's change in size. Extraction of an additional electron from iron by oxygen is required to explain both iron's smaller size and observed increased oxidation state, and oxygen's weaker bond.

The assignment of a whole-number oxidation state is a formalism, as the covalent bonds are not required to have perfect bond orders involving whole electron transfer. Thus, all three models for paramagnetic Hb-O₂ may contribute to some small degree (by resonance) to the actual electronic configuration of Hb-O₂. However, the model of iron in Hb-O₂ being Fe(III) is more correct than the classical idea that it remains Fe(II).

Cooperativity

A schematic visual model of oxygen-binding process, showing all four monomers and hemes, and protein chains only as diagrammatic coils, to facilitate visualization into the molecule. Oxygen is not shown in this model, but, for each of the iron atoms, it binds to the iron (red sphere) in the flat heme. For example, in the upper-left of the four hemes shown, oxygen binds at the left of the iron atom shown in the upper-left of diagram. This causes the iron atom to move backward into the heme that holds it (the iron moves upward as it binds oxygen, in this illustration), tugging the histidine residue (modeled as a red pentagon on the right of the iron) closer, as it does. This, in turn, pulls on the protein chain holding the histidine.

When oxygen binds to the iron complex, it causes the iron atom to move back toward the center of the plane of the porphyrin ring (see moving diagram). At the same time, the imidazole side-chain of the histidine residue interacting at the other pole of the iron is pulled toward the porphyrin ring. This interaction forces the plane of the ring sideways toward the outside of the tetramer, and also induces a strain in the protein helix containing the histidine as it moves nearer to the iron atom. This strain is transmitted to the remaining three monomers in the tetramer, where it induces a similar conformational change in the other heme sites such that binding of oxygen to these sites becomes easier.

As oxygen binds to one monomer of hemoglobin, the tetramer's conformation shifts from the T (tense) state to the R (relaxed) state. This shift promotes the binding of oxygen to the remaining three monomer's heme groups, thus saturating the hemoglobin molecule with oxygen.

In the tetrameric form of normal adult hemoglobin, the binding of oxygen is, thus, a cooperative process. The binding affinity of hemoglobin for oxygen is increased by the oxygen saturation of the molecule, with the first molecules of oxygen bound influencing the shape of the binding sites for the next ones, in a way favorable for binding. This positive cooperative binding is achieved through steric conformational changes of the hemoglobin protein complex as discussed above; i.e., when one subunit protein in hemoglobin becomes oxygenated, a conformational or structural change in the whole complex is initiated, causing the other subunits to gain an increased affinity for oxygen. As a consequence, the oxygen binding curve of hemoglobin is sigmoidal, or S-shaped, as opposed to the normal hyperbolic curve associated with noncooperative binding.

The dynamic mechanism of the cooperativity in hemoglobin and its relation with low-frequency resonance has been discussed.

Binding for ligands other than oxygen

Besides the oxygen ligand, which binds to hemoglobin in a cooperative manner, hemoglobin ligands also include competitive inhibitors such as carbon monoxide (CO) and allosteric ligands such as carbon dioxide (CO₂) and nitric oxide (NO). The carbon dioxide is bound to amino groups of the globin proteins to form carbaminohemoglobin; this mechanism is thought to account for about 10% of carbon dioxide transport in mammals. Nitric oxide can also be transported by hemoglobin; it is bound to specific thiol groups in the globin protein to form an S-nitrosothiol, which dissociates into free nitric oxide and thiol again, as the hemoglobin releases oxygen from its heme site. This nitric oxide transport to peripheral tissues is hypothesized to assist oxygen transport in tissues, by releasing vasodilatory nitric oxide to tissues in which oxygen levels are low.

Competitive

The binding of oxygen is affected by molecules such as carbon monoxide (for example, from tobacco smoking, exhaust gas, and incomplete combustion in furnaces). CO competes with oxygen at the heme binding site. Hemoglobin's binding affinity for CO is 250 times greater than its affinity for oxygen, meaning that small amounts of CO dramatically reduce hemoglobin's ability to deliver oxygen to the target tissue. Since carbon monoxide is a colorless, odorless and tasteless gas, and poses a potentially fatal threat, carbon monoxide detectors have become commercially available to warn of dangerous levels in residences. When hemoglobin combines with CO, it forms a very bright red compound called carboxyhemoglobin, which may cause the skin of CO poisoning victims to appear pink in death, instead of white or blue. When inspired air contains CO levels as low as 0.02%, headache and nausea occur; if the CO concentration is increased to 0.1%, unconsciousness will follow. In heavy smokers, up to 20% of the oxygen-active sites can be blocked by CO.

In similar fashion, hemoglobin also has competitive binding affinity for cyanide (CN⁻), sulfur monoxide (SO), and sulfide (S²⁻), including hydrogen sulfide (H₂S). All of these bind to iron in heme without changing its oxidation state, but they nevertheless inhibit oxygen-binding, causing grave toxicity.

The iron atom in the heme group must initially be in the ferrous (Fe²⁺) oxidation state to support oxygen and other gases' binding and transport (it temporarily switches to ferric during the time oxygen is bound, as explained above). Initial oxidation to the ferric (Fe³⁺) state without oxygen converts hemoglobin into "hemiglobin" or methemoglobin, which cannot bind oxygen. Hemoglobin in normal red blood cells is protected by a reduction system to keep this from happening. Nitric oxide is capable of converting a small fraction of hemoglobin to methemoglobin in red blood cells. The latter reaction is a remnant activity of the more ancient nitric oxide dioxygenase function of globins.

Allosteric

Carbon dioxide occupies a different binding site on the hemoglobin. At tissues, where carbon dioxide concentration is higher, carbon dioxide binds to allosteric site of hemoglobin, facilitating unloading of oxygen from hemoglobin and ultimately its removal from the body after the oxygen has been released to tissues undergoing metabolism. This increased affinity for carbon dioxide by the venous blood is known as the Bohr effect. Through the enzyme carbonic anhydrase, carbon dioxide reacts with water to give carbonic acid, which decomposes into bicarbonate and protons:

CO₂ + H₂O → H₂CO₃ → HCO₃⁻ + H⁺

The sigmoidal shape of hemoglobin's oxygen-dissociation curve results from cooperative binding of oxygen to hemoglobin.

