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Hemoglobin definition pdf

Continue transport metalloprotein in red cells (heterotetramer, (αβ)2)Structure of human hemoglobin. α and β subunits are in red and blue and the iron groups in green, respectively. From PDB: 1GZX Proteopedia HemoglobinProtein typemetalloprotein, globulinFunctionoxygen-transportCofactor(s) (4) Subunit name -n, -, -moŋ-/[1][2][3]), abbreviated Hb or Hgb, the ironوloŋbووmωوGene Chromosomal locus Hb-α1 HBA1 Chr. 16 p13.3 Hb-α2 HBA2 Chr. 16 p13.3 Hb-β HBB Chr. 11 p15.5 Hemoglobin (American English) or hemoglobin (British English) (Greek αἷμα (haîma, blood) + -in) + -o- + globulin (from Latin sphere (ball, sphere) + -in) (/ςhi containing metal transport is metalloprotein in the red blood cells (erythrocytes) of almost all vertebrates[4] (the exception is the fish family Channichthyidae[5]) as well as the tissues of some invertebrates. Hemoglobin in the blood carries oxygen from the lungs or gills to the rest of the body (i.e. the tissues). There it releases the oxygen to allow aerobic breathing 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 makes up about 96% of the dry content of red blood cells (in weight), and about 35% of the total content (including water). [6] Hemoglobin has an oxygen-binding capacity of 1.34 mL O2 per gram,[7] which increases the total capacity of the blood oxygen seventy compared to dissolved oxygen in blood. The mammalian hemoglobin molecule can bind (carry) up to four oxygen molecules. [8] Hemoglobin is involved in the transport of other gases: It carries part of the body's respiratory (about 20-25% of the total[9]) as , in which CO2 is bound to the heme protein. The molecule also carries the important regulatory molecule nitric oxide tied to a protein thiol group, releasing it at the same time as oxygen. [10] Hemoglobin is also found outside red blood cells and their precursor lines. Other cells containing hemoglobin are 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. [11] In these tissues, hemoglobin has a non-oxygen-carrying function as an antioxidant and a regulator of iron metabolism. [12] Excess glucose in his blood can attach to hemoglobin and raise the level of a1c hemoglobin. [13] Hemoglobin and hemoglobin-like molecules are also found in many invertebrates, fungi and plants. [14] In these organisms, can provide oxygen or they can act to transport and regulate other small molecules and ions such as carbon dioxide, nitric oxide, hydrogen sulfide and sulphide. A A the molecule, called , is used to scavenge oxygen away from anaerobic systems, such as the nitrogen-fixing nodules of legume plants, lest the oxygen venom (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 . Research history Max Perutz won the Nobel Prize in Chemistry for his work determining the molecular structure of hemoglobin and [15] In 1825, J. F. Engelhart discovered that the ratio of iron and protein is identical in the hemoglobins of different species. [16] [17] From the known atomic mass of iron he calculated the molecular mass of hemoglobin to one × 16000 (n = number of iron atoms per hemoglobin, now known to be 4), the first determination of the molecular mass of a protein. This hasty conclusion drew a lot of ridicule at the time from scientists who couldn't believe that a molecule could be that big. Gilbert Smithson Adair confirmed Engelhart's results in 1925 by measuring the osmotic pressure of hemoglobin solutions. [18] The oxygen-carrying possession of hemoglobin was discovered by Hünefeld in 1840. [19] In 1851, the 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. [20] [21] Hemoglobin's reversible oxygenation was described a few years later by Felix Hoppe-Seyler. [22] In 1959, Max Perutz determined the molecular structure of hemoglobin by x-ray crystallography. [23] [24] This work resulted in his sharing with John Kendrew the 1962 Nobel Prize in Chemistry for their studies of the structures of spherical . The role of hemoglobin in the blood was clarified by the French physiologist Claude Bernard. The name hemoglobin is derived from the words heme and globin, due to the fact that each subunit of hemoglobin is a spherical protein with an embedded heme group. Each heme group contains one iron atom, which can bind one oxygen molecule by [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 a polypeptide created by a cell is in turn determined by the pieces of DNA called genes. In all proteins, it is the amino acid sequence that the chemical and function of the protein. There is more than one hemoglobin gene: in humans, (the main form of hemoglobin present) is encoded for genes, HBA1, HBA2 and and 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 the alpha or beta globin protein chains. [26] [27] [28] While human and gorilla hemoglobin differ in one amino acid in both alpha and beta branches, these differences become greater between less closely related species. Even within a species, variants of hemoglobin exist, although one sequence is usually most common in each species. in the genes for the hemoglobin protein in a species result in . [29] [30] Many of these mutated forms of hemoglobin do not cause disease. However, some of these mutated forms of hemoglobin cause a group of inherited diseases called . The most famous is , the first human disease whose mechanism was understood at the molecular level. A (usually) separate set of diseases called involves underproduction of normal and sometimes abnormal hemoglobins, due to problems and mutations in globin gene regulation. All these diseases cause anemia. [31] Protein alignment of human hemoglobin proteins, alpha, beta, and delta subunits respectively. The alignments are made using Uniprot's alignment tool available online. Variations in hemoglobin amino acid sequences, as with other proteins, can be adaptive. For example, it has been found that hemoglobin adapts to high altitudes in different ways. Organisms living at high altitudes experience lower partial oxygen pressure compared to those at sea level. This poses a challenge