Sickle hemoglobin polymerization

Ferrone FA, Hofrichter J, Eaton WA. Kinetics of sickle hemoglobin polymerization II. A double nucleation mechanism. J Mol Biol 1985 183 611-633. 

Josephs R Research on sickle cell hemoglobin, virtual tour of sickle hemoglobin polymerization. Laboratory for Electron Microscopy at the University of Chicago, 1999. Available at http // gingi. uchicago. eduZsc2-tourl.htm, 2004. 

Ferrone, F. A. Hofrichter, J. Eaton, W. A. 1985a. Kinetics of Sickle Hemoglobin Polymerization I. Studies Using Temperature-Jump and Laser Photolysis Techniques, J. Mol. Biol. 183, 591-610. 

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... 

Figure 2-6. Electron micrograph of individual fibers of sickle hemoglobin. Individual strands of polymerized hemoglobin in red cell are shown. The inset shows an electron micrograph of an individual fiber with a periodicity of 22 A. The model reveals the seven double strands making up each hemoglobin S fiber with one pair detailing the helical arrangement of the fibers.Adapted with permission from Josephs (1999).

Eaton, W. A., and Hofrichter, J. 1990. Sickle cell hemoglobin polymerization. Adv. Prot. Chem. 40 63 279. 

Szabo, A. 1988. Fluctuations in the Polymerization of Sickle Hemoglobin. A Simple Analytic Model, J. Mol. Biol. 199, 539-542. 

Figure 3.14 Sickle-cell hemoglobin molecules polymerize due to the hydrophobic patch introduced by the mutation Glu 6 to Val in the P chain. The diagram (a) illustrates how this hydrophobic patch (green interacts with a hydrophobic pocket (red) in a second hemoglobin molecule, whose hydrophobic patch interacts with the pocket in a third molecule, and so on. Electron micrographs of sickle-cell hemoglobin fibers are shown in cross-section in (b) and along the fibers in (c). [(b) and (c) from J.T. Finch et al., Proc. Natl. Acad. Set. USA 70 718-722, 1973.)...

In sickle cell hemoglobin (HbS), Val replaces the P6 Glu of HbA, creating a sticky patch that has a complement on deoxyHb (but not on oxyHb). De-oxyHbS polymerizes at low O2 concentrations, forming fibers that distort erythrocytes into sickle shapes. 

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 ... 

Why does deoxygenated hemoglobin S polymerize Besides polymerization, what are the causes of the clinical manifestations of sickle cell disease ... 

Gonzalez, P. Hackney, A.C. Jones, S. Strayhorn, D. Hoffman, E.B. Hughes, G. Jacobs, E.E. Orringer, E.P. A phase I/II clinical study of polymerized bovine hemoglobin in adult patients with sickle cell disease not in crisis at the time of study. J. Invest. Med. 1997, 45 (5), 258-264. 

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