Hence, blood with high carbon dioxide levels is also lower in pH (more acidic). Hemoglobin can bind protons and carbon dioxide, which causes a conformational change in the protein and facilitates the release of oxygen. Protons bind at various places on the protein, while carbon dioxide binds at the α-amino group. Carbon dioxide binds to hemoglobin and forms carbaminohemoglobin. This decrease in hemoglobin's affinity for oxygen by the binding of carbon dioxide and acid is known as the Bohr effect. The Bohr effect favors the T state rather than the R state. (shifts the O₂-saturation curve to the right). Conversely, when the carbon dioxide levels in the blood decrease (i.e., in the lung capillaries), carbon dioxide and protons are released from hemoglobin, increasing the oxygen affinity of the protein. 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.

It is necessary for hemoglobin to release the oxygen that it binds; if not, there is no point in binding it. The sigmoidal curve of hemoglobin makes it efficient in binding (taking up O₂ in lungs), and efficient in unloading (unloading O₂ in tissues).

In people acclimated to high altitudes, the concentration of 2,3-Bisphosphoglycerate (2,3-BPG) in the blood is increased, which allows these individuals to deliver a larger amount of oxygen to tissues under conditions of lower oxygen tension. This phenomenon, where molecule Y affects the binding of molecule X to a transport molecule Z, is called a heterotropic allosteric effect. Hemoglobin in organisms at high altitudes has also adapted such that it has less of an affinity for 2,3-BPG and so the protein will be shifted more towards its R state. In its R state, hemoglobin will bind oxygen more readily, thus allowing organisms to perform the necessary metabolic processes when oxygen is present at low partial pressures.

Animals other than humans use different molecules to bind to hemoglobin and change its O₂ affinity under unfavorable conditions. Fish use both ATP and GTP. These bind to a phosphate "pocket" on the fish hemoglobin molecule, which stabilizes the tense state and therefore decreases oxygen affinity. GTP reduces hemoglobin oxygen affinity much more than ATP, which is thought to be due to an extra hydrogen bond formed that further stabilizes the tense state. Under hypoxic conditions, the concentration of both ATP and GTP is reduced in fish red blood cells to increase oxygen affinity.

A variant hemoglobin, called fetal hemoglobin (HbF, α₂γ₂), is found in the developing fetus, and binds oxygen with greater affinity than adult hemoglobin. This means that the oxygen binding curve for fetal hemoglobin is left-shifted (i.e., a higher percentage of hemoglobin has oxygen bound to it at lower oxygen tension), in comparison to that of adult hemoglobin. As a result, fetal blood in the placenta is able to take oxygen from maternal blood.

Hemoglobin also carries nitric oxide (NO) in the globin part of the molecule. This improves oxygen delivery in the periphery and contributes to the control of respiration. NO binds reversibly to a specific cysteine residue in globin; the binding depends on the state (R or T) of the hemoglobin. The resulting S-nitrosylated hemoglobin influences various NO-related activities such as the control of vascular resistance, blood pressure and respiration. NO is not released in the cytoplasm of red blood cells but transported out of them by an anion exchanger called AE1.

Types in humans

Hemoglobin variants are a part of the normal embryonic and fetal development. They may also be pathologic mutant forms of hemoglobin in a population, caused by variations in genetics. Some well-known hemoglobin variants, such as sickle-cell anemia, are responsible for diseases and are considered hemoglobinopathies. Other variants cause no detectable pathology, and are thus considered non-pathological variants.

In the embryo:

• Gower 1 (ζ₂ε₂)
• Gower 2 (α₂ε₂) (PDB: 1A9W​)
• Hemoglobin Portland I (ζ₂γ₂)
• Hemoglobin Portland II (ζ₂β₂).

In the fetus:

• Hemoglobin F (α₂γ₂) (PDB: 1FDH​).

After birth:

• Hemoglobin A (adult hemoglobin) (α₂β₂) (PDB: 1BZ0​) – The most common with a normal amount over 95%
• Hemoglobin A₂ (α₂δ₂) – δ chain synthesis begins late in the third trimester and, in adults, it has a normal range of 1.5–3.5%
• Hemoglobin F (fetal hemoglobin) (α₂γ₂) – In adults Hemoglobin F is restricted to a limited population of red cells called F-cells. However, the level of Hb F can be elevated in persons with sickle-cell disease and beta-thalassemia.

Gene expression of hemoglobin before and after birth. Also identifies the types of cells and organs in which the gene expression (data on Wood W.G., (1976). Br. Med. Bull. 32, 282.)

Variant forms that cause disease:

• Hemoglobin D-Punjab – (α₂β^D₂) – A variant form of hemoglobin.
• Hemoglobin H (β₄) – A variant form of hemoglobin, formed by a tetramer of β chains, which may be present in variants of α thalassemia.
• Hemoglobin Barts (γ₄) – A variant form of hemoglobin, formed by a tetramer of γ chains, which may be present in variants of α thalassemia.
• Hemoglobin S (α₂β^S₂) – A variant form of hemoglobin found in people with sickle cell disease. There is a variation in the β-chain gene, causing a change in the properties of hemoglobin, which results in sickling of red blood cells.
• Hemoglobin C (α₂β^C₂) – Another variant due to a variation in the β-chain gene. This variant causes a mild chronic hemolytic anemia.
• Hemoglobin E (α₂β^E₂) – Another variant due to a variation in the β-chain gene. This variant causes a mild chronic hemolytic anemia.
• Hemoglobin AS – A heterozygous form causing sickle cell trait with one adult gene and one sickle cell disease gene
• Hemoglobin SC disease – A compound heterozygous form with one sickle gene and another encoding Hemoglobin C.
• Hemoglobin Hopkins-2 - A variant form of hemoglobin that is sometimes viewed in combination with Hemoglobin S to produce sickle cell disease.