for the organisms that inhabit such environments, because hemoglobin, which normally binds oxygen at high partial pressure 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 living in the mountains can survive in the thin air that accompanies high altitudes. A researcher from the University of Nebraska-Lincoln found mutations in four different genes that may explain differences between deer mice that live in lowland prairies versus the mountains. After examining wild mice caught from both highlands and lowlands, it turned out that: the genes of the two breeds are virtually identical, except for those who control the oxygen-carrying capacity of their hemoglobin. The genetic difference sets up highland mice to make more efficient use of their oxygen, because there is less available at higher altitudes, such as those in the mountains. [32] Mammoth hemoglobin contained mutations that delivery at lower temperatures, allowing mammoths to migrate to higher latitudes during the Pleistocene. [33] This was also found in hummingbirds inhabiting the Andes. Hummingbirds already spend a lot of energy and therefore have a high oxygen requirement and yet Andeslibries appear to thrive at high altitudes. Non-synonym mutations in the hemoglobin gene of multiple species living at high altitudes (Oreotrochilus, A. castelnaudi, C. violifer, P. gigas and A. viridicuada) have reduced the affinity of the protein with inositol hexaphosfat (IHP), a molecule found in birds with a similar role to 2,3-B B in humans; this results in the ability to bind oxygen in lower partial pressure. [34] The birds' unique circulatory lungs also promote efficient use of oxygen at low partial pressure of the O2. These two adaptations reinforce each other and are responsible for the remarkable performance at high altitude of birds. Hemoglobin adaptation extends to humans, too. There is a higher survival rate in children with high oxygen saturation genotypes living at 4,000 m.[35] Natural selection appears to be the main force working on this gene, as the mortality rate of offspring is significantly lower for women with higher hemoglobin oxygen affinity compared to the mortality rate of offspring of women with low hemoglobin oxygen affinity. While the exact genotype and mechanism by which this happens is not yet clear, the selection works on these women's ability to bind oxygen in low partial pressure, allowing them to better support generally crucial metabolic processes. Synthesis Hemoglobin (Hb) is synthesized in a complex series of steps. The hemednt 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. [36] Hb production goes into the cell through its early development of proerythroblast to reticulocyte in the bone marrow. At this point, the nucleus is lost in red blood cells of mammals, but not in birds and many other species. Even after the loss of the nucleus in mammals, the remaining ribosomal RNA allows further synthesis of Hb until the reticulocyte loses its RNA shortly after entering the vasculature (this hemoglobin-synthetic RNA actually gives the reticulocyte its reticulocyte its reticulocyte and name). [37] The structure of heme Heme b hemoglobin group has a quaternary structure characteristic of many multi- subunit spherical proteins. [38] Most amino acids in hemoglobin form alphaheles, and these helices are connected by short non-spiral segments. Hydrogen bindings The spiral parts in this protein, causing attractions in the molecule, causing each polypeptide chain to fold into a specific shape. [39] Hemoglobin's quaternary structure comes from its four in about a tetrahedron scheme. [38] In most vertebrates, the hemoglobin molecule is an assembly of four spherical protein subunits. Each subunit consists of a protein chain closely associated with a non-protein prosthetic heme group. Each protein chain arranges in a series of alpha-helix structural segments that are connected in a globin folding control. Such a name is given because this arrangement is the same folding motif used in other heme/globin proteins such as myoglobin. [40] [41] This folding pattern contains a bag 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 porphyrination consists of four pyrolmolecules that are cyclically connected (by methine bridges) with the iron ion in the center. [42] The iron ion, which is the place of oxygen band, coordinates with the four nitrogen atoms in the center of the ring, which all lie in one plane. The iron is strongly (covalently) bound to the spherical protein via the N-atoms of the imidazole ring of F8 histidineresidu (also known as the proximal histidine) under the porphyrination. A sixth position can bind oxygen reversibly by a coördinal covalent band,[43] completing the octahedral group of six ligands. This reversible bond with oxygen is why hemoglobin is so useful for transporting oxygen around the body. [44] Oxygen binds in an end-up curved geometry where one binds oxygen atom to Fe and the other protrudes at an angle. When oxygen is not bound, a very weakly bound water molecule fills the site, forming a distorted octah edule. Although carbon dioxide is carried by hemoglobin, it does not compete with oxygen for the iron-binding positions, but is tied to the amine groups of the protein chains attached to the heme groups. The iron ion can enter the ferrous Fe2+ or ferric Fe3+ state, but ferrihemoglobin () (Fe3+) cannot bind oxygen. [45] In binding, oxygen temporarily and reversible oxidizes (Fe2+) (Fe3+) while the oxygen temporarily changes in the superoxide ion, so the iron must exist in the +2 oxidation state to bind oxygen. When superoxide ions associated with Fe3+ are protoned, the hemoglobin iron remains oxidized and unable to bind 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 referred to as α2β2. The subunits structurally comparable and about the same size. Each subunit has a molecular weight of approximately 16,000 daltons,[46] for a total molecular weight of the tetramer of approximately 64,000 daltons (64,458 g/mol). [47] [47] 1 g/dL = 0.1551 mmol/L. Hemoglobin A is the most intensively