Types of hemoglobin pdf

Hb is a protein found in the Red blood cells RBC. Hemoglobin is a protein found in Red blood cells RBC. It supplies oxygen from the lungs to the different parts of the body like the brain, hands, feet, etc. After providing oxygen, it brought back carbon dioxide CO2 to the lungs. The normal range of hemoglobin in males and females is as. Note : The different level of Hemoglobin in males and females is due to a different level of hormones.

When there is an initial decrease in hemoglobin , it does not affect how you feel. But when it becomes more severe, it will cause symptoms like tiredness. A low hemoglobin range indicates that you are anemic. There are three types of hemoglobin. WordPress Shortcode. Share Email. Top clipped slide. Download Now Download Download to read offline.

Hemoglobin Download Now Download Download to read offline. Aya Zakraya Follow. Hemoglobin -structure and functions. Haemoglobin chemistry. Structure and function of hemoglobin. Structure And Function Of Haemoglobin. Structure and function of haemoglobin. Related Books Free with a 30 day trial from Scribd. Related Audiobooks Free with a 30 day trial from Scribd. Outstanding Leadership Stan Toler.

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Hemoglobin 1. Elshishtawy 2. The globin tertiary structure comprises a helical structures joined by non-helical segments. Four such globins are arranged together, giving rise to the spherical quaternary structure of hemoglobin Hemoglobins are classified into different types, depending on the combination of the two sets of globin units. Oxygen equilibrium curve of Hb. The normal P 50 value is indicated by dashed lines.

The left-shift and right-shift in the curves are colored red and blue respectively. Fermi ; Safo and Bruno ; Safo et al. Crystal structure of hemoglobin. Note the larger central water cavity in the T structure. Each subunit has a binding pocket for heme formed by the E and F helices. The heme consists of a ferrous ion held in the center of a porphyrin and coordinated by the four nitrogen atoms of the porphyrin ring.

The Fe is also covalently anchored to Hb at the heme proximal pocket by an imidazole of a histidine residue located on the F helix known as the proximal histidine or His F8. This setup allows the Fe to bind O 2 or other gasses at the distal pocket of the heme by a covalent bond to fulfill the octahedral coordination of six ligands.

The imidazole of a histidine residue at the distal pocket His E7 stabilizes the bound O 2 through hydrogen-bond interaction. Some of these compounds bind with significantly higher affinity than oxygen, making these compounds highly toxic to humans.

For example, Hb binding affinity for CO is as much as times greater than O 2 , and a concentration of 0. Various allosteric models have been proposed to explain cooperative oxygen binding to hemoglobin. The MWC model assumes that, upon ligand binding, the T state switches to the R state without intermediate states Monod et al. The two-state model was based on a plethora of liganded and unliganded Hb crystal structures from different species, such as horse, human, and bovine Muirhead and Perutz ; Perutz et al.

Liganded Hb structures are mostly co-crystallized with CO as the heme ligand since CO-liganded Hb is chemically stable, rendering it easier to manipulate and crystallize compared to the O 2 -liganded Hb.

Nevertheless, the structures of O 2 - or CO-liganded Hb are very similar. Based on these crystal structures, Perutz partly attributed the low oxygen affinity in the T state to tension in the Fe—His F8 bond, which restrains the Fe from moving into the porphyrin plane on ligand binding Perutz a , b ; Perutz et al. This proposition was further supported by Paoli et al. Barrick et al. However, the group also suggested that additional communication pathways exist other than the Fe—His F8 bond that is responsible for the residual cooperativity observed Barrick et al.

Several variations of Hb allosteric models were consequently put forward. There are several excellent reviews of this topic, and the reader is referred to two such publications Yonetani and Kanaori ; Gell NMR and wide-angle X-ray scattering WAXS , studies showed that the time-averaged solution structure of liganded Hb is unlikely to be identical to crystallized structures Lukin et al.

Using laser photolysis and in the presence of the potent allosteric effector of Hb, inositol hexaphosphate IHP , Sawicki and Gibson observed quaternary conformational changes in CO-liganded human Hb Sawicki and Gibson , Perrella and Cera also showed, using rapid quenching of the reaction between human Hb and CO, that different ligation intermediates exist with distinct conformations and oxygen affinities.

Mozzarelli and collegues reported two distinct human Hb populations that had different oxygen-binding affinities and times lower than the high-O 2 affinity R state and were non-cooperative Mozzarelli et al.

