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Myoglobin
What is myoglobin: Myoglobin is a small, bright red monomeric heme protein. It has been obtained in pure crystalline form from many sources. It has a molecular weight of 16,700, about one-fourth that of hemoglobin ( resemble blood hemoglobin in function but with only one heme as part of the molecule and with one fourth the molecular weight. Also called muscle hemoglobin). Though the heme portion of all myoglobins is the same, the protein portions vary considerably between species. It is very common in muscle cells. Its job is to store oxygen for use when muscles are hard at work (oxymyoglobin releases its bound oxygen which is then used for metabolic purposes).

. Structure Of Myoglobin: Myoglobin protein molecule isolated from the cells of vertebrate skeletal muscle that is both a structural and functional relative of hemoglobin, the oxygen-transport protein of the blood of higher animals. Myoglobin, which is composed of a single polypeptide chain of 153 amino acid residues, has the ability to store oxygen by binding it to an iron atom; iron is part of myoglobin's essential chemical composition. The complete amino acid sequence of myoglobin has been determined; it is a relatively small protein with a molecular weight of approximately 17,000 grams per mole. The distribution of myoglobin among the higher animals is a reflection of its physiological function. It is found abundantly in the tissues of diving mammals, e.g., the whale, the seal, and the dolphin. High concentrations of myoglobin in these animals presumably allows them to store sufficient oxygen to remain underwater for long periods.

Myoglobin consists of a backbone and heme-binding domain. (A) Myoglobin was the first protein to be subjected to X-ray crystallography. The backbone of myoglobin consists of eight -helices (blue) that wrap around a central pocket containing a heme group (red), which is capable of binding various ligands including oxygen, carbon monoxide and nitric oxide. (B) The protoheme group is bracketed or stabilized by histidine residues above (His64) and below (His93).(fig.1)

Myoglobin is found abundantly in man only in cardiac muscle, which, by virtue of its essential function, must possess the capacity for continued activity when environmental oxygen concentrations are low. Myoglobin has been investigated intensely and is the first protein molecule to have been completely described in terms of its three-dimensional geometry. This achievement won the British scientist John Kendrew a share in the 1962 Nobel Prize for Chemistry

The tertiary structure of myoglobin is that of a typical water soluble globular protein. Its secondary structure is unusual in that it contains a very high proportion (75%) of a-helical secondary structure. A myoglobin polypeptide is comprised of 8 separate right handed a-helices, designated A through H, that are connected by short non helical regions. Amino acid R-groups packed into the interior of the molecule are predominantly hydrophobic in character while those exposed on the surface of the molecule are generally hydrophilic, thus making the molecule relatively water soluble.

Each myoglobin molecule contains one heme prosthetic group inserted into a hydrophobic cleft in the protein. Each heme residue contains one central coordinately bound iron atom that is normally in the Fe2+, or ferrous, oxidation state. The oxygen carried by hemeproteins is bound directly to the ferrous iron atom of the heme prosthetic group. Oxidation of the iron to the Fe3+, ferric, oxidation state renders the molecule incapable of normal oxygen binding. Hydrophobic interactions between the tetrapyrrole ring and hydrophobic amino acid R groups on the interior of the cleft in the protein strongly stabilize the heme protein conjugate. In addition a nitrogen atom from a histidine R group located above the plane of the heme ring is coordinated with the iron atom further stabilizing the interaction between the heme and the protein. In oxymyoglobin the remaining bonding site on the iron atom (the 6th coordinate position) is occupied by the oxygen, whose binding is stabilized by a second histidine residue. Myoglobin is a cytoplasmic hemoprotein consisting of a single polypeptide chain of 154 amino acids. Expressed solely in cardiac myocytes and oxidative skeletal muscle fibers (types I>2A>>2X) .Myoglobin was so named because of its functional and structural similarity to hemoglobin. Evolutionarily, myoglobin and hemoglobin arose from a common ancestral gene over 500 million years ago. Like hemoglobin, myoglobin reversibly binds O2 and thus may facilitate O2 transport from red blood cells to mitochondria during periods of increased metabolic activity or serve as an O2 reservoir during hypoxic or anoxic conditions. Unlike hemoglobin, however, monomeric myoglobin with a single O2-binding site has a hyperbolic O2-saturation curve characteristic of normal Michaelis–Menten enzyme kinetics rather than the sigmoid-shaped curve seen with tetrameric hemoglobin. Myoglobin avidly binds oxygen. Myoglobin and hemoglobin function as oxygen transporters. Myoglobin displays a hyperbolic-shaped oxygen-binding curve whereas hemoglobin displays a sigmoidal-shaped oxygen-binding curve. (Fig.2)

Carbon monoxide also binds coordinately to heme iron atoms in a manner similar to that of oxygen, but the binding of carbon monoxide to heme is much stronger than that of oxygen. The preferential binding of carbon monoxide to heme iron is largely responsible for the asphyxiation that results from carbon monoxide poisoning.

