Myoglobin

Oxygen Storage and Diffusion Protein

Carlos Hernandez S. '24, Riley Orth '24, Evan Bongers '23

Contents:

I. Introduction

Myoglobin proteins are classified as globular proteins that can be found in many vertebrates and mammals. Myoglobin is an oxygen and iron binding protein that is found in the cardiac and skeletal muscles, as a storage unit. This protein is often compared to hemoglobin due to the similarity in function and structure. The simpler of the two proteins, myoglobin, only has one polypeptide chain and one binding site. On the other hand, the structure of hemoglobin is much more complex as it has four polypeptide chains and four oxygen binding sites. These differences lead to a major difference in binding. Myoglobin has a higher affinity for oxygen due to its single binding site and therefore does not have the cooperative binding that hemoglobin does.

Myoglobin is associated with getting oxygen to muscles when oxygen delivery is insufficient, temporarily supplying oxygen to areas as a local oxygen reserve. This is especially important in marine mammals that often hold their breath for long periods of time. In mammals like whales and seals, very high concentrations of myoglobin are seen in their blood. They can pack up to 20 times the amount of myoglobin in their cells that a human can hold. 

II. Structure

The simple structure of myoglobin led it to be the first protein to have its 3-D structure displayed via X-ray crystallography in 1958 (image). The overall shape of the protein is a sphere that is flattened at the poles. The polypeptide chain that makes up myoglobin has all of its amino acids in the trans configuration. The chain is arranged in eight major alpha-helical structures (each shown as a different color), which are all right handed . The latter two are connected by sharp corners containing all helical residues. Five others are composed of one to eight residues. There are also two end segments that are non-helical and made up of two to four residues. These amino acids are folded into the flattened spherical shape. The heme group which binds to an iron atom , is buried in the center with one edge exposed. This forms part of the surface of the protein and gives the binding site for oxygen (Watson et al., 1969).



Fig. 1. The X-ray crystallography of a myoglobin crystal (Watson et al., 1969)

III. Oxygen Binding

The heme iron in myoglobin can take on two different oxidation states allowing for it to bind to different molecules. In the oxidized state Fe3+, or ferric state, the myoglobin molecule is able to bind to a water molecule or many anionic molecules. In the Fe2+ oxidation state, or the ferrous state, the myoglobin can bind to O2, CO, NO, aryl nitroso compounds and alkyl isocyanides. We will focus on the bonding to O2. The O2 binds in a bent end configuration with the iron atom. (IMAGE) The polar bond formed creates an opportunity for hydrogen bonding between the distal histidine, and the bonded oxygen (image). This hydrogen bonding creates a greater affinity for oxygen in the myoglobin (Springer et al.,1994). Fig. 2 - Hydrogen bonding between distal histidine and oxygen attached to Heme group iron (Structural Biochemistry/Protein Function/Heme Group/Myoglobin, 2021)

IV. Regulation of O2 vs CO binding

The function of myoglobin has been confirmed in many instances to store and provide oxygen. This function is essential for organisms to keep oxygen flow to key cells and muscles to survive. Therefore, there has to be a mechanism to recognize or discourage binding to certain molecules over others. The oxidation state of the Fe molecule plays an important role in determining the molecules that bind. To bind to O2 iron has to be in the reduced state. To mediate this, there is slowing down of the process because it takes time for the iron to reduce to its 2+ oxidation state in cells (Springer et al.,1994). Another key to favor O2 binding is the hydrogen bonds formed between the FeO2 complex and a distal histidine (HisE7). This increases the stability of the O2 by about 1000 times. This interaction greatly favors bonding to O2 because CO does not have an affinity for HisE7 which makes a myoglobin molecule more unstable when bound to CO. Similarly, NO is less stable than O2 when bound to myoglobin despite being more stable than the CO complex. The distal histidine drives the binding of gasses and heavily favors bonding to O2 (Olson and Phillips Jr., 1997) . 

V. Implications

Questions have been raised about the actual significance of myoglobin. There have been studies on mice that knock out the gene for myoglobin to see the effects on the absence of this seemingly vital protein. In these studies, the mice showed little to no difference in growth and maturity with or without myoglobin. The size during each life stage, aerobic ability, and sexual maturity all remained relatively the same. This is an unexpected result that leads us to question the true function and importance of myoglobin for the survival of an organism (Garry et al., 1998).


VI. References

Springer, B. A., Sligar, S. G., Olson, J. S., & Phillips, G. N. J. (1994). Mechanisms of ligand recognition in myoglobin. Chemical Reviews, 94(3), 699-714. https://pubs.acs.org/doi/pdf/10.1021/cr00027a007?casa_token=dfU7XIjE4u0AAAAA:6u54QX3ZJ8ilslqCwgSOXpXa1qbW8PAQSKO0u1hm-MILLmDwM-dqbFBFnNrvO1yEfbwU_03hDPMsx48SxQ

Watson, H.C. THE STEREOCHEMISTRY OF THE PROTEIN MYOGLOBIN. Progress in Stereochemistry, vol. 4, 1969, pp. 299, 333. https://www.jstor.org/stable/pdf/1711083.pdf

Olson, J., Phillips Jr., G. Myoglobin discriminates between O2, NO, and CO by electrostatic interactions with the bound ligand. JBIC 2, 544,552 (1997). https://doi.org/10.1007/s007750050169

Kendrew, John C. Myoglobin and the Structure of Proteins. Science, vol. 139, no. 3561, American Association for the Advancement of Science, 1963, pp. 1259, 66, http://www.jstor.org/stable/1711083.

Garry, D., Ordway, G., Lorenz, J. et al. Mice without myoglobin. Nature 395, 905, 908 (1998). https://doi.org/10.1038/27681

Structural Biochemistry/Protein Function/Heme Group/Myoglobin. Wikibooks, Open Books for an open World, https://en.wikibooks.org/wiki/Structural_Biochemistry/Protein_function/Heme_group/Myoglobin

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