studied hemoglobin mol. In human infants, the hemoglobin molecule consists of 2 α chains and 2 γ chains. The gamma chains are gradually replaced by β chains as the child grows. [48] The four polypeptide chains are bound to each other through salt bridges, hydrogen bonds, and the hydrophobic effect. Oxygen saturation Hemoglobin may be saturated with oxygen molecules (oxyhemoglobin), or desaturated with oxygen molecules (deoxyhemoglobin). [49] Oxyhemoglobin Oxyhemoglobin is formed during physiological respiration when oxygen binds to the heme component of the protein hemoglobin in red blood cells. This process takes place in the pulmonary vessels adjacent to the alve vesicers of the lungs. The oxygen then travels through the blood stream to be deposited at cells where it is used as a terminal electron acceptor in the production of ATP through the process of oxidative phosphorylation. However, it does not help to prevent a decrease in the pH of the blood. Ventilation, or breathing, can reverse this condition by removing carbon dioxide, causing a shift in pH. [50] Hemoglobin consists of two forms, a tight (tense) shape (T) and a relaxed shape (R). Several factors such as low pH, high CO2 and high 2.3 BPG at the level of the tissues in favor of the tight shape, which has low oxygen affinity and releases oxygen into the tissues. Conversely, a high pH, low CO2, or low 2.3 BPG favors the relaxed shape, which can better bind oxygen. [51] The partial pressure of the system affects also affinity O2 where, at high partial pressure of oxygen (as those present in alve vesiclers), relaxed (high affinity, R) state is accepted. Conversely, at low partial pressure (such as those present in respiring tissues), the (low affinity, T) tense state is favored. [52] In addition, the band of oxygen pulls to the iron(II) heme the iron in the porphyrination plane, causing a slight conformation shift. The shift encourages oxygen to bind to the three remaining heme units within hemoglobin (so oxygen bonding is cooperative). Low-oxygen hemoglobin Deoxygenated hemoglobin is the form of hemoglobin without the bonded oxygen. The absorption specra of oxyhemoglobin and deoxyhemoglobin differ. The oxyhemoglobin has a significantly lower absorption of the 660 nm wavelength than deoxyhemoglobin, while at 940 nm the absorption is slightly higher. This difference is used to measure the amount of oxygen in a patient's blood by an instrument called a pulsoximeter. This difference is also good for the presentation of cyanosis, the blue to purered color that tissues develop during hypoxia. Deoxygenated hemoglobin is paramagnetic; It is weakly attracted to magnetic fields. [54] [55] In contrast, oxygen-rich hemoglobin exhibits diamagnetism, a weak rejection of a magnetic field. [55] [55] of vertebrate hemoglobin Scientists agree that the event that separated myoglobin from hemoglobin occurred after lampreys deviated from vertebrate quays. [56] This separation of myoglobin and hemoglobin allowed the different functions of the two molecules to occur and develop: myoglobin has more to do with oxygen storage while hemoglobin is responsible for oxygen transport. [57] The α and β-like globin genes encode the individual subunits of the protein. [25] The predecessors of these genes arose by another doubling event also after gnathosome common ancestor derived from jawless fish, approximately 450-500 million years ago. [56] The development of α and β genes created the potential for hemoglobin to be composed centrally from multiple subunits, a physical composition hemoglobin ability to transport oxygen. Having multiple subunits contributes to the ability of hemoglobin to bind oxygen cooperatively and to be allosterically regulated. [57] Later, the α gene also underwent a duplication event to form the HBA1 and HBA2 genes. [58] These further duplications and differences have led to a diverse range of α- and β-like globin genes regulated so that certain forms occur at different stages of development. [57] Most ice fish of the Channichthyidae family have lost their hemoglobin genes as an adaptation to cold water. [5] The oxidation state of the iron in oxyhemoglobin Assigning oxygen-rich hemoglobin 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 unpaid electronin 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 must therefore have one or more unpaired electrons, in any energy state. All these structures are paramagnetic (have unpaired electrons), not diamagnetic. For example, a non-intuitive (e.g. a higher energy for at least one type) distribution of electrons in the combination of iron and oxygen must exist to explain the observed diamagnetism and not unpaired electrons. The two logical possibilities to produce diamagnetic (no net spin) Hb-O2 are: Low-spin Fe2 + singlet oxygen. Both low-spin iron and singlet oxygen are diamagnetic. However, the only form of oxygen is the higher-energy form of the molecule. Low-spin Fe3+ binds to O2•− (the superoxide ion) and the two unpaired electrons pair antiferromagnetic, thus causing observed diamagnetic properties. Properties. the iron is oxidized (has lost an electron), and the oxygen is reduced (has gained an electron). Another possible model in which low- spin Fe4+ binds to peroxide, O22 −, can be excluded on its own, because the iron is paramagnetic (although the peroxide-ion is diamagnetic). Here the iron is oxidized by two electrons, and the oxygen reduced by two electrons. Direct experimental data: X-ray spectroscopy suggests that iron has an oxidation state of about 3.2. Infrared vibration frequencies of the O-O binding suggest a binding length that matches superoxide (a binding order of about 1.6, where superoxide is 1.5). X-ray absorption At Edge Structures at the iron K-edge. The energy shift of 5 eV between deoxyhemoglobin and oxyhemoglobin, as for all methemoglobin species, strongly suggests an actual local charge closer to Fe3+ than Fe2+. [59] [60] [61] Thus, the nearest formal oxidation state of iron in Hb-O2 is the +3 state, with oxygen in −1 state (as superoxide . O2−). The