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When we breathe in oxygen, the red blood cells transport it around to every cell in the body – a critical process that has far-reaching evolutionary consequences. The advent of aerobic respiration, which added the oxygen-utilising tricarboxylic acid cycle and electron transport system onto anaerobic glycolysis, allowed aerobic organisms to extract 18 times more energy from glucose in the form of ATP. Initially, organisms relied on diffusion to transport oxygen to their cells, an inefficient system that kept them microscopic in size. Then with the development of the body cavity came a primitive circulatory system involving the flow of interstitial fluid through the action of muscular movement; yet, body size remained small, as this system of circulation was limited in its effectiveness. Nematode worms have a primitive type of body cavity (pseudocoelom) and circulation; these tiny animals consist of just under a 1000 cells and as such are barely visible with the naked eye. With the advent of a true circulatory system to transport highly specialised red blood cells close to every cell in the body no matter how large the organism, so that oxygen could now reach all cells, body size was able to expand radically up to the largest animal to currently inhabit the earth: the blue whale, which can weight up to 150 tons and stretch 100 feet in length from head to tail.
Haemoglobin, an Oxygen Carrier
A drop of blood contains millions of red blood cells, or erythrocytes. These specialised cells are like flattened discs, which gives them a much greater surface area with which to exchange oxygen and carbon dioxide in the lungs and with body cells. Red blood cells are able to carry oxygen so efficiently because of a special protein Red blood cells inside them: haemoglobin. In fact, it is the haemoglobin that is responsible for the colour of the red blood cell. Haemoglobin contains a haem prosthetic group that has an iron atom at its centre. When the iron is bound to oxygen, the haem group is red in colour (oxyhameoglobin), and when it lacks oxygen (deoxygenated form) it is blue-red. As blood passes through the lungs, the haemoglobin picks up oxygen because of the increased oxygen pressure in the capillaries of the lungs, and can then release this oxygen to body cells where the oxygen pressure in the tissues is lower. In addition, the red blood cells can pick up the waste product, carbon dioxide, some of which is carried by the haemoglobin (at a different site from where it carries the oxygen), while the rest is dissolved in the plasma. The high carbon dioxide levels in the tissues lowers the pH, and the binding of haemoglobin to carbon dioxide causes a conformational change that facilitates the release of oxygen. The carbon dioxide is then released once the red blood cells reach the lungs. Haemoglobin is composed of four polypeptide chains, which in adults consist of two alpha ( ) globin chains and two beta ( ) globin chains (i.e. 2 2). Each polypeptide has a haem prosthetic group attached, where each haem can bind one oxygen
molecule - so there are four haem groups per haemoglobin molecule that together bind four oxygen molecules.
3-dimensional structure of hemoglobin. The four subunits are shown in red and yellow, and the heme groups in green. Hemoglobin or haemoglobin (frequently abbreviated as Hb) is the iron-containing oxygen-transport metalloprotein in the red cells of the blood in mammals and other animals. Hemoglobin in vertebrates transports oxygen from the lungs to the rest of the body, such as to the muscles, where it releases the oxygen load. Hemoglobin also has a variety of other gas-transport and effect-modulation duties, which vary from species to species, and which in invertebrates may be quite diverse. The name hemoglobin is the concatenation of heme and globin, reflecting the fact that each subunit of hemoglobin is a globular protein with 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, each with one heme group. Mutations in the genes for the hemoglobin protein in humans result in a group of hereditary diseases termed the hemoglobinopathies, the most common members of which are sickle-cell disease and thalassemia. Historically in human medicine, hemaglobinopathies were the first diseases to be understood in mechanism of dysfunction, down to the molecular level. Hemoglobin is synthesized in the mitochondria of the immature red blood cell throughout its early development from the proerythroblast to the reticulocyte in the bone marrow, when the nucleus has been lost. Even after the loss of the nucleus, residual ribosomal 29
RNA allow further synthesis of Hb until the reticulocyte loses its RNA on entering the vasculature. Hemoglobin is chemically represented by (C2952H4664N812O832S8Fe4).
