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Transcript of Hemeproteins
Hemeproteins are a group of specalized proteins that contain heme as a tightly bound proshetic group
are most abundant hemeproteins in humans, their heme group serves to reversibly bind oxygen
heme group of
functions as electron carrier that is alternatively reduced and oxidized
Structure and function of hemoglobin
Hemoglobin is found exclusively in red blood cells (RBCs), where its main function is to transport oxygen (O2) from the lungs to the capillaries of the tissues. Hemoglobin A, the major hemoglobin in adults,is composed of four polypeptide chains—two alpha α chains and two beta chains—held together by noncovalent interactions.
Each subunit has stretches of alphaα-helical structure, and a heme-binding pocket similar to that described for myoglobin
Prosthetic group - is a nonpolipeptide moiety that forms a functional part of a protein.
Without its prosthetic group, protein is designed an
With prosthetic group it is a
A. hemoprotein (cytchrome c)
B. Structure of Heme
alpha Helical content
: Myoglobin is a compact molecule, with approximately
80% of its polypeptide chain folded into eight stretches of helix.
The interior of the myoglobin molecule is composed almost entirely of nonpolar amino acids.
polar amino acids are located almost exclusively on the surface of the molecule,where they can form hydrogen bonds, both with each other andwith water.
polar and nonpolar amino acids
polar amino acids - may participate in hydrogen bonds. (Glutamine Asparagine Histidine Serine Threonine Tyrosine Cysteine Methionine Tryptophan )
nonpolar (Hydrophobic ) - normally buried inside the protein core. ( Alanine Isoleucine Leucine Phenylalanine Valine Proline
Binding of the heme group:
The heme group of myoglobin sits in a crevice in the molecule, which is lined with nonpolar amino
acids. Notable exceptions are two histidine residues . One, the proximal histidine , binds directly to the iron of
heme. The second, or distal histidine, does not directly interact
with the heme group, but helps stabilize the binding of oxygen
to the ferrous iron.
Quaternary structure of hemoglobin:
The hemoglobin tetramer
can be envisioned as being composed of two identical dimers,
(αalpha betaβ)1 and (alpha betaαβ)2, in which the numbers refer to dimers one and
two. The two polypeptide chains within each dimer are held tightly
together, primarily by hydrophobic interactions
In contrast, the two dimers are able to move with respect to each other, being held together primarily by polar
The weaker interactions between these mobile dimers
result in the two dimers occupying different relative positions in
deoxyhemoglobin as compared with oxyhemoglobin
: The deoxy form of hemoglobin is called the “T,” or taut (tense) form. In the T form, the two αβ dimers interact through a network of ionic bonds and hydrogen bonds that constrain the movement of the polypeptide chains. The T form is the lowoxygen-affinity form of hemoglobin.
: The binding of oxygen to hemoglobin causes the rupture of some of the ionic bonds and hydrogen bonds between the αβ dimers. This leads to a structure called the “R,” or relaxed form, in which the polypeptide chains have more
freedom of movement . The R form is the high oxygen-
affinity form of hemoglobin
Binding of oxygen to myoglobin and hemoglobin
Myoglobin can bind only one molecule of oxygen, because it contains only one heme group.
In contrast, hemoglobin can bind four oxygen molecules —one at each of its four heme groups. The degree of saturation (Y) of these oxygen-binding sites on all myoglobin or hemoglobin molecules can vary between zero (all sites are empty) and 100% (all sites are full)
A plot of Y measured at different partial
pressures of oxygen (pO2) is called the oxygen dissociation curve.This graph illustrates that myoglobin has a higher oxygen affinity at all pO2 values than does
hemoglobin. The partial pressure of oxygen needed to achieve half-saturation of the binding sites (P50) is approximately 1 mm Hg for myoglobin and 26 mm Hg for hemoglobin. The higher the oxygen affinity (that is, the more tightly oxygen binds), the lower the P50.
Oxygen dissociation curve
The oxygen dissociation curve for myoglobin
has a hyperbolic shape. This reflects the fact
that myoglobin reversibly binds a single molecule of oxygen.
The oxygen dissociation curve for hemo globin is sigmoidal in shape indicating that the subunits cooperate in binding oxygen. Cooperative binding of oxygen by the four subunits of hemoglobin means that the binding of an oxygen molecule at one heme group increases the oxygen affinity of the remaining heme groups in the same hemoglobin molecule. This effect is referred to as heme-heme interaction Although it is more difficultfor the first oxygen molecule to bind to hemoglobin, thesubsequent binding of oxygen occurs with high affinity.
Allosterism -A change in the activity and conformation of an enzyme resulting from the binding of a compound at a site on the enzyme other than the active binding site.
The ability of hemoglobin to reversibly bind oxygen is affected by the
pO2 (through heme-heme interactions), the pH of the environment, the partial pressure of carbon dioxide, pCO2, and the availability of 2,3-bisphosphoglycerate.