diamagnetism in this configuration stems from the single unpaired electron on superoxide that aligns antiferromagnetically with the single unpaired electron on iron (in a low spin d5 state), so as not to give a net spin to the entire configuration, in accordance with diamagnetic oxyhemoglobin of experiment. [62] [63] The second choice of the logical possibilities above for diamagnetic oxyhemoglobin found correctly by experiment, is not surprising: singlet oxygen (possibility #1) is an unrealistically high energy state. The model 3 leads to unfavorable separation of charge (and does not agree with the magnetic data), although it could make a small contribution as resonance form. Iron's shift to a higher oxidation state in Hb-O2 reduces the size of the atom, and allows it into the plane of the porphyrination, pulling on the coordinated histidineresidu and initiating the allosteric changes seen in the spheres. Early postulates by bio-inorganic chemists claimed that the possibility #1 (above) was correct and that iron should exist in oxidation state II. This conclusion seemed likely, since the iron oxidation states III as methemoglobin, when not accompanied by superoxide . O2− to hold the oxidative electron, was known for not being able to bind hemoglobin to normal triplet O2 as it occurs in the air. It was therefore assumed that iron remained as Fe(II) when oxygen gas was bound into 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 iron (II) placed in an octahedral field of strong field sands; This change in the field would increase the crystal field splitting energy, allowing iron electrons to link in the low-spin configuration, which would be diamagnetic Fe(II). This forced low-spin pairing is indeed thought to happen in iron when oxygen binds, but is not enough to explain iron change in size. Extraction of an additional electron from iron by oxygen is necessary to explain both the smaller size of iron and the observed increased oxidation state and the weaker binding of oxygen. The allocation of an entire-number oxidation state is a formalism, as the covalent bonds are not required to have perfect bond orders involving whole electron transfer. For example, all three models for paramagnetic Hb-O2 can contribute to the actual electronic configuration of Hb-O2 to a small extent (by resonance). However, the model of iron in Hb-O2 that is Fe(III) is more correct than the classic idea that it remains Fe(II). Cooperativity A schematic visual model of oxygen-binding process, with all four monomers and kisses, and protein chains only as diagrammatic coils, to facilitate visualization in 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 hem. For example, in the upper left corner of the four shown, oxygen binds to the left side of the iron atom shown in the upper left corner of the diagram. This causes the iron atom to move backwards in the heme that holds it (the iron moves up as it binds oxygen, in this illustration), pulling the histidine residue (modeled as a red pentagon on the right side of the iron) closer, as it does. This, in turn, pulls on the protein chain with the histidine. When oxygen binds to the iron complex, it causes the iron atom to return to the center of the plane of the porphyrination (see moving diagram). At the same time, the imidazole side chain of the histidineresidu interacting on the other pole of the iron is drawn to the porphyrination. This interaction forces the plane of the ring sideways to the outside of the tetramer, and also induces a strain in the protein helix with the histidine as it moves closer to the iron atom. This strain is transferred to the remaining three monomers in the tetramer, where it causes a similar conformation change in the other hemesites, making the binding of oxygen to these sites easier. As oxygen binds to a 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 heme groups, leaving the hemoglobin molecule with oxygen. [64] In the tetrameric form of normal adult hemoglobin, the band of oxygen is, thus, a cooperative process. Hemoglobin's binding affinity for oxygen is by the oxygen saturation of the molecule, in which the first molecules of oxygen are bound that affect the shape of the binding sites for the next, in a way that is beneficial for bonding. This positive cooperative bond is achieved through steric conformation conformation hemoglobin protein complex as discussed above; i.e. when a subunit protein in hemoglobin becomes oxygenated, a conformational or structural change is initiated throughout the complex, giving the other subunits an increased affinity for oxygen. As a result, the oxygen-binding curve of hemoglobin is sigmoidal, or S-shaped, as opposed to the normal hyperbolic curve associated with non-cooperative bonding. The dynamic mechanism of cooperation in hemoglobin and the relationship with low frequency resonance has been discussed. [65] Binding for ligands other than oxygen In addition to the oxygen ligdering, 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 form amino groups of the globin proteins carbaminohemoglobin; this mechanism is believed 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 releases back into free nitric oxide and thiol, because the hemoglobin releases oxygen from its heme place. This nitric oxide transport to peripheral tissues is believed to help oxygen transport in tissues, by releasing vascular-deleting nitric oxide to tissues in which oxygen levels are low. [66] Competitive The binding of oxygen is influenced by molecules such as carbon monoxide (e.g. tobacco smoking, exhaust gas and incomplete combustion in furnaces). CO competes with oxygen on the heme binding site. Hemoglobin's binding affinity for CO is 250 times greater than its affinity for oxygen,[67][68] which means that small amounts of CO dramatically reduce the ability of hemoglobin to deliver oxygen to the target tissue. [69] 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 homes. When hemoglobin combines with CO, it forms a very bright red compound called , which can cause the skin of CO poisoning victims to