The hemoglobin molecule in humans is an assembly of four globular protein subunits. Each subunit is composed of a protein chain tightly associated with a non-protein heme group. Each individual protein chain arranges in a set of alpha-helix structural segments connected together in a globin fold arrangement, so called because this arrangement is the same folding motif used in other heme/globin proteins such as myoglobin. 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 heterocyclic ring, known as a porphyrin. This iron atom is the site of oxygen binding. The iron atom is bonded equally to all four nitrogens in 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 a fifth and sixth bonding position, one connected strongly to the protein, the other available for binding of an oxygen molecule. The iron atom may either be in the Fe2+ or Fe3+ state, but ferrihemoglobin (methemoglobin) (Fe3+) cannot bind oxygen. The Fe2+ in hemoglobin may exist in either a high-spin (deoxygenated) or low-spin (oxygenated) state, according to population of the iron (II) d-orbital structure with its 6 available d electrons, as understood in crystal field theory. With the binding of an oxygen molecule as a sixth ligand to iron, the iron (II) atom finds itself in a octahedral field (defined by the six ligand points of the four porphyrin ring nitrogens, the histamine
nitrogen, and the O2). In these circumstances, with strong-field ligands, the five d-orbitals (these are the “3d” orbitals of the iron) undergo a splitting in energy between two of the d-orbitals which point directly in the direction of the ligands (dz2 and dx2-y2 orbitals, hybridized in these circumstances into two eg orbitals), and three of the d-orbitals which are pointed in off-directions (the dxy ,dxz, and dyz, hybridized in these circumstances into three t2g orbitals). When oxygen is bound to Fe2+ in heme, all 6 d-electrons of the iron atom are forced into the three lower-energy t2g orbitals, where they must all be paired (see crystal field theory for diagram). This produces the “low-spin” state of oxyhemoglobin. The sharp highenergy of transition between the t2g and empty eg states of d-orbital electrons in oxyhemoglobin is responsible for the bright red color of the substance. When oxygen leaves, the Fe2+ is allowed to move out of the porphyrin ring plane, away from its five ligands toward the empty space formerly occupied by the O2, and in these circumstances eg orbital energies drop and t2g electrons move into them. This causes the iron atom to expand and increase its net spin, as d-orbitals become populated with unpaired electrons. In these circumstances, the absorption spectrum becomes broader, with smaller transition levels, producing the dark color of deoxyhemoglobin. In adult humans, the most common hemoglobin type is a tetramer (which contains 4 subunit proteins) called hemoglobin A, consisting of two α and two β subunits noncovalently 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. Hemoglobin A is the most intensively studied of the hemoglobin molecules. The four polypeptide chains are bound to each other by salt bridges, hydrogen bonds and hydrophobic interaction. There are two kinds of contacts between the α and β chains: α1β1 and α1β2. [[Image:|px|Hemoglobin structure]] chemical
Identifiers Symbol(s) Entrez OMIM RefSeq UniProt PDB Other data EC number Locus HBB 3043 141900 NM_000518 P68871   Chr. 11 p15.5
Types of hemoglobins in humans
In the embryo:
• • •
Gower 1 (ξ2ε2) Gower 2 (α2ε2) (PDB 1A9W) Hemoglobin Portland (ξ2γ2)
In the fetus:
Hemoglobin F (α2γ2) (PDB 1FDH)
• • •
Hemoglobin A (α2β2) (PDB 1BZ0) - The most common type. Hemaglobin A2 (α2δ2) - δ chain synthesis begins late in the third trimester and in adults, it has a normal level of 2.5% Hemoglobin F (α2γ2) - In adults Hemoglobin F is restricted to a limited population of red cells called F cells.
Binding of ligands
Binding and release of ligands induces a conformational (structural) change in hemoglobin. Here, the binding and release of oxygen illustrates the structural differences between oxy- and deoxyhemoglobin, respectively. As discussed above, when oxygen is bound to Fe2+ in heme, all 6 d-electrons are forced into three lower-energy t2g orbitals, where they are all paired. This causes contraction of the iron atom, and causes it to move back into the center of the porphyrin ring plane (see moving diagram). At the same time, the porphyrin ring plane itself is pushed away from the oxygen and toward the histamine interacting at the other pole of the iron. The interaction here forces the ring plane sideways toward the outside of the tetramer, and also induces a strain on the protein helix containing the histamine, as it moves nearer the iron. This causes a tug on this peptide strand which tends to open up heme units in the remainder of the molecule, so that there is more room for oxygen to bind at their heme sites. 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 oxygens bound influencing the shape of the binding sites for the next oxygens, 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, this induces a conformational or structural change in the whole complex, causing the other subunits to gain an increased affinity for oxygen. As a 32
consequence, the oxygen binding curve of hemoglobin is sigmoidal, or S-shaped, as opposed to the normal hyperbolic curve associated with noncooperative binding. Hemoglobin's oxygen-binding capacity is decreased in the presence of carbon monoxide because both gases compete for the same binding sites on hemoglobin, carbon monoxide binding preferentially in place of oxygen. Carbon dioxide occupies a different binding site on the hemoglobin. 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 along the protein, and carbon dioxide binds at the alpha-amino group forming carbamate. 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. This control of hemoglobin's affinity for oxygen by the binding and release of carbon dioxide and acid, 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.