Degradation in vertebrate animals

When red blood cells reach the end of their life due to aging or defects, they are removed from the circulation by the phagocytic activity of macrophages in the spleen or the liver or hemolyze within the circulation. Free hemoglobin is then cleared from the circulation via the hemoglobin transporter CD163, which is exclusively expressed on monocytes or macrophages. Within these cells the hemoglobin molecule is broken up, and the iron gets recycled. This process also produces one molecule of carbon monoxide for every molecule of heme degraded. Heme degradation is the only natural source of carbon monoxide in the human body, and is responsible for the normal blood levels of carbon monoxide in people breathing normal air. The other major final product of heme degradation is bilirubin. Increased levels of this chemical are detected in the blood if red blood cells are being destroyed more rapidly than usual. Improperly degraded hemoglobin protein or hemoglobin that has been released from the blood cells too rapidly can clog small blood vessels, especially the delicate blood filtering vessels of the kidneys, causing kidney damage. Iron is removed from heme and salvaged for later use, it is stored as hemosiderin or ferritin in tissues and transported in plasma by beta globulins as transferrins. When the porphyrin ring is broken up, the fragments are normally secreted as a yellow pigment called bilirubin, which is secreted into the intestines as bile. Intestines metabolise bilirubin into urobilinogen. Urobilinogen leaves the body in faeces, in a pigment called stercobilin. Globulin is metabolised into amino acids that are then released into circulation.

Diseases related to hemoglobin

Hemoglobin deficiency can be caused either by a decreased amount of hemoglobin molecules, as in anemia, or by decreased ability of each molecule to bind oxygen at the same partial pressure of oxygen. Hemoglobinopathies (genetic defects resulting in abnormal structure of the hemoglobin molecule) may cause both. In any case, hemoglobin deficiency decreases blood oxygen-carrying capacity. Hemoglobin deficiency is, in general, strictly distinguished from hypoxemia, defined as decreased partial pressure of oxygen in blood, although both are causes of hypoxia (insufficient oxygen supply to tissues).

Other common causes of low hemoglobin include loss of blood, nutritional deficiency, bone marrow problems, chemotherapy, kidney failure, or abnormal hemoglobin (such as that of sickle-cell disease).

The ability of each hemoglobin molecule to carry oxygen is normally modified by altered blood pH or CO₂, causing an altered oxygen–hemoglobin dissociation curve. However, it can also be pathologically altered in, e.g., carbon monoxide poisoning.

Decrease of hemoglobin, with or without an absolute decrease of red blood cells, leads to symptoms of anemia. Anemia has many different causes, although iron deficiency and its resultant iron deficiency anemia are the most common causes in the Western world. As absence of iron decreases heme synthesis, red blood cells in iron deficiency anemia are hypochromic (lacking the red hemoglobin pigment) and microcytic (smaller than normal). Other anemias are rarer. In hemolysis (accelerated breakdown of red blood cells), associated jaundice is caused by the hemoglobin metabolite bilirubin, and the circulating hemoglobin can cause kidney failure.

Some mutations in the globin chain are associated with the hemoglobinopathies, such as sickle-cell disease and thalassemia. Other mutations, as discussed at the beginning of the article, are benign and are referred to merely as hemoglobin variants.

There is a group of genetic disorders, known as the porphyrias that are characterized by errors in metabolic pathways of heme synthesis. King George III of the United Kingdom was probably the most famous porphyria sufferer.

To a small extent, hemoglobin A slowly combines with glucose at the terminal valine (an alpha aminoacid) of each β chain. The resulting molecule is often referred to as Hb A_1c, a glycated hemoglobin. The binding of glucose to amino acids in the hemoglobin takes place spontaneously (without the help of an enzyme) in many proteins, and is not known to serve a useful purpose. However, as the concentration of glucose in the blood increases, the percentage of Hb A that turns into Hb A_1c increases. In diabetics whose glucose usually runs high, the percent Hb A_1c also runs high. Because of the slow rate of Hb A combination with glucose, the Hb A_1c percentage reflects a weighted average of blood glucose levels over the lifetime of red cells, which is approximately 120 days. The levels of glycated hemoglobin are therefore measured in order to monitor the long-term control of the chronic disease of type 2 diabetes mellitus (T2DM). Poor control of T2DM results in high levels of glycated hemoglobin in the red blood cells. The normal reference range is approximately 4.0–5.9%. Though difficult to obtain, values less than 7% are recommended for people with T2DM. Levels greater than 9% are associated with poor control of the glycated hemoglobin, and levels greater than 12% are associated with very poor control. Diabetics who keep their glycated hemoglobin levels close to 7% have a much better chance of avoiding the complications that may accompany diabetes (than those whose levels are 8% or higher). In addition, increased glycated of hemoglobin increases its affinity for oxygen, therefore preventing its release at the tissue and inducing a level of hypoxia in extreme cases.

Elevated levels of hemoglobin are associated with increased numbers or sizes of red blood cells, called polycythemia. This elevation may be caused by congenital heart disease, cor pulmonale, pulmonary fibrosis, too much erythropoietin, or polycythemia vera. High hemoglobin levels may also be caused by exposure to high altitudes, smoking, dehydration (artificially by concentrating Hb), advanced lung disease and certain tumors.

A recent study done in Pondicherry, India, shows its importance in coronary artery disease.

Diagnostic uses

A hemoglobin concentration measurement being administered before a blood donation at the American Red Cross Boston Blood Donation Center.

Hemoglobin concentration measurement is among the most commonly performed blood tests, usually as part of a complete blood count. For example, it is typically tested before or after blood donation. Results are reported in g/L, g/dL or mol/L. 1 g/dL equals about 0.6206 mmol/L, although the latter units are not used as often due to uncertainty regarding the polymeric state of the molecule. This conversion factor, using the single globin unit molecular weight of 16,000 Da, is more common for hemoglobin concentration in blood. For MCHC (mean corpuscular hemoglobin concentration) the conversion factor 0.155, which uses the tetramer weight of 64,500 Da, is more common. Normal levels are:

• Men: 13.8 to 18.0 g/dL (138 to 180 g/L, or 8.56 to 11.17 mmol/L)
• Women: 12.1 to 15.1 g/dL (121 to 151 g/L, or 7.51 to 9.37 mmol/L)
• Children: 11 to 16 g/dL (110 to 160 g/L, or 6.83 to 9.93 mmol/L)
• Pregnant women: 11 to 14 g/dL (110 to 140 g/L, or 6.83 to 8.69 mmol/L) (9.5 to 15 usual value during pregnancy)

Normal values of hemoglobin in the 1st and 3rd trimesters of pregnant women must be at least 11 g/dL and at least 10.5 g/dL during the 2nd trimester.