These are collectively called allosteric (“other site”) effectors, because their interaction at one site on the hemoglobin molecule affects the binding of
oxygen to heme groups at other locations on the molecule.
The sigmoidal oxygen dissociation
curve reflects specific structural changes that are initiated at one
heme group and transmitted to other heme groups in the
hemoglobin tetramer. The net effect is that the affinity of
hemoglobin for the last oxygen bound is approximately 300 times
greater than its affinity for the first oxygen bound.
The cooperative binding of
oxygen allows hemoglobin to deliver more oxygen to the
tissues in response to relatively small changes in the partial
pressure of oxygen. For example, in the lung, the concentration of oxygen is high and hemoglobin becomes virtually saturated (or
“loaded”) with oxygen. In contrast, in the peripheral tissues,
oxyhemoglobin releases (or “unloads”) much of its oxygen for
use in the oxidative metabolism of the tissues
The Bohr effect is a physiological phenomenon first described in 1904 by the Danish physiologist Christian Bohr (father of physicist Niels Bohr and so grandfather of physicist Aage Bohr), stating that hemoglobin's oxygen binding affinity is inversely related both to acidity and to the concentration of carbon dioxide.
A decrease in blood pH or an increase in blood CO2 concentration will result in hemoglobin proteins releasing their loads of oxygen and a decrease in carbon dioxide or increase in pH will result in hemoglobin picking up more oxygen.
The Bohr effect reflects the fact
that the deoxy form of hemoglobin has a greater affinity for
protons than does oxyhemoglobin.
3. Effect of 2,3-bisphosphoglycerate on oxygen affinity:
2,3-Bis -phospho glycerate (2,3-BPG) is an important regulator of the binding
of oxygen to hemoglobin. It is the most abundant organic phosphate in the RBC, where its concentration is approximately
that of hemoglobin. 2,3-BPG is synthesized from an intermediate
of the glycolytic pathway
the oxygen affinity of hemoglobin by binding to deoxy -
hemoglobin but not to oxyhemoglobin. This preferential binding
stabilizes the taut conformation of deoxyhemoglobin
which 2,3-BPG has been removed has a high affinity for oxygen.
However, as seen in the RBC, the presence of 2,3-BPG
significantly reduces the affinity of hemoglobin for oxygen, shifting
the oxygen dissociation curve to the right. This
reduced affinity enables hemoglobin to release oxygen efficiently
at the partial pressures found in the tissues.
The concentration of 2,3-BPG in the RBC increases in
response to chronic hypoxia, such as that observed in chronic
obstructive pulmonary disease (COPD) like emphysema, or at
high altitudes, where circulating hemoglobin may have difficulty
receiving sufficient oxygen.
Elevated 2,3-BPG levels lower the oxygen affinity of hemo -
globin, permitting greater unloading of oxygen in the capillaries of the tissues
4. Binding of CO2
Most of the CO2 produced in metabolism is
hydrated and transported as bicarbonate ion. However,
some CO2 is carried as carbamate bound to the N-terminal amino groups of hemoglobin (forming carbaminohemoglobin,)which can be represented schematically as follows:
The binding of CO2 stabilizes the T (taut) or deoxy form of
hemoglobin, resulting in a decrease in its affinity for oxygen and a right shift in the oxygen dissociation. In the lungs, CO2 dissociates from the hemoglobin, and is released in the breath.
5. Binding of CO:
Carbon monoxide (CO) binds tightly (but
reversibly) to the hemoglobin iron, forming carbon monoxy hemoglobin (or carboxyhemoglobin). When CO binds to one or more of the four heme sites, hemoglobin shifts to the relaxed conformation,causing the remaining heme sites to bind oxygen with high affinity. This shifts the oxygen dissociation curve to the left, and
changes the normal sigmoidal shape toward a hyperbola. As a result, the affected hemoglobin is unable to release oxygen to the tissues
The affinity of hemoglobin for CO is 220 times greater than for oxygen. Consequently, even minute concentrations of CO in the environment can produce toxic concentrations of carbon monoxyhemoglobin in the blood.
increased levels of CO are found in the blood of tobacco
In addition to O2, CO2, and CO, nitric oxide gas (NO) also is carried by hemoglobin.
NO is a potent vasodilator .
It can be taken up (salvaged) or released from RBCs, thus modulating NO availability and influencing vessel diameter.
Sturcture of Heme
Heme is a complex of protoporphyrin IX and ferrous iron (Fe 2+)
The iron is held in the center of heme molecule by bonds to the 4 nitrogens of the porphyrin ring.
The heme (Fe 2+) can form 2 additional bonds
In Myoglobin and Hemoglobin one of this positions is coordinated to the side chain of a histidine residue of the globin molecule, whereas the other position is aviable to bind oxygen
Stricture and Function of myoglobin
Myoglobin is a hemoprotein present in heart and skeletal muscle.It functions both as a reservoir for oxygen and as an oxygen carrier that increases the rate of transport f oxygen within muscle cell.It consists of a single polypeptide chain that is structurally similar to individual polypeptide chains of the hemoglobin