In similar fashion, hemoglobin also has competitive binding affinity for cyanide (CN-), sulfur monoxide (SO), nitrogen dioxide (NO2), 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 be in the Fe2+ oxidation state to support oxygen and other gases' binding and transport. Oxidation to Fe3+ state converts hemoglobin into hemiglobin or methemoglobin (pronounced "MET-hemoglobin"), which cannot bind oxygen. Hemoglobin in normal red blood cells is protected by a reduction system to keep this from happening. Nitrogen dioxide and nitrous oxide are capable of converting a small fraction of hemoglobin to methemoglobin, however this is not usually of medical importance (nitrogen dioxide is poisonous by other mechanisms, and nitrous oxide is routinely used in surgical anesthesia in most people without undue methemoglobin buildup). In people acclimated to high altitudes, the concentration of 2,3-bisphosphoglycerate (2,3BPG) 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. 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.
Degradation of hemoglobin in vertebrate animals
When red cells reach the end of their life due to aging or defects, they are broken down, and the hemoglobin molecule broken up and the iron recycled. When the porphyrin ring is broken up, the fragments are normally secreted in the bile by the liver. The major final product of heme 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 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.
Hemoglobin levels are amongst the most commonly performed blood tests, usually as part of a full blood count or complete blood count. Results are reported in g/L, g/dL or mol/L. For conversion, 1 g/dL is 0.621 mmol/L. If the total hemoglobin concentration in the blood falls below a set point, this is called anemia. Anemias are further subclassified by the size of the red blood cells, which are the cells which contain hemoglobin in
vertebrates. They can be classified as microcytic (small sized red blood cells), normocytic (normal sized red blood cells), or macrocytic (large sized red blood cells). Glucose levels 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 halflife of albumin molecules in the circulation.
Hemoglobin in the biological range of life
Hemoglobin is by no means unique to vertebrates; there are a variety of oxygen transport and binding proteins throughout the animal (and plant) kingdom. Other 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 also the heme moiety (iron in a flat porphyrin support), these substances are often simply referred to as 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 which deals with oxygen transport (for example, many insects and other arthropods). In all these groups, heme/globin containing molecules (even monomeric globin ones) which deal with gas-binding are referred to as hemoglobins. In addition to dealing with transport and sensing of oxygen, these molecules may also deal with NO, CO2, sulfide compounds, and even O2 scavenging in environments which must be anaerobic. They may even deal with detoxification of chlorinated materials in a manner analogous to heme-containing P450 enzymes and peroxidases. The structure of hemoglobins varies across species. Hemoglobin occurs in all kingdoms of organism, but not in all organisms. Single-globin hemoglobins tend to be found in primative species such as bacteria, protozoa, algae, and plants. Nematode worms, moluscs and crustaceans, however, many contain very large multisubunit molecules much larger than those in vertebrates. Particularly worth noting are chimeric hemoglobins found in fungi and giant annelids, which may contain both globin and other types of
proteins [PMID 11274340]. One of the most striking occurrences and uses of hemoglobin in organisms occurs in the (up to) 2.4 meter giant tube worm (Riftia pachyptila also called Vestimentifera) which populates ocean volcanic vents at the sea floor. These worms have no digestive tract, but instead contain a population of bacteria constituting half the organism’s weight, which react H2S from the vent and O2 from the water to produce energy to make food from H2O and CO2. These organisms end with a deep red fan-like structure ("plume") which extends into the water and which absorbs H 2S and O2 for the bacteria, and also absorbs CO2 for use as synthetic raw material (after the manner of photosynthetic plants). The bright red color of the structures results from several extraordinarily complex hemoglobins found in them which contain up to 144 globin chains (presumably each including associated heme structures). These tube worm hemoglobins are remarkable for being able to carry oxygen in the presence of sulfide, and indeed to also carry sulfide, without being completely "poisoned" or inhibited by this molecule, as hemoglobins in most other species are [PMID 8621529].
