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Hemoglobin

Image:Hemoglobin.jpg Hemoglobin or haemoglobin (frequently abbreviated as Hb) is the iron-containing oxygen-transport metalloproteinin the red cellsof the bloodin mammalsand other animals. Hemoglobin transports oxygen from the lungsto the rest of the body, such as to the muscles, where it releases the oxygen load.

The name hemoglobin is the concatenation of heme and globin, reflecting the fact that each subunitof hemoglobin is a globular proteinwith an embedded heme(or haem) group; each heme group contains an iron atom, and this is responsible for the binding of oxygen. The most common types of hemoglobin contains four such subunits.

Mutations in the genefor the haemoglobin protein result in a group of hereditary diseasestermed the hemoglobinopathies, the most common members of which are sickle-cell diseaseand thalassemia.

Inhaltsverzeichnis

  • 1 Structure
  • 2 Types of haemoglobins in humans
  • 3 Binding of ligands
  • 4 Degradation of hemoglobin
  • 5 Role in disease
  • 6 Diagnostic use
  • 7 Other biological oxygen-binding proteins
  • 8 See also
  • 9 References
  • 10 External links

Structure

Image:Heme.png

The Haemoglobin moleculeis an assembly of four globular proteinsubunits. Each subunitis composed of a proteinchain tightly associated with a non-protein hemegroup.

Each individual protein chain arranges in a set of alpha-helixstructural segments connected together in a "myoglobinfold" arrangment, so called because this arrangment is the same folding motif used in the heme/globin proteins. This folding pattern contains a pocket which is suitable to strongly bind the heme group.

A heme group consists of an iron atom held in a heterocyclicring, known as a porphyrin. This iron atom is the site of oxygen binding. The iron atom is bonded equally to all four nitrogensin the center of the ring, which lie in one plane. Two additional bonds perpendicular to the plane on each side can be formed with the iron to form the fifth and sixth positions, one connected strongly to the protein, the other available for binding of oxygen. The iron atom can either be in the Fe2+ or Fe3+ state, but ferrihaemoglobin (Methaemoglobin) (Fe3+) cannot bind oxygen.

In adult humans, the most common haemoglobin type is a tetramer (which contains 4 subunit proteins) called haemoglobin A, consisting of two α and two β subunits non-covalently bound. 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 weightof the tetramer of about 64,000 daltons. Haemoglobin A is the most intensively studied of the haemoglobin molecules.

The four polypeptide chainsare bound to each other by salt bridges, hydrogen bondsand hydrophobic interaction. There are two kinds of contacts between the α and β chains: α1β1 and α1β2.

Types of haemoglobins in humans

In the embryo:

  • Gower 1 (ξ2ε2)
  • Gower 2 (α2ε2) (PDB1A9W)
  • Haemoglobin Portland (ξ2γ2)

In the fetus:

  • Haemoglobin F(α2γ2) (PDB1FDH)

In adults:

  • Haemoglobin A (α2β2) (PDB1BZ0) - The most common type.
  • Haemaglobin A22δ2) - δ chain synthesis begins late in the third trimester and in adults, it has a normal level of 2.5%
  • Haemoglobin F(α2γ2) - In adults Haemoglobin F is restricted to a limited population of red cells called F cells.

Binding of ligands

Image:Hemoglobin t-r state ani.gif In the tetrameric form of normal adult hemoglobin, the binding of oxygen is a cooperativeprocess. The binding affinity of hemoglobin for oxygen is increased by the oxygen saturation of the molecule. As a consequence, the oxygen binding curve of hemoglobin is sigmoidal, or 'S' shaped, as opposed to the normal hyperbolic (noncooperative) curve. This positive cooperative binding is achieved through stericconformational changes of the hemoglobin protein complex: when one subunit protein in hemoglobin becomes oxygenated it induces a confirmation or structural arrangement change in the whole complex causing the other 3 subunits to gain an increased affinity for oxygen.

Hemoglobin's affinity for oxygen is decreased in the presence of carbon monoxidebecause both gases compete for the same binding sites on hemoglobin, carbon monoxide binding preferentially to oxygen. Carbon dioxide occupies a different binding site on the hemoglobin. Carbon dioxide reacts with water to give bicarbonate, carbonic acidfreed protons via the reaction, which is catalyzed by carbonic anhydrase:

CO2 + H2O <-> HCO3- + H+

Image:Hb saturation curve.png

So blood with high carbon dioxide levels is also lower in pH(more acidic). Hemoglobin can bind protonsand carbon dioxide which causes a conformational change in the protein and facilitates the release of oxygen. Protons bind at various places along the protein and carbon dioxide binds at the alpha-amino groupforming carbamate. Conversely, when the carbon dioxide levels in the blood decrease (i.e. around the lungs), carbon dioxide is released, increasing the oxygen affinity of the protein. This control of hemoglobin's affinity for oxygen by the binding and release of carbon dioxide is known as the Bohr effect.

The binding of oxygen is affected by molecules such as carbon monoxide(CO) (for example from tobacco smoking, cars and furnaces). CO competes with oxygen at the heme binding site. Hemoglobin binding affinity for CO is 200 times greater than its affinity for oxygen, meaning that small amounts of CO dramatically reduces hemoglobin?s ability to transport oxygen. When hemoglobin combines with CO, it forms a very bright red compound called carboxyhemoglobin. 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.