The former species was proposed to have T state like conformation, while the latter showed relaxed features that placed it closer to the R state. A horse deoxygenated Hb trapped in the high-affinity relaxed state was reported to be a ligation intermediate of the R state Wilson et al. Cross-linked human Hb, with trimesic acid exhibiting low oxygen affinity, was reported by Schumacher et al. Safo et al. In the presence of heterotropic effectors, Yonetani and Tsuneshinge observed that liganded Hb exhibits T state constraint within an R-like quaternary structure.

Several of the proposed allosteric models maintain the original MWC tenet that cooperative oxygen binding cannot occur in the absence of quaternary transition, consistent with the fact that a fully liganded T state hemoglobin heterotetramer, obtained from crystallizing ligated hemoglobin in solution, has never been reported.

It was later used by several investigators to analyze the quaternary differences between several Hb states that were, in some instances, as significant or even larger than those between the T structure and the classical R structure Silva et al.

A smaller rotation of His E7 is also observed in the R3 structure Fig. Overall, two trajectories have been proposed for the transition between the T and the relaxed states Safo and Abraham ; Jenkins et al. The R3 structure shows a partially opened ligand channel. Schematic representation of the proposed allosteric pathway between the different Hb states.

The discovery of the R2 structure in the early s Smith et al. Later studies and comprehensive analysis of the R and R2 structures, however, suggested that the R2 is not an intermediate, but rather an end-state relaxed structure Doyle et al. The argument for assigning the R2 structure as the physiologically relevant relaxed state, and R structure as an artifact was partly due to the former being crystallized with low-salt that mimics the in vivo environment, while the latter was crystallized with non-physiological high-salt condition.

However, Safo and co-workers later crystallized the R2 structure using high-salt condition Safo et al. Of interest is that the R2 crystals only form in high-salt when co-crystallized with antisickling aromatic aldehydes Safo et al.

Consistently, an NMR study by Lukin et al. The existence of a multi-relaxed Hb states is appreciated even more when one considers crystal structures of liganded Hb in the presence of allosteric effectors.

As noted above, in high-salt liganded Hb without aromatic aldehyde crystallizes in R or RR2 or RR3 form depending on the pH, but in the presence of aromatic aldehyde appears to shift the equilibrium to the R2 form that crystallizes out. The binding pockets of the R, R3, and RR3 structures are sterically crowded, explaining the preferential binding of aromatic aldehyde to the R2 Hb Safo et al. Gong et al. Not clear is how the different liganded relaxed states fit in the overall scheme of Hb oxygen transport function.

Based on the fact that the His E7 ligand channel in the R, RR2, and R2 structures are closed, while R3 and RR3 are partially or fully opened, respectively, prompted Safo and colleagues to suggest that the R, R2, and RR2 conformations are involved in heme ligand transport, while the R3 and RR3 may be involved in ligand release Safo and Abraham ; Jenkins et al. Perutz has previously predicted such a rotation of His E7 for access of ligand Perutz Birukou et al.

The dynamics of the His E7 rotation is likely pH-dependent as relatively low pH appears to stabilize the open ligand channel conformation as observed in the RR3 structure, while high pH may favor closure of the channel Safo and Abraham ; Jenkins et al.

Consistently, the rate constant for ligand binding to myoglobin increases with a decrease in pH Traylor et al. Not obvious is whether His E7 rotation out of the distal pocket in the T state is also pH-dependent since the pH in the lungs is not expected to be as low as in the tissues.

Over naturally occurring hemoglobin variants have been identified, and although most are yet to be associated with any disease state, significant numbers are implicated in pathologies ranging from mild to severe, such as polycythemia or anemia, methemoglobinemia, cyanosis, tissue hypoxia and respiratory distress Reissmann et al. The mutation is located at the surface of the protein.

Although the mutation does not directly affect the protein oxygen-binding property, a presumed elevation of 2,3-BPG in sickle red blood cells has been proposed to worsen the disease progression Torrance et al. Unfortunately, in SCD, the repetitive deoxygenation-reoxygenation cycles with cell sickling lead to RBC membrane damage and hemolysis, reducing the life span to 10—20 days from 90 to days for normal RBCs , which manifests in chronic anemia Zago and Bottura ; Connor et al.

This counterproductive response, increases deoxygenated HbS concentration, worsening the HbS polymerization and thus the concomitant RBC sickling process.

In vitro manipulation to reduce 2,3-BPG content has been suggested as a means to reduce the hypoxia-induced sickling Poillon et al. It is, therefore, no surprise that several mutations affecting this interface have been reported to affect the oxygen affinity of Hb Reissmann et al.

It is one of the few mutations where both the T and R structures of the mutant have been elucidated Safo et al. These unique T state features in the R structure explain Hb Bassett low affinity for oxygen Safo et al.