Other biological oxygen-binding proteins
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 binding and 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 arthropods and 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 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, and 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 Chromagen are found in the blood of Sea squirt and 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 mollusk Pinna 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.
Foetal Haemoglobin, in a Class of its Own
The foetus has different haemoglobin needs from that of an adult. The foetus receives its blood supply via the umbilical vein from the placenta. However, by the time the blood has reached the placenta, much of its oxygen has already been used up by the mother. Consequently, foetal haemoglobin needs to be able to bind oxygen with a higher affinity than maternal blood, if enough oxygen is to reach the foetus. Initially, embryonic haemoglobin is the main form, consisting of at least three types: Gower1 (zeta2 epsilon2, or 2 2), Gower2 (alpha2 epsilon2, or 2 2), and Portland (zeta2 gamma2, or 2 2). The and globin chains are unique to embryonic haemoglobin and appear to be synthesised almost entirely in the yolk sac. After the second month of development, the foetus switches to foetal haemoglobin (haemoglobin F; alpha2 gamma2, or 2 2). At birth, approximately 5095% of the child’s haemoglobin is foetal haemoglobin, but after six months, these levels decline and adult haemoglobin (haemoglobin A, 2 2) becomes the predominant form, as it is better suited to the oxygen transport requirements after birth. There is also haemoglobin A2 (alpha2 delta2, or 2 2), which is synthesised late in the third trimester and continues into adulthood at a level of 2.5%.
Haemoglobin and High Altitudes
People living at high altitudes, such as in the Tibetan Plateau or the Andes Mountains, have developed unique and often different ways to cope with the reduced amount of oxygen available at higher altitudes. Natives of the Andes Mountains in South America have a higher concentration of haemoglobin in their blood, allowing more oxygen to be carried by the same volume of blood. However, there are other means of coping with high altitudes. For instance, the people living in the Tibetan Plateau have doubled their nitric oxide levels. Nitric oxide is a blood vessel dilator, which is thought to boost the uptake of oxygen.
Haemoglobin and 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 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 renal failure.
Anaemia may be caused by excessive loss of blood, by destruction of red cells or by decreased red cell production. Only the first two of these causes will be discussed here (see separate factsheet for anaemia caused by decreased red blood cell production). Excessive loss of blood may be sudden:
• • • •
Accidents Childbirth Surgery A ruptured blood vessel
Excessive blood loss may also occur over a long period of time (chronic bleeding):
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Heavy menstruation Bleeding cancer or polyps (benign growths) in the gut Bleeding gastric or duodenal ulcers Nosebleeds Bleeding haemorrhoids (piles)
Increased destruction of red blood cells occurs in hereditary conditions in which either the haemoglobin molecules or the red cells themselves are abnormal:
• • • • •
Thalassaemia (abnormal haemoglobin) Sickle cell disease (abnormal haemoglobin) Hereditary spherocytosis (abnormally shaped red cells) Hereditary elliptocytosis (abnormally shaped red cells) G6PD deficiency (lack of an enzyme in red cells)
These hereditary conditions are fairly common throughout the world but different types are more common in different races. Increased destruction of red blood cells also occurs in conditions in which the immune system produces antibodies (molecules normally produced to kill bacteria and viruses) that bind to and destroy red cells. This is called 'autoimmune haemolytic anaemia' and many people with this type of anaemia have an underlying condition such as an infection, primary autoimmune disease or leukaemia. Any condition in which the spleen is enlarged also causes destruction of red cells. Symptoms and complications of anaemia The symptoms will depend on the severity of the anaemia. Pallor (a pale complexion) is a poor indication of the degree of anaemia. If the excessive bleeding is chronic, such as from a stomach ulcer or heavy periods, there may be no symptoms at all or there may be:
• • •
Tiredness Faintness Dizziness (especially when standing) 38
If the blood loss is more severe or more rapid (as in an accident) there may be:
• • • • • • •
Thirst Sweating Severe fatigue Breathlessness Chest pain Heart attack Stroke (due to lack of oxygen to the brain)
In people who have increased red cell destruction, the breakdown products of haemoglobin may cause jaundice (a yellow colouring of the skin and eyes).