Dehydration or hyperhydration can greatly influence measured hemoglobin levels. Albumin can indicate hydration status.

If the concentration is below normal, this is called anemia. Anemias are classified by the size of red blood cells, the cells that contain hemoglobin in vertebrates. The anemia is called "microcytic" if red cells are small, "macrocytic" if they are large, and "normocytic" otherwise.

Hematocrit, the proportion of blood volume occupied by red blood cells, is typically about three times the hemoglobin concentration measured in g/dL. For example, if the hemoglobin is measured at 17 g/dL, that compares with a hematocrit of 51%.

Laboratory hemoglobin test methods require a blood sample (arterial, venous, or capillary) and analysis on hematology analyzer and CO-oximeter. Additionally, a new noninvasive hemoglobin (SpHb) test method called Pulse CO-Oximetry is also available with comparable accuracy to invasive methods.

Concentrations of oxy- and deoxyhemoglobin can be measured continuously, regionally and noninvasively using NIRS. NIRS can be used both on the head and on muscles. This technique is often used for research in e.g. elite sports training, ergonomics, rehabilitation, patient monitoring, neonatal research, functional brain monitoring, brain–computer interface, urology (bladder contraction), neurology (Neurovascular coupling) and more.

Long-term control of blood sugar concentration can be measured by the concentration of Hb A_1c. Measuring it directly would require many samples because blood sugar levels vary widely through the day. Hb A_1c is the product of the irreversible reaction of hemoglobin A with glucose. A higher glucose concentration results in more Hb A_1c. Because the reaction is slow, the Hb A_1c proportion represents glucose level in blood averaged over the half-life of red blood cells, is typically ~120 days. An Hb A_1c proportion of 6.0% or less show good long-term glucose control, while values above 7.0% are elevated. This test is especially useful for diabetics.

The functional magnetic resonance imaging (fMRI) machine uses the signal from deoxyhemoglobin, which is sensitive to magnetic fields since it is paramagnetic. Combined measurement with NIRS shows good correlation with both the oxy- and deoxyhemoglobin signal compared to the BOLD signal.

Athletic tracking and self tracking uses

Hemoglobin can be tracked noninvasively, to build an individual data set tracking the hemoconcentration and hemodilution effects of daily activities for better understanding of sports performance and training. Athletes are often concerned about endurance and intensity of exercise. The sensor uses light-emitting diodes that emit red and infrared light through the tissue to a light detector, which then sends a signal to a processor to calculate the absorption of light by the hemoglobin protein. This sensor is similar to a pulse oximeter, which consists of a small sensing device that clips to the finger.

Analogues in non-vertebrate organisms

A variety of oxygen-transport and -binding proteins exist in organisms throughout the animal and plant kingdoms. Organisms including bacteria, protozoans, and fungi all have hemoglobin-like proteins whose known and predicted roles include the reversible binding of gaseous ligands. Since many of these proteins contain globins and the heme moiety (iron in a flat porphyrin support), they are often called hemoglobins, even if their overall tertiary structure is very different from that of vertebrate hemoglobin. In particular, the distinction of "myoglobin" and hemoglobin in lower animals is often impossible, because some of these organisms do not contain muscles. Or, they may have a recognizable separate circulatory system but not one that deals with oxygen transport (for example, many insects and other arthropods). In all these groups, heme/globin-containing molecules (even monomeric globin ones) that deal with gas-binding are referred to as oxyhemoglobins. In addition to dealing with transport and sensing of oxygen, they may also deal with NO, CO₂, sulfide compounds, and even O₂ scavenging in environments that must be anaerobic. They may even deal with detoxification of chlorinated materials in a way analogous to heme-containing P450 enzymes and peroxidases.

The giant tube worm Riftia pachyptila showing red hemoglobin-containing plumes

The structure of hemoglobins varies across species. Hemoglobin occurs in all kingdoms of organisms, but not in all organisms. Primitive species such as bacteria, protozoa, algae, and plants often have single-globin hemoglobins. Many nematode worms, molluscs, and crustaceans contain very large multisubunit molecules, much larger than those in vertebrates. In particular, chimeric hemoglobins found in fungi and giant annelids may contain both globin and other types of proteins.

One of the most striking occurrences and uses of hemoglobin in organisms is in the giant tube worm (Riftia pachyptila, also called Vestimentifera), which can reach 2.4 meters length and populates ocean volcanic vents. Instead of a digestive tract, these worms contain a population of bacteria constituting half the organism's weight. The bacteria oxidize H₂S from the vent with O₂ from the water to produce energy to make food from H₂O and CO₂. The worms' upper end is a deep-red fan-like structure ("plume"), which extends into the water and absorbs H₂S and O₂ for the bacteria, and CO₂ for use as synthetic raw material similar to photosynthetic plants. The structures are bright red due to their content of several extraordinarily complex hemoglobins that have up to 144 globin chains, each including associated heme structures. These hemoglobins are remarkable for being able to carry oxygen in the presence of sulfide, and even to carry sulfide, without being completely "poisoned" or inhibited by it as hemoglobins in most other species are.

Other oxygen-binding proteins

Myoglobin

Found in the muscle tissue of many vertebrates, including humans, it gives muscle tissue a distinct red or dark gray color. It is very similar to hemoglobin in structure and sequence, but is not a tetramer; instead, it is a monomer that lacks cooperative binding. It is used to store oxygen rather than transport it.

Hemocyanin

The second most common oxygen-transporting protein found in nature, it is found in the blood of many arthropods and molluscs. Uses copper prosthetic groups instead of iron heme groups and is blue in color when oxygenated.