appear pink in death, rather than white or blue. When inspired air co-levels contain as low as 0.02%, headaches and nausea occur; if the CO concentration is increased to 0.1%, unconsciousness will follow. In heavy smokers, up to 20% of oxygen-active locations can be blocked by CO. Similarly, hemoglobin also has competitive affinity for cyanide (CN−), (SO) and sulphide (S2−), including hydrogen sulfide (H2S). All of these bind to iron in heme without changing the oxidation state, but they nonetheless inhibit oxygen-binding, causing severe toxicity. The iron atom in the heme group should initially be (Fe2+) oxidation state to support the binding and transport of oxygen and other gases (it temporarily switches to iron during the time oxygen is bound, as explained above). Initial oxidation in 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 prevent this. Nitric oxide is able to convert a small fraction of hemoglobin into methemoglobin into red blood cells. The latest reaction is a remnant activity of the more ancient nitric oxide dioxygenase function of . Allosterisch Further information: Oxygen-hemoglobin dissociation curve Carbon dioxide takes another binding place on the hemoglobin. In tissues, where the carbon dioxide concentration is higher, carbon dioxide binds to the allosteric site of hemoglobin, facilitating the discharge of oxygen from hemoglobin and ultimately removing its removal from the body after the oxygen is released to tissues undergoing metabolism. This increased affinity for carbon dioxide from the venous blood is known as the . Via the enzyme carbonic anhydrase reacts carbon dioxide with water to give carbon dioxide, which dissects into and protons: CO2 + H2O → H2CO3 → HCO3− + H+ The sigmoidal form of the oxygen dissociation curve of hemoglobin results from cooperative bonding of oxygen to hemoglobin. Hence, blood with a high carbon dioxide content is also lower in the pH (more acidic). Hemoglobin can bind protons and carbon dioxide, causing a change in the protein and facilitating the release of oxygen. Protons bind to the protein in different places, while carbon dioxide binds to the α amino group. [70] Carbon dioxide binds to hemoglobin and forms carbaminohemoglobin. [71] This decrease in hemoglobin affinity for oxygen due to the binding of carbon dioxide and acid is known as the Bohr effect. The Bohr effect favors the T-state instead of 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 vessels), 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 downwards, not just to the right) due to reduced pH is called the root effect. This is seen in legged fish. It is necessary for hemoglobin to release the oxygen it binds; if not, there is no point in tying it. The sigmoidal curve of hemoglobin makes it efficient in binding (incorporating O2 into the efficient in unloading (unloading O2 into tissues). [72] In people acclimatized to high altitudes, the concentration of 2,3-Bisphoglycerate (2,3-BPG) in the blood is increased, allowing these individuals to deliver a greater amount of oxygen to tissues conditions with a lower oxygen voltage. This phenomenon, in which molecule Y affects the binding of molecule X to a transport molecule Z, is called a heterotropic allosteric effect. Hemoglobin in high-altitude organisms has also adapted to reduce affinity with 2,3-BPG, so the protein will be shifted more to its R state. In its R state, hemoglobin will bind oxygen more easily, allowing organisms to perform the necessary metabolic processes when oxygen is present at low partial pressure. [73] Animals outside 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 bag on the fish hemoglobin molecule, which stabilizes the tense state and thus reduces oxygen affinity. [74] GTP reduces hemoglobin oxygen affinity much more than atp, which is believed to be due to an additional hydrogen band further stabilizing the tense state. [75] Under hypoxic conditions, the concentration of both ATP and GTP is reduced in vis-red blood cells to increase oxygen affinity. [76] A variant hemoglobin, called (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-hand shifted (i.e. a higher percentage of hemoglobin has oxygen attached to it at lower oxygen voltage), compared to that of adult hemoglobin. As a result, fetal blood in the placenta is able to take oxygen from mother's blood. Hemoglobin also carries nitric oxide (NO) in the globin part of the molecule. This improves the oxygen supply in the periphery and contributes to the control of breathing. NO binds reversible to a specific cystine sidu in globin; the binding depends on the condition (R or T) of the hemoglobin. The resulting S-nitrosylated hemoglobin affects various NO-related activities such as controlling vascular resistance, blood pressure and breathing. NO is not released into the cytoplasm of red blood cells, but transported from them by an anion changer called AE1. [77] Types in humans Hemoglobin variants are part of normal embryonic and fetal development. They can also be pathological mutant forms of hemoglobin in a population, caused by variations in genetics. Some known hemoglobin variants, such as sickle cell anemia, are responsible for diseases and are considered hemoglobinopathies. Other variants do not cause detectable pathology and are therefore considered non-pathological variants. [78] [79] In the Gower 1 (γ2ε2) Gower 2 (α2ε2) (PDB: 1A9W ) Hemoglobin Portland I (γ2γ2) Hemoglobin Portland II (γ2β2). In the fetus: Hemoglobin F (α2γ2) (PDB: 1FDH). After birth: Hemoglobin A (adult hemoglobin) (α2β2) (PDB: 1BZ0) – The most common with a normal amount of more than 95% A2 – 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 limited to a limited population of red cells called F cells. However, the level of Hb F can be increased in individuals with sickle cell disease and beta-. Gene expression of hemoglobin before and after birth. Also identifies the types of cells and organs in which gene expression (data on Wood W.G., (1976). Br. Med. Bull. 32, 282.) Variant forms that cause disease: Hemoglobin D-Punjab – (α2βD2) – A