Sickle Cell Anaemia
Sickle Cell Anaemia affects the shape of red blood cells, changing them from a flattened disc to a sickle or crescent shape. Whereas normal red blood cells are smooth and move easily through blood vessels, sickle blood cells are hard, inflexible and tend to clump together, causing them to get stuck in blood vessels as blood clots, thereby blocking the flow of blood. This can cause pain, blood vessel damage and a low red blood cell count (anaemia) due to the more fragile nature of sickle blood cells. The abnormal A sickle cell next sickle shape is due to the presence of abnormal haemoglobin to regular red (haemoglobin S), which contains abnormal beta polypeptide with a blood cells single amino acid substitution at position 6 along the polypeptide chain (the alpha chain is normal). The abnormal chain reduces the amount of oxygen inside the red blood cell, altering its shape. Heterozygotes, where one beta chain gene is affected and the other is normal, usually display normal red blood cells, and it is only when both beta chain genes are affected (homozygote) that the sickle cell disease is seen. However, heterozygote carriers
of the disease are better protected against malaria than people with two normal beta chain genes. This malarial protection has caused the sickle cell gene to reach high levels in indigenous populations in Africa and India.
Thalassaemia is caused when the production of haemoglobin chains is impaired, the most common forms affecting the alpha globin chain (alpha Thalassaemia) or the beta globin chain (beta Thalassaemia). The chains themselves can be normal, but the amounts produced are not; sometimes the genes can even be missing. There are four genes needed to make the alpha globin chain, with moderate to severe anaemia resulting when more than two genes are affected. With the beta globin chain there are two genes required, the most severe form of the disease affecting both genes. An equal number of alpha and beta globin proteins are required to make functional adult haemoglobin, and a deficiency in either chain will cause an imbalance that damages and destroys red blood cells, thereby producing anaemia. The deficiency in globin chains can cause the an abnormal association of globin chains: in the case of alpha Thalassaemia, beta globin chains combine to produce abnormal beta tetramers that cannot bind oxygen, whereas with beta Thalassaemia no such alpha tetramers exist – instead the alpha globin chains become degraded in the absence of beta globin chains.
Porphyria disorders affect the production of functional haem molecules in haemoglobin. The haem component is composed of a porphyrin ring complex and iron. Porphyria affects the production of a functional porphyrin complex through a genetic mutation at any one of the many enzymatic steps involved in its production. While most haem is in the blood associated with haemoglobin, haem is also required for in several other tissues, including the liver. Porphyrias can affect either the skin (cutaneous porphyria) or the nervous system (acute porphyria). Cutaneous porphyria causes the development of blisters, itching and swelling upon exposure to light, while acute porphyria causes pain, numbness, paralysis or mental disorders. Certain light-sensitive drugs have been developed based on the abnormal porphyrin structures that result from cutaneous porphyria. These drugs have been used to treat cancer: cancer cells preferentially absorb these porphyrin-like structures and help to destroy the cancer cells upon exposure to light treatment involving lasers.
Carbon Monoxide Poisoning
Carbon monoxide (CO) binds to haemoglobin with a higher affinity (200x greater) than oxygen, and at the same binding site. Consequently, carbon monoxide will bind haemoglobin preferentially over oxygen when both are present in the lungs - even small amounts of carbon monoxide can dramatically reduce the ability of haemoglobin to transport oxygen. Levels as low as 0.02% carbon monoxide can cause headaches and 40
nausea, while a concentration of 0.1% can lead to unconsciousness. This accounts for the suffocation caused by carbon monoxide fumes, such as from the exhaust of a car engine. People who smoke heavily can block up to 20% of the oxygen binding sites in haemoglobin with carbon monoxide. When carbon monoxide binds to haemoglobin it becomes a very bright cherry red (carboxyhaemoglobin), giving the person the appearance of a ‘healthy glow’. By contrast, carbon dioxide (CO2), which is produced as a waste product after aerobic respiration, binds to haemoglobin at a different site, therefore does not compete with oxygen for binding to haemoglobin.
Mutations in the globin chain are associated with the hemoglobinopathies, such as sickle-cell disease and 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 Kingdom was probably the most famous porphyria sufferer. To a small extent, hemoglobin A slowly combines with glucose at a certain location in the molecule. The resulting molecule is often referred to as Hb A1c. As the concentration of glucose in the blood increases, the percentage of Hb A that turns into Hb A1c increases. In diabetics whose 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).
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