Structurally, this mutation results in the inhibition of the cleavage of the initiator methionine, which becomes acetylated. However, the reduced oxygen affinity was not severe enough to produce any hematological abnormalities in the male carrier Vasseur et al. The introduction of a glutamic acid residue in Hb Doha also prevented the removal of the initiator methionine extending the N-terminus by one residue Kamel et al.

Unfortunately, we are not aware of any structural data for Hb Doha. These individuals are clinically characterized by erythrocytosis Hardison et al. Interestingly, this variant exhibits variable oxygen affinities, including both low and high affinity Sharma et al.

The chloride ion was suggested to affect the solution properties of this mutant, especially at varying chloride concentration that may explain the variations in oxygen binding properties Kavanaugh et al. Mutations in the heme pocket are also known to affect Hb oxygen binding properties Thom et al. Finally, mutations, deletions or insertions in the core nonpolar regions of Hb have been reported to produce unstable hemoglobins Carrell et al.

Its effect on Hb oxygen affinity was first reported by Benesch and Benesch As noted above 2,3-BPG has been proposed to be involved in the pathogenesis of sickle cell disease by its elevation in sickle RBC, which leads to further decrease in Hb affinity for oxygen to increase the concentration of the polymer forming deoxygenated HbS. S1P Fig.

Interaction between S1P and hemoglobin was first uncovered by the Xia group after a metabolomic screen identified the pathological role of elevated S1P in SCD Zhang et al. The ternary complex leads to a significant conformational change that not only increase the T state character of the T structure but also sterically impede diffusion of diatomic ligands O 2 into the heme pocket Sun et al.

These structural changes have been proposed to in part explain the observed decrease in Hb—O 2 affinity of HbS and the concomitant sickling of RBC Sun et al.

An interesting structural observation is that the last 3—4 carbon atoms of the bound S1P do not make any interaction with the Hb residue but hang out in the bulk solvent. These carbon atoms are hypothesized to mediate the hydrophobic interactions with cdB3, to also promote SCD pathogenesis Sun et al. These findings add significant new insight to erythrocyte pathology and physiology, which paves the way for novel therapeutic interventions in SCD.

Binding of S1P purple on the surface of deoxygenated Hb. For most mammalian hemoglobins, the heme affinity for ligands is dependent upon ambient pH Bohr effect , due to tertiary structural perturbations Shibayama and Saigo ; Yonetani et al. In , CO 2 was discovered by Christian Bohr to lower the oxygen affinity of Hb, allowing efficient delivery of oxygen to tissues Bohr et al.

These interactions stabilize the low-affinity T structure, consequently, facilitating O 2 release. At low pH especially in the tissues, these salt-bridge interactions are broken Figs. Chloride ions contribute to the Bohr effect by neutralizing these positive charges to stabilize Hb Perutz et al.

More chloride ions are found in the larger T structure central water cavity when compared to the smaller R structure central water cavity, leading to greater stabilization of the T state with concomitant lowering of Hb oxygen affinity. Several Hb surface located histidines have also been suggested to contribute to the Bohr effect Busch and Ho ; Sun et al.

Contribution to the Bohr effect by the various relaxed Hb structures may be different due to obvious tertiary and quaternary differences. A fundamental importance of Hb allostery is taking advantage of it to develop therapeutics for diseases. The discovery of 2,3-BPG prompted the search for synthetic Hb effectors for the treatment of ischemic-related diseases.

One of the earliest compounds to be studied was inositol hexaphosphate IHP Fig. IHP has limited absorption profile for a useful therapeutic application Stucker et al. Nonetheless, it has been beneficial in investigating the allosteric properties of Hb. Analogs of IHP, such as myoinositol trispyrophosphate that are capable of crossing the membrane of erythrocytes, have been shown to enhance the exercise capacity in mice with severe heart failure Biolo et al.

Propionates are a class of synthetic effectors that also induce low-O 2 affinity by binding to Hb and stabilizing the T state. These compounds, unlike IHP or 2,3-BPG effect their allosteric activity in part by binding to the middle of the central water cavity of deoxygenated Hb. RSR aka Efaproxiral , the most well-known propionate was originally synthesized to mimic allosteric effects first seen with BZF, but with less protein binding in serum Randad et al.

The mode of atomic interactions of the propionates with deoxygenated Hb are very similar. X-ray crystal structures indicated that a pair of RSR form noncovalent interactions with three subunits of the deoxygenated Hb tetramer within the central water cavity in a symmetry-related fashion Fig.

Its specific interactions to the protein are illustrated in Fig.