Barker's Models of Myoglobin : In 1958, John Kendrew and his team reported the first glimpse ever at the structure of a protein, that of myoglobin. It was the result of a low resolution x-ray crystallographic analysis (6Å). The model they proposed gave a rough outline of the tertiary structure of myoglobin and looked somewhat like a contorted sausage out of a Daliesque nightmare. In 1960, Kendrew reported the result of a 2Å analysis of the structure. Through this analysis, most of the atoms in the polypeptide chain backbone and the heme group could be resolved with a fair amount of confidence, but not that of the side-chains. Improved interpretative techniques finally allowed to identify most of the side chains, and a full atomic-level model of the structure was finally produced. This was by far the most complex structure ever solved crystallographically, and it raised question of how it should be represented for publication purposes. The report of this work in Nature includes the black-and-white picture of a skeletal model of the structure. This photograph is a testimony to the complexity of the structure and most of its details are lost in the apparent entanglement of its components. The spatial relationship between groups is very difficult to evaluate or appreciate. A white cord was used to help identify the course of the main chain and made it the only easily identifiable feature. After learning to solve protein structure, x-ray crystallographers would have to deal with the problem of the graphical representations of these structures. An X-Ray diffraction for the protein myoglobin ( fig.3).

One particular solution was of course to produce models of the structure of myoglobin. Shortly after the 1961 publication, Kendrew started to receive requests for such models. It is not until 1965 that Kendrew approached A. A. Barker, an employee of the Cambridge University Engineering Laboratories and owner-operator of "a small model making concern as a private venture". At the time, Barker was offering two dozen models of interest to chemists and biochemists, including DNA, vitamin B12, insulin and the alpha helix. These models were of the ball-and-stick type, assembled on a scale of 2,5 cm per Å. Kendrew's plan was to use components (balls and spokes) provided by C. A. Beevers, professor of chemistry at the University of Edinburgh. Beevers had recently devised a machine to drill holes in small perspex balls and had a small outfit producing a variety of crystal models, which is still active today. With a diameter of 6.9 mm (or 9/32"), these balls allowed for models on a much smaller scale (1cm=1Å) than the scales typically found in ball-and-stick models, a scale suitable for such a large structure. Kendrew started to take orders for the models in May 1966. The price was set at £210 (roughly 600$US), a considerable sum at the time. In all, 29 orders were received between May 1966 and March 1968 for models which were produced at the rate of one per month. Functional roles of myoglobin: 1. Oxygen storage

Myoglobin is perhaps best known as an O2-storage protein in muscle. This role is especially evident in marine mammals and birds that undergo extended periods of apnea when diving. In the absence of inspired O2, stored O2(oxymyoglobin releases its bound oxygen which is then used for metabolic purposes) becomes available to supply locomotor muscles involved in diving-related activities. The role of myoglobin as a store of O2 is supported by the observation that diving mammals and birds can have muscle myoglobin contents that are increased 10- to 30-fold compared with those seen in animals that do not experience prolonged apnea. Thus, when oxygen delivery ceases during breath-hold diving, O2 bound to myoglobin is released to sustain aerobic metabolism in active muscles. Skeletal muscle myoglobin concentration is positively and significantly correlated with dive duration in some species. Myoglobin concentration in skeletal muscle is also increased in humans and other species living at high altitude. In addition, myoglobin expression is increased in response to chronic contractile activity in animal models. 2.PO2 buffering

Related to its role as a tissue reservoir of O2, myoglobin has been proposed to also serve as a buffer of intracellular PO2 in a number of species including the human, rodent and bovine models. Similar to the role of creatine phosphokinase, which functions to buffer ATP concentrations when muscle activity increases, myoglobin functions to buffer O2 concentrations under similar conditions. As a result, the intracellular concentration of O2 remains relatively constant and homogeneous despite dramatic activity-induced increases in O2 flux from capillary to mitochondria. Myoglobin saturation has been shown to decrease rapidly at the onset of muscle activity and reach its nadir (30–60%) at approximately half-maximal levels of work. As work increased to maximal effort, however, myoglobin saturation remained relatively constant, indicating that O2 concentration was likewise relatively constant. By contrast, although myoglobin saturation was approximately 48% at peak muscle O2 consumption, the degree of desaturation increased linearly as a function of muscle work output. Irrespective of this difference, these studies indicate that myoglobin may provide a source of readily available O2 at the onset of exercise and increase the PO2 gradient from capillary to muscle cell even at low levels of activity, suggesting that myoglobin has a role that is intermediate between two other functions, O2 storage and facilitated O2 diffusion. 3. Facilitated O2 diffusion