variant 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. (γ4) – A variant form of hemoglobin, formed by a tetramer of γ chains, which may be present in variants of α thalassemia. Hemoglobin S (α2βS2) – 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, resulting in sickle of red blood cells. (α2βC2) – Another variant due to a variation in the β-chain gene. This variant causes mild chronic hemolytic anemia. (α2βE2) – Another variant due to a variation in the β-chain gene. This variant causes mild chronic hemolytic anemia. Hemoglobin AS – A heterozygous form causes sickle cell migration with an adult gene and a sickle cell disease gene Hemoglobin SC disease – A composite heterozygous form with a sickle gene and another coding Hemoglobin C. Hemoglobin Hopkins-2 - A variant of hemoglobin that is sometimes viewed in combination with Hemobin S to produce sickle cell disease. Degradation in vertebrates When red blood cells reach the end of life due to aging or defects, they are removed from circulation by the phgogocytic activity of macrophages in the spleen or liver or hemolyze within circulation. Free hemoglobin is then taken out of circulation via the hemoglobin transporter CD163, which is expressed exclusively on monocytes or macrophages. In these cells, the hemoglobin molecule is broken down and the iron is recycled. This process also produces a molecule of carbon monoxide for each molecule of heme broken down. [80] Heme degradation is one of the few natural sources of carbon monoxide in the human body, and is responsible for the normal blood levels of carbon monoxide even in people who breathe pure air. The other important end product of heme degradation is bilirubin. Elevated levels of this chemical are detected in the blood as red blood cells become faster than usual. Misgraded hemoglobin protein or hemoglobin that has been released from blood cells too quickly can clog small blood vessels, blood vessels, the delicate blood filter vessels of the kidneys, causing kidney damage. Iron is removed from heme and salvaged for later use, it is stored as hemosiderine or ferritin in tissues and transported in plasma by beta globulins as transferrines. When the porphyrin ring is broken down, the fragments are normally secreted as a yellow pigment called bilirubin, which is secreted in the intestines as bile. Intestines metabolize bilirubin in urobilinogen. Urobilinogen leaves the body in the stool, in a pigment called stercobilin. Globulin is converted into amino acids which are then put into circulation. Role in hemoglobin deficiency disease can be caused by a reduced amount of hemoglobin molecules, such as in anemia, or by reduced ability of each molecule to bind oxygen at the same partial pressure of oxygen. Hemoglobinopathies (genetic abnormalities resulting in abnormal structure of the hemoglobin molecule)[81] can cause both. In any case, hemoglobin deficiency reduces the oxygen-carrying capacity of the blood. Hemoglobin deficiency is generally strictly distinguished from hypoxemia, defined as reduced partial oxygen pressure in the blood,[82][83][84][85] although both are causes of hypoxia (insufficient oxygen supply to tissues). Other common causes of low hemoglobin are 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 altered by altered blood pressure or CO2, creating an altered oxygen hemoglobin dissociation curve. However, it can also be pathologically altered in, for example, carbon monoxide poisoning. Decrease in hemoglobin, with or without an absolute decrease in red blood cells, leads to symptoms of anemia. Anemia has many different causes, although iron deficiency and resulting iron deficiency anemia are the most common causes in the Western world. If the absence of iron reduces heme synthesis, red blood cells in iron deficiency anemia are hypochromic (lacking the red hemoglobin pigment) and microcytic (smaller than normal). Other are rarer. In hemolysis (accelerated breakdown of red blood cells) is associated jaundice caused by the hemoglobin metabolite bilirubine, and the circulating hemoglobin can cause kidney failure. Some mutations in the globin chain are associated with hemoglobinopathies, such as sickle cell disease and thalassemia. Other mutations, as discussed at the beginning of the article, are benign and are referred to only as hemoglobin variants. There is a group of genetic known as the porphyries 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. Hemoglobin A slowly combines with glucose in the terminal valine (a amino acid) of each β chain. The resulting molecule is often referred to as Hb A1c, a glycosylated hemoglobin. The binding of glucose to amino acids in the hemoglobin occurs 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 changes in Hb A1c increases. In diabetics whose glucose levels are usually high, the rate of Hb A1c is also high. Due to the slow rate of Hb A combination with glucose, the Hb A1c rate reflects a weighted average of blood sugar levels over the life of red cells, which is about 120 days. [86] The levels of glycosylated hemoglobin are therefore measured to control the long-term control of chronic type 2 diabetes mellitus (T2DM). Poor control of T2DM results in high levels of glycosylated hemoglobin in red blood cells. The normal reference range is about 4.0–5.9%. Although difficult to obtain, values below 7% are recommended for people with T2DM. Levels greater than 9% are associated with poor control of glycosylated hemoglobin, and levels greater than 12% are associated with very poor control. Diabetics who keep their glycosylated hemoglobin levels close to 7% have a much better chance of avoiding the complications that can accompany diabetes (than those whose levels are 8% or higher). [87] In addition, the increased glycosylation of hemoglobin increases its affinity for oxygen, therefore preventing its release at the tissue and causing a level of hypoxia in extreme cases. [88] Elevated levels of hemoglobin are associated with increased numbers or size of red blood cells, called polycythemia. This increase can be