Hemerythrin

Some marine invertebrates and a few species of annelid use this iron-containing non-heme protein to carry oxygen in their blood. Appears pink/violet when oxygenated, clear when not.

Chlorocruorin

Found in many annelids, it is very similar to erythrocruorin, but the heme group is significantly different in structure. Appears green when deoxygenated and red when oxygenated.

Vanabins

Also known as vanadium chromagens, they are found in the blood of sea squirts. They were once hypothesized to use the metal vanadium as an oxygen binding prosthetic group. However, although they do contain vanadium by preference, they apparently bind little oxygen, and thus have some other function, which has not been elucidated (sea squirts also contain some hemoglobin). They may act as toxins.

Erythrocruorin

Found in many annelids, including earthworms, it is a giant free-floating blood protein containing many dozens—possibly hundreds—of iron- and heme-bearing protein subunits bound together into a single protein complex with a molecular mass greater than 3.5 million daltons.

Pinnaglobin

Only seen in the mollusc Pinna nobilis. Brown manganese-based porphyrin protein.

Leghemoglobin

In leguminous plants, such as alfalfa or soybeans, the nitrogen fixing bacteria in the roots are protected from oxygen by this iron heme containing oxygen-binding protein. The specific enzyme protected is nitrogenase, which is unable to reduce nitrogen gas in the presence of free oxygen.

Coboglobin

A synthetic cobalt-based porphyrin. Coboprotein would appear colorless when oxygenated, but yellow when in veins.

Presence in nonerythroid cells

Some nonerythroid cells (i.e., cells other than the red blood cell line) contain hemoglobin. In the brain, these include the A9 dopaminergic neurons in the substantia nigra, astrocytes in the cerebral cortex and hippocampus, and in all mature oligodendrocytes. It has been suggested that brain hemoglobin in these cells may enable the "storage of oxygen to provide a homeostatic mechanism in anoxic conditions, which is especially important for A9 DA neurons that have an elevated metabolism with a high requirement for energy production". It has been noted further that "A9 dopaminergic neurons may be at particular risk since in addition to their high mitochondrial activity they are under intense oxidative stress caused by the production of hydrogen peroxide via autoxidation and/or monoamine oxidase (MAO)-mediated deamination of dopamine and the subsequent reaction of accessible ferrous iron to generate highly toxic hydroxyl radicals". This may explain the risk of these cells for degeneration in Parkinson's disease. The hemoglobin-derived iron in these cells is not the cause of the post-mortem darkness of these cells (origin of the Latin name, substantia nigra), but rather is due to neuromelanin.

Outside the brain, hemoglobin has non-oxygen-carrying functions as an antioxidant and a regulator of iron metabolism in macrophages, alveolar cells, and mesangial cells in the kidney.

In history, art and music

Heart of Steel (Hemoglobin) (2005) by Julian Voss-Andreae. The images show the 5-foot (1.50 m) tall sculpture right after installation, after 10 days, and after several months of exposure to the elements.

Historically, an association between the color of blood and rust occurs in the association of the planet Mars, with the Roman god of war, since the planet is an orange-red, which reminded the ancients of blood. Although the color of the planet is due to iron compounds in combination with oxygen in the Martian soil, it is a common misconception that the iron in hemoglobin and its oxides gives blood its red color. The color is actually due to the porphyrin moiety of hemoglobin to which the iron is bound, not the iron itself, although the ligation and redox state of the iron can influence the pi to pi* or n to pi* electronic transitions of the porphyrin and hence its optical characteristics.

Artist Julian Voss-Andreae created a sculpture called Heart of Steel (Hemoglobin) in 2005, based on the protein's backbone. The sculpture was made from glass and weathering steel. The intentional rusting of the initially shiny work of art mirrors hemoglobin's fundamental chemical reaction of oxygen binding to iron.

Montreal artist Nicolas Baier created Lustre (Hémoglobine), a sculpture in stainless steel that shows the structure of the hemoglobin molecule. It is displayed in the atrium of McGill University Health Centre's research centre in Montreal. The sculpture measures about 10 metres × 10 metres × 10 metres.

Myoglobin

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Myoglobin 

 

MB

Myoglobin (symbol Mb or MB) is an iron- and oxygen-binding protein found in the skeletal muscle tissue of vertebrates in general and in almost all mammals. Myoglobin is distantly related to hemoglobin. Compared to hemoglobin, myoglobin has a higher affinity for oxygen and does not have cooperative-binding with oxygen like hemoglobin does. But at the core, it is an oxygen-binding protein in red blood cells. In humans, myoglobin is only found in the bloodstream after muscle injury.

High concentrations of myoglobin in muscle cells allow organisms to hold their breath for a longer period of time. Diving mammals such as whales and seals have muscles with particularly high abundance of myoglobin. Myoglobin is found in Type I muscle, Type II A, and Type II B, but most texts consider myoglobin not to be found in smooth muscle.

Myoglobin was the first protein to have its three-dimensional structure revealed by X-ray crystallography. This achievement was reported in 1958 by John Kendrew and associates. For this discovery, Kendrew shared the 1962 Nobel Prize in chemistry with Max Perutz. Despite being one of the most studied proteins in biology, its physiological function is not yet conclusively established: mice genetically engineered to lack myoglobin can be viable and fertile, but show many cellular and physiological adaptations to overcome the loss. Through observing these changes in myoglobin-depleted mice, it is hypothesised that myoglobin function relates to increased oxygen transport to muscle, and to oxygen storage; as well, it serves as a scavenger of reactive oxygen species.

In humans, myoglobin is encoded by the MB gene.

Myoglobin can take the forms oxymyoglobin (MbO₂), carboxymyoglobin (MbCO), and metmyoglobin (met-Mb), analogously to hemoglobin taking the forms oxyhemoglobin (HbO₂), carboxyhemoglobin (HbCO), and methemoglobin (met-Hb).

