Hemoglobin, deoxygenation

Stohler R, Dursteler KM, Stormer R, Seifritz E, Hug I, Sattler-Mayr J, Muller-Spahn F, Ladewig D, Hock C. Rapid cortical hemoglobin deoxygenation after heroin and methadone injection in humans a preliminary report. Drug Alcohol Depend 1999 57(l) 23-8. 

The allosteric effect is seen in hemoglobin which can exist in two quaternary stmctural states oxygenated (R) or deoxygenated (T). The binding of one O2 or some other effector to one of the subunits stabilizes the R form as compared to the T form. Binding of a second and third O2 stabilizes it even further. 

Deoxygenated blood Blood containing hemoglobin with oxygen levels be-... 

Figure 38-4. Examples of three types of missense mutations resulting in abnormal hemoglobin chains. The amino acid alterations and possible alterations in the respective codons are indicated. The hemoglobin Hikari p-chain mutation has apparently normal physiologic properties but is electrophoretically altered. Hemoglobin S has a p-chain mutation and partial function hemoglobin S binds oxygen but precipitates when deoxygenated. Hemoglobin M Boston, an a-chain mutation, permits the oxidation of the heme ferrous iron to the ferric state and so will not bind oxygen at all.

The primary event in the molecular pathogenesis of SCD involves polymerization of deoxygenated HbS. Since RBCs are packaged with such a high concentration of hemoglobin (32-34 g/dL, 320 to 340 g/L or 19.9-21 mmol/L), it is important... 

Polymerization allows deoxygenated hemoglobin to exist as a semisolid gel that protrudes into the cell membrane, distorting RBCs into sickle shapes. Sickle-shaped RBCs increase blood viscosity and encourage sludging in the capillaries and small vessels. Such obstructive events lead to local tissue hypoxia and accentuate the pathologic process. 

Deoxygenated sickle cell hemoglobin (deoxyHbS), the j8-Glu-6-Val point mutant form of adult hemoglobin, appears to obey the following empirical rate law for nucleation of polymerization ... 

T. Kutsuzawa, S. Shioya, D. Kurita and M. Haida, Deoxygenated hemoglobin/myoglobin kinetics of forearm muscle from rest to exercise in patients with chronic obstructive pulmonary disease. Tohoku ]. Exp. Med., 2009, 217,9-15. 

In the majority of patients with sickle cell disease, anemia is not the major problem the anemia is generally well compensated even though such individuals have a chronically low hematocrit (20-30%), a low serum hemoglobin level (7-10 g/dL), and an elevated reticulocyte count. Instead, the primary problem is that deoxygenated HbS chains form polymeric structures that dramatically change erythrocyte shape, reduce deformability, and elicit membrane permeability changes that further promote hemoglobin polymerization. Abnormal erythrocytes... 

Sickle-cell anemia, as we have noted, occurs in individuals homozygous for the sickle-cell allele of the gene encoding the )3 subunit of hemoglobin. Individuals who receive the sickle-cell allele from only one parent and are thus heterozygous experience a milder condition called sickle-cell trait only about 1% of their erythrocytes become sickled on deoxygenation. These individuals may live completely normal lives if they avoid vigorous exercise or other stresses on the circulatory system. 

Schematic diagram showing structural changes resulting from oxygenation and deoxygenation of hemoglobin.

When HbS is deoxygenated it tends to "crystallize" in red blood cells, which contain 33% by weight hemoglobin. The crystallization (actually gel formation) distorts the cells into a sickle shape and these distorted corpuscles are easily destroyed, leading to anemia. The introduction of the hydrophobic valine residue in Hb S at position 6 near the end of the molecule helps form a new bonding domain by which the hemoglobin tetramers associate to form long semicrystalline microfilamentous arrays. 3 6 s... 

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