Hemoglobin also has competitive binding affinity for sulfur monoxide(SO), nitrogen dioxide(NO2) and hydrogen sulfide(H2S). The iron atom in the heme group must be in the Fe+2 oxidation state to support oxygen transport. Oxidation to Fe+3 state converts hemoglobin into hemiglobin or methemoglobinwhich cannot bind oxygen. Nitrogen dioxide and nitrous oxideare capable of converting hemoglobin to methemoglobin.

In people acclimated to high altitudes, the concentration of 2,3-diphosphoglycerate (2,3-DPG) 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 allostericeffect.

A variant hemoglobin, called fetal hemoglobin(Hb F, 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 placentais able to take oxygen from maternal blood.

Degradation of hemoglobin

When red cellsreach the end of their life due to aging or defects, they are broken down, and the haemoglobin molecule broken up and the iron recycled. When the porphyrin ring is broken up, the fragments are normally secreted in the bileby the liver. The major final product of haem degradation is bilirubin. Increased levels of this chemical are detected in the blood if red cells are being destroyed more rapidly than usual. Improperly degraded haemoglobin protein or haemoglobin that has been released from the blood cells can clog small blood vessels especially the delicate blood filtering vessels of the kidneys, causing kidneydamage.

Role in disease

Decreased levels of hemoglobin, with or without an absolute decrease of red blood cells, leads to symptoms of anemia. Anemia has many different causes, although iron deficiencyand its resultant iron deficiency anemiaare the most common causes in the Western world. As absence of iron decreases hemesynthesis, 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 jaundiceis caused by the hemoglobin metabolite bilirubin, and the circulating hemoglobin can cause renal failure.

Mutations in the globin chain are associated with the haemoglobinopathies, such as sickle-cell diseaseand thalassemia.

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 Kingdomwas probably the most famous porphyria sufferer.

To a small extent, hemoglobin A slowly combines with glucoseat a certain location in the molecule. The resulting molecule is often referred to as Hb A1c. As the concentrationof glucose in the blood increases, the percentage of Hb A that turns into Hb A1c increases. In diabeticswhose glucose usually runs high, the percent Hb A1c also runs high. Because of the slow rate of Hb A combination with glucose, the Hb A1c percentage is representative of glucose level in the blood averaged over a longer time (the half-life of red blood cells, which is typically 50-55 days).

Diagnostic use

Hemoglobin levels are amongst the most commonly performed blood tests, usually as part of a full blood countor complete blood count. Results are reported in g/L, g/dlor mmol/L. For conversion, 1 g/dl is 0.62 mmol/L.


Glucoselevels in blood can vary widely each hour, so one or only a few samples from a patient analyzed for glucose may not be representative of glucose control in the long run. For this reason a blood sample may be analyzed for Hb A1c level, which is more representative of glucose control averaged over a longer time period (determined by the half-life of the individual's red blood cells, which is typically 50-55 days). People whose Hb A1c runs 6.0% or less show good longer-term glucose control. Hb A1c values which are more than 7.0% are elevated. This test is especially useful for diabetics.


This Hb A1c level is only useful in individuals who have red blood cells (RBCs) with normal survivals (i.e., normal half-life). In individuals with abnormal RBCs, whether due to abnormal hemoglobin molecules (such as Hemoglobin S in Sickle Cell Anemia) or RBC membrane defects - or other problems, the RBC half-life is frequently shortened. In these individuals an alternative test called "fructosamine level" can be used. It measures the degree of glycation (glucose binding) to albumin, the most common blood protein, and reflects average blood glucose levels over the previous 18-21 days, which is the half-life of albumin molecules in the circulation.

Other biological oxygen-binding proteins

Hemoglobin is by no means unique; there are a variety of oxygen transport and binding proteins throughout the animal (and plant) kingdom. Other organisms including bacteria, protozoansand fungiall have hemoglobin-like proteins whose known and predicted roles include the reversible binding of gaseous ligands.

Myoglobin: Found in the muscle tissue of many vertebrates including humans (gives muscle tissue a distinct red or dark gray color). Is very similar to hemoglobin in structure and sequence, but is not arranged in tetramers, it is a monomer and lacks cooperative bindingand is used to store oxygen rather than transport it.

Hemocyanin: Second most common oxygen transporting protein found in nature. Found in the blood of many arthropodsand molluscs. Uses copper prosthetic group instead of iron heme groups and is blue in color when oxygenated.

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

Vanabins: also known as VanadiumChromagen are found in the blood of Sea squirtand are hypothesised to use the rare metal Vanadium as its oxygen binding prosthetic group, but this hypothesis is unconfirmed.

Erythrocruorin: found in many annelids, including earthworms. Giant free-floating blood protein, contains many dozens even hundreds of Iron heme containing protein subunits bound together into a single protein complex with a molecular masses greater than 3.5 million daltons.

Pinnaglobin: Only seen in the molluskPinna squamosa. 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.

See also

  • Hemoprotein
  • Hemocyanin
  • Chlorophyll
  • Hemoglobin A1C
  • Hemoglobin S
  • Hemoglobin C
  • Hemoglobin F
  • Hemoglobin A2

References

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| Title=A brief history of hemoglobins: plant, animal, protist, and bacteria
| Periodical=Proc Natl Acad Sci USA
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External links

  • Interactive models of hemoglobinar:??????????

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Retrieved from "http://en.wikipedia.org/Hemoglobin"



This article is licensed under the GNU Free Documentation License.
It uses material from the http://en.wikipedia.org/wiki/Hemoglobin Wikipedia article Hemoglobin.

 
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