Differences from hemoglobin

Like hemoglobin, myoglobin is a cytoplasmic protein that binds oxygen on a heme group. It harbors only one globulin group, whereas hemoglobin has four. Although its heme group is identical to those in Hb, Mb has a higher affinity for oxygen than does hemoglobin. This difference is related to its different role: whereas hemoglobin transports oxygen, myoglobin's function is to store oxygen.

Role in cuisine

Myoglobin contains hemes, pigments responsible for the colour of red meat. The colour that meat takes is partly determined by the degree of oxidation of the myoglobin. In fresh meat the iron atom is in the ferrous (+2) oxidation state bound to an oxygen molecule (O₂). Meat cooked well done is brown because the iron atom is now in the ferric (+3) oxidation state, having lost an electron. If meat has been exposed to nitrites, it will remain pink because the iron atom is bound to NO, nitric oxide (true of, e.g., corned beef or cured hams). Grilled meats can also take on a reddish pink "smoke ring" that comes from the heme center binding to carbon monoxide. Raw meat packed in a carbon monoxide atmosphere also shows this same pink "smoke ring" due to the same principles. Notably, the surface of this raw meat also displays the pink color, which is usually associated in consumers' minds with fresh meat. This artificially induced pink color can persist, reportedly up to one year. Hormel and Cargill (meat processing companies in the US) are both reported to use this meat-packing process, and meat treated this way has been in the consumer market since 2003.

Role in disease

Myoglobin is released from damaged muscle tissue (rhabdomyolysis), which has very high concentrations of myoglobin. The released myoglobin is filtered by the kidneys but is toxic to the renal tubular epithelium and so may cause acute kidney injury. It is not the myoglobin itself that is toxic (it is a protoxin) but the ferrihemate portion that is dissociated from myoglobin in acidic environments (e.g., acidic urine, lysosomes).

Myoglobin is a sensitive marker for muscle injury, making it a potential marker for heart attack in patients with chest pain. However, elevated myoglobin has low specificity for acute myocardial infarction (AMI) and thus CK-MB, cardiac troponin, ECG, and clinical signs should be taken into account to make the diagnosis.

Structure and bonding

Myoglobin belongs to the globin superfamily of proteins, and as with other globins, consists of eight alpha helices connected by loops. Myoglobin contains 153 amino acids.

Myoglobin contains a porphyrin ring with an iron at its center. A proximal histidine group (His-93) is attached directly to iron, and a distal histidine group (His-64) hovers near the opposite face. The distal imidazole is not bonded to the iron but is available to interact with the substrate O₂. This interaction encourages the binding of O₂, but not carbon monoxide (CO), which still binds about 240× more strongly than O₂.

The binding of O₂ causes substantial structural change at the Fe center, which shrinks in radius and moves into the center of N4 pocket. O₂-binding induces "spin-pairing": the five-coordinate ferrous deoxy form is high spin and the six coordinate oxy form is low spin and diamagnetic.

• 

  Molecular orbital description of Fe-O₂ interaction in myoglobin.

• 

  This is an image of an oxygenated myoglobin molecule. The image shows the structural change when oxygen is bound to the iron atom of the heme prosthetic group. The oxygen atoms are colored in green, the iron atom is colored in red, and the heme group is colored in blue.

Synthetic analogues

Many models of myoglobin have been synthesized as part of a broad interest in transition metal dioxygen complexes. A well known example is the picket fence porphyrin, which consists of a ferrous complex of a sterically bulky derivative of tetraphenylporphyrin. In the presence of an imidazole ligand, this ferrous complex reversibly binds O₂. The O₂ substrate adopts a bent geometry, occupying the sixth position of the iron center. A key property of this model is the slow formation of the μ-oxo dimer, which is an inactive diferric state. In nature, such deactivation pathways are suppressed by protein matrix that prevents close approach of the Fe-porphyrin assemblies.

A picket-fence porphyrin complex of Fe, with axial coordination sites occupied by methylimidazole (green) and dioxygen. The R groups flank the O₂-binding site.

Neodymium magnet

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Neodymium_magnet 

 

Nickel-plated neodymium magnet on a bracket from a hard disk drive

 

Nickel-plated neodymium magnet cubes

 

Left: high-resolution transmission electron microscopy image of Nd₂Fe₁₄B; right: crystal structure with unit cell marked

A neodymium magnet (also known as NdFeB, NIB or Neo magnet) is the most widely used type of rare-earth magnet. It is a permanent magnet made from an alloy of neodymium, iron, and boron to form the Nd₂Fe₁₄B tetragonal crystalline structure. Developed independently in 1984 by General Motors and Sumitomo Special Metals, neodymium magnets are the strongest type of permanent magnet available commercially. Because of different manufacturing processes, they are divided into two subcategories, namely sintered NdFeB magnets and bonded NdFeB magnets. They have replaced other types of magnets in many applications in modern products that require strong permanent magnets, such as electric motors in cordless tools, hard disk drives and magnetic fasteners.

History

General Motors (GM) and Sumitomo Special Metals independently discovered the Nd₂Fe₁₄B compound almost simultaneously in 1984. The research was initially driven by the high raw materials cost of SmCo permanent magnets, which had been developed earlier. GM focused on the development of melt-spun nanocrystalline Nd₂Fe₁₄B magnets, while Sumitomo developed full-density sintered Nd₂Fe₁₄B magnets. GM commercialized its inventions of isotropic Neo powder, bonded neo magnets, and the related production processes by founding Magnequench in 1986 (Magnequench has since become part of Neo Materials Technology, Inc., which later merged into Molycorp). The company supplied melt-spun Nd₂Fe₁₄B powder to bonded magnet manufacturers. The Sumitomo facility became part of the Hitachi Corporation, and has manufactured but also licensed other companies to produce sintered Nd₂Fe₁₄B magnets. Hitachi has held more than 600 patents covering neodymium magnets.

Chinese manufacturers have become a dominant force in neodymium magnet production, based on their control of much of the world's rare-earth mines.