A third role purported for myoglobin is facilitated or myoglobin-mediated O2 diffusion. As indicated, myoglobin desaturates rapidly at the onset of muscle activity, increasing the PO2 gradient from capillary blood to cytoplasm. Furthermore, it has been proposed that desaturated myoglobin close to the cell membrane then binds O2 and diffuses to the mitochondria, providing a parallel path that supplements simple diffusion of dissolved O2. Compelling theoretical and experimental evidence has been presented for and against this purported role for myoglobin, so its contribution to overall O2 flux in exercising muscle remains equivocal. 4. Other recent functions A number of recent studies have demonstrated that myoglobin may have important functions beyond those associated with O2 binding. One of these is its ability to bind NO, a molecule whose effects can be either beneficial or detrimental to cellular function. In addition to its role as a potent vasodilator, NO has been shown to inhibit cytochrome c oxidase and thus impair mitochondrial respiration. Brunori proposed recently that, based on its ability to bind NO, myoglobin may serve as an important scavenger of NO in heart and oxidative skeletal muscle. A subsequent report by Flögel provided convincing experimental evidence supporting this proposal. Additional support comes from studies showing NO-related alterations in skeletal and cardiac muscle function in myoglobin-deficient mice .Myoglobin is also known to have peroxidase activity, and a similar additional role for this protein as a scavenger of reactive O2 species has recently been demonstrated. Future studies will be necessary to further define the functional role(s) for myoglobin in oxidative skeletal muscle. For example, important questions regarding myoglobin biology that remain unanswered include: what are the genetic factors that regulate myoglobin expression in response to an acute or chronic hypoxic stimulus; is the transcriptional regulation of myoglobin a hypoxia inducible factor (HIF-1)-dependent mechanism; does the induction of myoglobin expression in response to hypoxia require muscle activity (i.e. swimming, running, etc.)? Moreover, the recent identification of additional tissue hemoglobins–neuroglobin and cytoglobin–suggests a physiological model in skeletal muscle that is increasingly complex and fluid regarding the role of tissue hemoglobins and muscle biology. different properties between myoglobin & hemoglobin although their both same function of O2 binding: 1. Myoglobin has a higher affinity for O2 than hemoglobin, e.g., at 20mm Hg myoglobin is 95% saturated with O2, haemoglobin only 40%. 2. Myoglobin has a hyperbolic O2 binding curve, hemoglobin a sigmoidal one.(fig.2) Hemoglobin has a low binding affinity for the first O2 but once the first O2 has bound, there is an increase in binding affinity for the next O2 - binds about 500 times more easily. The 4 polypeptide chains (subunits) making up hemoglobin are not identical and are not independent in their O2 binding affinities. COOPERATIVE INTERACTIONS occur between the subunits so that binding of one O2 increases the chances of another binding. This does NOT occur in myoglobin. 3. Blood is aerated in the lungs: The partial pressure of O2 (pO2) is 100mm Hg.O2 levels are depleted in the muscles, however, and the pO2 drops to 26mm Hg. Therefore, in the lungs hemoglobin will become almost fully saturated - 96% saturated - while it will RELEASE O2 in the muscles where the pO2 is low - loses about 36% of its bound O2. Can see that hemoglobin is ideal for O2 transport from lungs to tissues. Myoglobin on the other hand would release only 2% of its bound O2 at 26mm Hg: it is an ideal molecule for O2 storage. 4. Hemoglobin also binds H+ and CO2 from the tissues and transports these to the lungs. H+ causes a drop in pH in the tissues. Two important points arise from this: Hemoglobin has a lower affinity for O2 at lower pH and binding of H+ and CO2 decreases the affinity for O2 and vice versa - Bohr effect. These factors explain why O2 is released in tissues and H+ and CO2 at the lungs. H+ is bound by His146 in the b-chains. Positive charges on these 2 Histidines help to make salt bridges that stabilize the deoxy form of haemoglobin. CO2 is bound by the N-terminal amino group. There is also a 3-carbon molecule called glycerate-2,3-bisphosphate (or BPG for short) which is a metabolite occurring in tissues short of O2. It can bind to hemoglobin in its central cavity between the b-chains. This brings about an even greater release of O2 at low pO2 (i.e. in the tissues) by lowering hemoglobin's affinity for O2. 5. If one exposes crystals of deoxy hemoglobin to O2, they shatter. O2 binding gives rise to a change in hemoglobin's shape - the new shape is not compatible with the old crystal structure and it breaks.

NOTE that the shape change is not in the tertiary structure but in the QUATERNARY structure: the change occurs in the way the a1b1 and a2b2 pairs fit together. Oxyhemoglobin has a more compact structure than deoxy: the two b-subunits move closer together and the two a-subunits move further apart when O2 binds. This causes a conformational change which in turn increases the affinity of the molecule for additional O2. After O2 has bound, the conformational changes favour release of H+ and CO2, e.g., the H+-binding His146 of the b-chain shifts from a hydrophilic to a hydrophobic environment favouring H+ release.