caused by congenital heart disease, cor pulmonary hormonal, pulmonary fibrosis, too much erythropoietin, or polycythemia vera. [89] High hemoglobin levels can also be caused by exposure to high altitudes, smoking, dehydration (artificially by concentrating HB), advanced lung disease and certain tumors. [48] A recent study done in Pondicherry, India, shows its importance in coronary heart disease. [90] Diagnosis uses Editorial: Hemoglobinometer A hemoglobin concentration measurement administered before a blood donation at the American Red Cross Boston Donation Center. Hemoglobin concentration measurement is one of the most commonly performed blood tests, usually as part of a full blood count. For example, it is usually tested before or after blood donation. The results are reported in g/L, g/dL or mol/L. 1 g/dL is equal to approximately 0,6206 mmol/L, although the latter units are not used as often uncertainty about the polymeric state of the molecule. [91] This conversion factor, using the only globin unit molecular weight of 16,000 Da, occurs more common for hemoglobin concentration in blood. For MCHC MCHC corpuscular hemoglobin concentration) the conversion factor 0.155, which uses the tetramer weight of 64,500 Da, is more common. [92] 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 14 00 ml/ 15 usual value during pregnancy)[93][94] The normal values of hemoglobin in the 1st and 3rd trimesters of pregnant women should be at least 11 g/dL and at least 10,5 g/dL during the 2nd trimester. [95] Dehydration or hyperhydration can have a strong impact on measured hemoglobin levels. Albumin can indicate hydration status. If the concentration is lower than 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 when red cells are small, macrocytic when they are large, and normocytically different. Hematocrit, the proportion of blood volume occupied by red blood cells, is usually about three times the hemoglobin concentration measured in g/dL. For example, if the hemoglobin is measured at 17 g/dL, that compares to a hematocrite of 51%. [96] Laboratory hemoglobin testing methods require a blood sample (arterial, venous, or capillary) and analysis on hematology analyzer and CO-oximeter. In addition, a new non-invasive hemoglobin (SpHb) test method called Pulse CO-Oximetry is also available with similar accuracy for invasive methods. [97] Concentrations of oxy and deoxyhemoglobin can be measured continuously, regionally and non-invasively using NIRS. [98] [99] [100] [101] [102] NIRS can be used on both the head and muscles. This technique is often used for research in sports training, ergonomics, rehabilitation, patient monitoring, neonatal research, functional brain monitoring, brain-computer interface, urology (bladder contraction), neurology (Neurovascular coupling) and more. The long-term control of blood sugar levels can be measured by the concentration of Hb A1c. Measuring it directly would require many samples because blood sugar levels vary greatly throughout the day. Hb A1c is the product of the irreversible reaction of hemoglobin A with glucose. A higher glucose concentration results in more Hb A1c. Because the reaction is slow, the Hb A1c share represents the glucose level in the blood that is averaged over the half-life of red blood cells, usually 50- 55 days. An Hb A1c rate of 6.0% or less shows good long-term glucose control, while values above 7.0% Increased. This test is especially useful for diabetics. [103] Functional magnetic resonance imaging (fMRI) machine uses the signal of deoxyhemoglobin, which is sensitive to magnetic fields as it is paramagnetic. Combined measurement with NIRS shows good good oxy and deoxyhemoglobin signals compared to the BOLD signal. [104] Athletic tracking and self tracking uses Hemoglobin can be tracked non-invasively, to build an individual data set tracking the hemo concentration and hemodilution effects of daily activities for a better understanding of sports performance and training. Athletes are often concerned about endurance and intensity of exercise. The sensor uses luminous 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 through the hemoglobin protein. [105] This sensor is similar to an impulse oximeter, which consists of a small realising device clamping to the finger. Analogues in non-vertebrate organisms A variety of oxygen transport and binding proteins exist in organisms in 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 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 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 convex) that deal with gas binding are referred to as oxyhemoglobins. In addition to handling the transport and sensing of oxygen, they may also have to deal with NO, CO2, sulfide compounds, and even O2 scavenging in environments that need to be anaerobic. [106] They can even treat detoxification of chlorinated materials in a way analogous to heme-containing enzymes P450 and peroxidases. The giant riftia pachyptila tubeworm shows red hemoglobin-containing plumes The structure of hemoglobins varies by 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 can contain both globins and other types of proteins. [14] One of the most striking occurrences and of hemoglobin in organisms is in the giant tubeworm (Riftia pachyptila, also called Vestimentifera), which can reach 2.4 meters length and ocean volcanic vents populated. Instead of a digestive tract, these worms contain a population bacteria that make up half the weight of the organism. The bacteria oxidize H2S from the vent with O2 from the water to produce energy to make food from H2O and CO2. The upper end of the worms 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 a synthetic raw material similar to photosynthetic plants. The structures are bright red because of their contents of several extraordinarily complex hemoglobins that have up to 144 globin chains, each including corresponding heme structures. These hemoglobins are remarkable because they can carry oxygen in the presence of sulphide, and even to carry sulphide, without being