The United States Department of Energy has identified a need to find substitutes for rare-earth metals in permanent magnet technology and has funded such research. The Advanced Research Projects Agency-Energy has sponsored a Rare Earth Alternatives in Critical Technologies (REACT) program, to develop alternative materials. In 2011, ARPA-E awarded 31.6 million dollars to fund Rare-Earth Substitute projects. Because of its role in permanent magnets used for wind turbines, it has been argued that neodymium will be one of the main objects of geopolitical competition in a world running on renewable energy. But this perspective has been criticized for failing to recognize that most wind turbines do not use permanent magnets and for underestimating the power of economic incentives for expanded production.

Composition

Neodymium is a metal that magnetically orders only below 19 K (−254.2 °C; −425.5 °F), where it develops complex antiferromagnetic orders. However, compounds of neodymium with transition metals such as iron can order ferromagnetically with Curie temperatures well above room temperature, and these are used to make neodymium magnets.

The strength of neodymium magnets is the result of several factors. The most important is that the tetragonal Nd₂Fe₁₄B crystal structure has exceptionally high uniaxial magnetocrystalline anisotropy (H_A ≈ 7 T – magnetic field strength H in units of A/m versus magnetic moment in A·m²). This means a crystal of the material preferentially magnetizes along a specific crystal axis but is very difficult to magnetize in other directions. Like other magnets, the neodymium magnet alloy is composed of microcrystalline grains which are aligned in a powerful magnetic field during manufacture so their magnetic axes all point in the same direction. The resistance of the crystal lattice to turning its direction of magnetization gives the compound a very high coercivity, or resistance to being demagnetized.

The neodymium atom can have a large magnetic dipole moment because it has 4 unpaired electrons in its electron structure as opposed to (on average) 3 in iron. In a magnet it is the unpaired electrons, aligned so that their spin is in the same direction, which generate the magnetic field. This gives the Nd₂Fe₁₄B compound a high saturation magnetization (J_s ≈ 1.6 T or 16 kG) and a remnant magnetization of typically 1.3 teslas. Therefore, as the maximum energy density is proportional to J_s², this magnetic phase has the potential for storing large amounts of magnetic energy (BH_max ≈ 512 kJ/m³ or 64 MG·Oe). This magnetic energy value is about 18 times greater than "ordinary" ferrite magnets by volume and 12 times by mass. This magnetic energy property is higher in NdFeB alloys than in samarium cobalt (SmCo) magnets, which were the first type of rare-earth magnet to be commercialized. In practice, the magnetic properties of neodymium magnets depend on the alloy composition, microstructure, and manufacturing technique employed.

The Nd₂Fe₁₄B crystal structure can be described as alternating layers of iron atoms and a neodymium-boron compound. The diamagnetic boron atoms do not contribute directly to the magnetism but improve cohesion by strong covalent bonding. The relatively low rare earth content (12% by volume, 26.7% by mass) and the relative abundance of neodymium and iron compared with samarium and cobalt makes neodymium magnets lower in price than samarium-cobalt magnets.

Properties

Neodymium magnets (small cylinders) lifting steel spheres. Such magnets can easily lift thousands of times their own weight.

 

Ferrofluid on a glass plate displays the strong magnetic field of the neodymium magnet underneath.

Grades

Neodymium magnets are graded according to their maximum energy product, which relates to the magnetic flux output per unit volume. Higher values indicate stronger magnets. For sintered NdFeB magnets, there is a widely recognized international classification. Their values range from 28 up to 52. The first letter N before the values is short for neodymium, meaning sintered NdFeB magnets. Letters following the values indicate intrinsic coercivity and maximum operating temperatures (positively correlated with the Curie temperature), which range from default (up to 80 °C or 176 °F) to AH (230 °C or 446 °F).

Grades of sintered NdFeB magnets:

• N30 – N52
• N30M – N50M
• N30H – N50H
• N30SH – N48SH
• N30UH – N42UH
• N28EH – N40EH
• N28AH – N35AH

Magnetic properties

Some important properties used to compare permanent magnets are:

• Remanence (B_r), which measures the strength of the magnetic field.
• Coercivity (H_ci), the material's resistance to becoming demagnetized.
• Maximum energy product (BH_max), the density of magnetic energy, characterized by the maximum value of magnetic flux density(B) times magnetic field strength (H).
• Curie temperature (T_C), the temperature at which the material loses its magnetism.

Neodymium magnets have higher remanence, much higher coercivity and energy product, but often lower Curie temperature than other types of magnets. Special neodymium magnet alloys that include terbium and dysprosium have been developed that have higher Curie temperature, allowing them to tolerate higher temperatures. The table below compares the magnetic performance of neodymium magnets with other types of permanent magnets.

Magnet	Br (T)	Hci (kA/m)	BHmax (kJ/m3)	TC
				(°C)	(°F)
Nd2Fe14B, sintered	1.0–1.4	750–2000	200–440	310–400	590–752
Nd2Fe14B, bonded	0.6–0.7	600–1200	60–100	310–400	590–752
SmCo5, sintered	0.8–1.1	600–2000	120–200	720	1328
Sm(Co, Fe, Cu, Zr)7, sintered	0.9–1.15	450–1300	150–240	800	1472
Alnico, sintered	0.6–1.4	275	10–88	700–860	1292–1580
Sr-ferrite, sintered	0.2–0.78	100–300	10–40	450	842

Physical and mechanical properties

Photomicrograph of NdFeB. The jagged edged regions are the metal crystals, and the stripes within are the magnetic domains.

 

Comparison of physical properties of sintered neodymium and Sm-Co magnets

Property	Neodymium	Sm-Co
Remanence (T)	1–1.5	0.8–1.16
Coercivity (MA/m)	0.875–2.79	0.493–2.79
Recoil permeability	1.05	1.05–1.1
Temperature coefficient of remanence (%/K)	−(0.12–0.09)	−(0.05–0.03)
Temperature coefficient of coercivity (%/K)	−(0.65–0.40)	−(0.30–0.15)
Curie temperature (°C)	310–370	700–850
Density (g/cm3)	7.3–7.7	8.2–8.5
Thermal expansion coefficient, parallel to magnetization (1/K)	(3–4)×10−6	(5–9)×10−6
Thermal expansion coefficient, perpendicular to magnetization (1/K)	(1–3)×10−6	(10–13)×10−6
Flexural strength (N/mm2)	200–400	150–180
Compressive strength (N/mm2)	1000–1100	800–1000
Tensile strength (N/mm2)	80–90	35–40
Vickers hardness (HV)	500–650	400–650
Electrical resistivity (Ω·cm)	(110–170)×10−6	(50–90)×10−6

Corrosion problems

These neodymium magnets corroded severely after five months of weather exposure.

