Mutations in the genes that encode the α or β subunits of hemoglobin potentially can affect its biologic function. However, of more than 1100 known genetic mutations affecting human hemoglobins, most are both rare and benign, presenting no clinical abnormalities. When a mutation does compromise biologic function, the condition is termed ahemoglobinopathy. It is estimated that more than 7% of the globe’s population are carriers for hemoglobin disorders. The URL http://globin.cse. psu.edu/ (Globin Gene Server) provides information about— and links for—normal and mutant hemoglobins. Selected examples are as follows.

 Methemoglobin & Hemoglobin M

In methemoglobinemia, the heme iron is ferric rather than ferrous, rendering methemoglobin unable to bind or trans port O₂ . Normally, the Fe³⁺ of methemoglobin is returned to Fe²⁺ state through the action of the enzyme methemoglobin reductase. Methemoglobin levels can rise to pathophysiologically significant levels from a number of causes: oxidation of Fe²⁺ to Fe³⁺ as a side effect of agents such as sulfonamides, reductions in the activity of methemoglobin reductase, or inheritance of the gene for a mutationally altered form of hemoglobin called HbM.

In hemoglobin M, histidine F8 (His F8) has been replaced by tyrosine. The iron of HbM forms a tight ionic complex with the phenolate anion of tyrosine that stabilizes the Fe³⁺ form. In α-chain hemoglobin M variants, the R-T equilibrium favors the T state. Oxygen affinity is reduced, and the Bohr effect is absent. β-Chain hemoglobin M variants exhibit R-T switching, and the Bohr effect is therefore present.

Mutations that favor the R state (eg, hemoglobin Chesapeake) increase O₂ affinity. These hemoglobins therefore fail to deliver adequate O₂ to peripheral tissues. The resulting tissue hypoxia leads to polycythemia, an increased concentration of erythrocytes.

Hemoglobin S

 In HbS, the nonpolar amino acid valine has replaced the polar surface residue Glu6 of the β subunit, generating a hydrophobic “sticky patch” on the surface of the β subunit of both oxyHbS and deoxyHbS. Both HbA and HbS contain a complementary sticky patch on their surfaces that is exposed only in the deoxygenated T state. Thus, at low Po₂ , deoxyHbS can polymerize to form long, twisted helical fibers. Binding of deoxyHbA terminates fiber polymerization, since HbA lacks the second sticky patch necessary to bind another Hb molecule (Figure 1). These insoluble fibers distort the erythrocyte into a characteristic sickle shape, rendering it vulnerable to lysis in the interstices of the splenic sinusoids. They also cause multiple secondary clinical effects. A low Po₂ , such as that at high altitudes, exacerbates the tendency to polymerize. The terms sickle cell trait and sickle cell disease refer to persons in whom the gene for either one or both β subunits are mutated, respectively. Emerging treatments for sickle cell disease include inducing HbF expression to inhibit the polymerization of HbS, stem cell transplantation, and, in the future, gene therapy.

Fig1. Polymerization of deoxyhemoglobin S. The dissociation of oxygen from hemoglobin S (HbS) unmasks a sticky patch (red triangle) on the surface of its β subunits (green) that can adhere to a complementary site on the β subunits of other molecules of deoxyHbS. Polymerization to a fibrous polymer is interrupted deoxyHbA, whose β subunits (lavender) lack the sticky patch required for binding additional HbS subunits.

مواضيع ذات صلة

Prosthetic Groups, Cofactors, & Coenzymes play Important Roles in Catalysis

البيوتين ( الفيتامين H) Biotin

حمض البانتوثينيك Pantothenic acid

النياسين Niacin

الريبوفلافين Riboflavin B2) B2)

الثيامين (B1)

مجموعة الفيتامينات B Complex Vitamins) B)

وظائف الفيتامين Vitamin C Functions C

وظائف الفيتامين Vitamin K Functions K

وظائف فيتامين Vitamin E Functions E

عوز الفيتامين Vitamin D Deficiency D

The Allosteric Properties of Hemoglobins Result From Their Quaternary structures