completely poisoned or inhibited by it as hemoglobins in most other species are. [107] [108] Other oxygen-binding myoglobin proteins found in the muscle tissue of many vertebrates, including humans, give the muscle tissue a distinct red or dark gray color. It is very similar to hemoglobin in structure and order, but is not a tetramer; instead, it is a monomer that lacks cooperative bonding. It is used to store oxygen instead of transporting it. The second most common oxygen transport protein found in nature, it is found in the blood of many arthropods and molluscs. Uses copper prosthesis 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 ferrous non-heme protein to carry oxygen in their blood. Looks pink/violet when oxygenated, clearly when not. Chlorocruorin Found in many annelids, it is very similar to erythrocruorine, but the heme group is significantly different in structure. Appears green when deoxygenated and red when oxygenated. Vanabines Also known as vanadium chromagenes, they are found in the blood of sea syringes. They were once believed to use the rare metal vanadium as an oxygen-binding prosthetic group. However, although they contain vanadium preferably, they apparently bind little oxygen, and thus have another function, which is not clarified (sea syringes also contain some hemoglobin). They can act as toxins. Found in many annelids, including earthworms, it is a giant free-floating blood protein with many tens -possibly hundreds-of-iron- and heme-carrying protein subunits bound together in a single protein complex with a molecular mass larger than 3.5 million daltons. Pinnaglobin seen only in the mollusk Pinna nobilis. Brown manganese-based porphyrin protein. Leghemoglobin alfalfa or soybeans, the nitrogen-binding bacteria in the roots are protected from oxygen by this iron heme that contains oxygen-binding protein. The specific protected enzyme is nitrogenase, which is unable to reduce nitrogen gas in the presence of free oxygen. Coboglobin A synthetic cobalt-based porphyrin. porphyrin. seems colorless when oxygenated, but yellow when in veins. Presence in non-roid cells Some non-whiter cells (i.e. cells other than the 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 adult oligodendrocytes. [12] It has been suggested that brain hemoglobin in these cells may contain oxygen to create a homeostatic mechanism in anoxic conditions, which is especially important for A9 DA neurons that have an increased metabolism with a high requirement for energy production. [12] It has also been noted that A9 dopaminergic neurons may be at particular risk because, in addition to their high mitochondrial activity, they are under intense oxidative stress caused by the production of hydrogen peroxide via autoxidation and/or monoamineoxidase (MAO) mediated disinfection of dopamine and the subsequent reaction of accessible iron to generate highly toxic hydroxylradicals. [12] This may explain the risk of these cells for degeneration in Parkinson's disease. [12] 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,[109] alveolan cells,[110] and mesangial cells in the kidney. [111] In history, art and music Heart of Steel (Hemoglobin) (2005) by Julian Voss-Andreae. The images show the 1.50 meter high sculpture immediately after installation, after 10 days, and after several months of exposure to the elements. Historically, there is an association between the color of blood and rust in the association of the planet Mars, with the Roman god of war, because the planet is an orange-red, reminiscent of the ancients of blood. Although the color of the planet is due to iron compounds combined with oxygen in the Martian soil, it is a common misconception that the iron in hemoglobin and the oxides gives blood its red color. The color is actually due to porphyrin moiety of hemoglobin to which the iron, not the iron itself is bound,[112] although the ligation and redox state of the iron pi to pi* or n to pi* electronic transitions of porphyrin and hence its optical characteristics may affect. In 2005, artist Julian Voss-Andreae created a sculpture called Heart of Steel (Hemoglobin), based on the backbone of the protein. The image is made of glass and weathering steel. The deliberate rusting of the initially shiny artwork reflects hemoglobin's fundamental chemical reaction of oxygen to iron. [113] [114] Montreal artist Nicolas Baier created Sheen (Hémoglobine), a sculpture in stainless steel that hemoglobin molecule. It is exhibited in the atrium of the research centre of the McGill University Health Centre in Montreal. The image measures about 10 meters × 10 meters × 10 meters. [115] [116] See also Hemoglobin variants: Hb A1C Hemoglobin A2 Hemoglobin C Hemoglobin f Hemoglobin protein subunits (genes): Alpha globin 1 Beta globin Delta globin Hemoglobin compounds: Carbaminohemoglobin (with carbon dioxide, dark red) colored Carboxyhemoglobin (with carbon monoxide, colored cherry red) Oxyhemoglobin (with diatomumic oxygen, colored blood red) Biology portal Medicine portal Chlorophyll Complete Blood Count Globin fold Hemocyanin Hemoglobineia Hemoglobineometer Hemoglobinometer Sickle Cell Disease Vaska's complex – iridium organometal complex notable for its ability to bind to O2 reversible. References ^ Jones, Daniel (2003) [1917], Peter Roach; James Hartmann; Jane Setter (eds.), English Pronouncing Dictionary, Cambridge: Cambridge University Press, ISBN 978-3125396838 ^ Haemoglobine. Dictionary.com unabridged. Random House. ^ Haemoglobine. Merriam-Webster Dictionary. ^ Maton, Anthea; Jean Hopkins; Charles William McLaughlin; Susan Johnson. 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External links Wikimedia Commons has media related to Hemoglobin. Proteopedia Hemoglobin National Anemia Action Council – anemia.org New Hemoglobin Type Causes Mock Diagnosis With Pulsoxymeters Animation of Hemoglobin: From Deoxy to Oxy Form Related Questions: Ideal Hemoglobin Level in Pregnancy How low can hemoglobin go before death Hemoglobin Level Retrieved from

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