Sintered Nd₂Fe₁₄B tends to be vulnerable to corrosion, especially along grain boundaries of a sintered magnet. This type of corrosion can cause serious deterioration, including crumbling of a magnet into a powder of small magnetic particles, or spalling of a surface layer.

This vulnerability is addressed in many commercial products by adding a protective coating to prevent exposure to the atmosphere. Nickel plating or two-layered copper-nickel plating are the standard methods, although plating with other metals, or polymer and lacquer protective coatings, are also in use.

Temperature effects

Neodymium has a negative coefficient, meaning the coercivity along with the magnetic energy density (BH_max) decreases with temperature. Neodymium-iron-boron magnets have high coercivity at room temperature, but as the temperature rises above 100 °C (212 °F), the coercivity decreases drastically until the Curie temperature (around 320 °C or 608 °F). This fall in coercivity limits the efficiency of the magnet under high-temperature conditions such as in wind turbines, hybrid motors, etc. Dysprosium (Dy) or terbium (Tb) is added to curb the fall in performance from temperature changes, making the magnet even more expensive.

Hazards

The greater forces exerted by rare-earth magnets create hazards that may not occur with other types of magnet. Neodymium magnets larger than a few cubic centimeters are strong enough to cause injuries to body parts pinched between two magnets, or a magnet and a ferrous metal surface, even causing broken bones.

Magnets that get too near each other can strike each other with enough force to chip and shatter the brittle magnets, and the flying chips can cause various injuries, especially eye injuries. There have even been cases where young children who have swallowed several magnets have had sections of the digestive tract pinched between two magnets, causing injury or death. Also this could be a serious health risk if working with machines that have magnets in or attached to them  The stronger magnetic fields can be hazardous to mechanical and electronic devices, as they can erase magnetic media such as floppy disks and credit cards, and magnetize watches and the shadow masks of CRT type monitors at a greater distance than other types of magnet. In some cases, chipped magnets can act as a fire hazard as they come together, sending sparks flying as if they were a lighter flint, because some neodymium magnets contain ferrocerium.

Production

There are two principal neodymium magnet manufacturing methods:

• Classical powder metallurgy or sintered magnet process
  • Sintered Nd-magnets are prepared by the raw materials being melted in a furnace, cast into a mold and cooled to form ingots. The ingots are pulverized and milled; the powder is then sintered into dense blocks. The blocks are then heat-treated, cut to shape, surface treated and magnetized.
• Rapid solidification or bonded magnet process
  • Bonded Nd-magnets are prepared by melt spinning a thin ribbon of the NdFeB alloy. The ribbon contains randomly oriented Nd₂Fe₁₄B nano-scale grains. This ribbon is then pulverized into particles, mixed with a polymer, and either compression- or injection-molded into bonded magnets.

In 2015, Nitto Denko Corporation of Japan announced their development of a new method of sintering neodymium magnet material. The method exploits an "organic/inorganic hybrid technology" to form a clay-like mixture that can be fashioned into various shapes for sintering. Most importantly, it is said to be possible to control a non-uniform orientation of the magnetic field in the sintered material to locally concentrate the field to, e.g., improve the performance of electric motors. Mass production is planned for 2017.

As of 2012, 50,000 tons of neodymium magnets are produced officially each year in China, and 80,000 tons in a "company-by-company" build-up done in 2013. China produces more than 95% of rare earth elements and produces about 76% of the world's total rare-earth magnets, as well as most of the world's neodymium.

Applications

Existing magnet applications

Ring magnets

 

Most hard disk drives incorporate strong magnets

 

This manually-powered flashlight uses a neodymium magnet to generate electricity

Neodymium magnets have replaced alnico and ferrite magnets in many of the myriad applications in modern technology where strong permanent magnets are required, because their greater strength allows the use of smaller, lighter magnets for a given application. Some examples are:

• Head actuators for computer hard disks
• Mechanical e-cigarette firing switches
• Locks for doors
• Loudspeakers and headphones
• Mobile phone speakers, taptic feedback and auto focus actuators
• Magnetic bearings and couplings
• Benchtop NMR spectrometers
• Electric motors
  • Cordless tools
  • Servomotors
  • Lifting and compressor motors
  • Synchronous motors
  • Spindle and stepper motors
  • Electrical power steering
  • Drive motors for hybrid and electric vehicles. The electric motors of each Toyota Prius require one kilogram (2.2 lb) of neodymium.
  • Actuators

• Electric generators for wind turbines (only those with permanent magnet excitation)
• Voice coil
• Retail media case decouplers
• In process industries, powerful neodymium magnets are used to catch foreign bodies and protect product and processes

New applications

Neodymium magnet spheres assembled in the shape of a cube

The greater strength of neodymium magnets has inspired new applications in areas where magnets were not used before, such as magnetic jewelry clasps, children's magnetic building sets (and other neodymium magnet toys) and as part of the closing mechanism of modern sport parachute equipment. They are the main metal in the formerly popular desk-toy magnets, "Buckyballs" and "Buckycubes", though some U.S. retailers have chosen not to sell them because of child-safety concerns, and they have been banned in Canada for the same reason.

The strength and magnetic field homogeneity on neodymium magnets has also opened new applications in the medical field with the introduction of open magnetic resonance imaging (MRI) scanners used to image the body in radiology departments as an alternative to superconducting magnets that use a coil of superconducting wire to produce the magnetic field.

Neodymium magnets are used as a surgically placed anti-reflux system which is a band of magnets surgically implanted around the lower esophageal sphincter to treat gastroesophageal reflux disease (GERD). They have also been implanted in the fingertips in order to provide sensory perception of magnetic fields, though this is an experimental procedure only popular among biohackers and grinders.