Hemoglobino-pathies

Comparison  of primary sequences  of hemoglobin  chains from over 60 different  species  reveals  that  only  9  residues  in polypeptide  chain  are

                     Figure. The switch in human globin chain synthesis at the time of birth.
 
invariant (that is the same) between all the species. These 9 residues include proximal  and  distal  histidines  that  are  essential  for  the  correct  functioning of the protein. Many of the other residues can be replaced from one species to the other by residues with the similar properties  (for example  the hydrophobic  valine  is replaced  with hydrophobic  isoleucine,  or polar serine  is replaced  with polar asparagine),  so-called  conservative  substitutions.  On the contrary only a few residues  have  changed  between the species  to a completely  different  residue (such as  a  hydrophobic   leucine  to  positively   charged   lysine  or negatively charged glutamate  to positively  charged arginine),  called as nonconservative substitutions,  as this type of change could have a major effect on structure and function of protein.

Several hundred abnormal hemoglobins have been characterized, which gives rise to the so-called hemoglobinopathies. Probably the best characterized hemoglobin-pathy is sickle-cell anemia (sickle-cell hemoglobin;  HbS).  This disease can be characterized by the patient’s erythrocytes which has characteristic sickle or is having cres cent shape. The basis for this disease is change of a glutamic acid residue for valine at position 6 of β-chain, resulting in substitution of a polar residue by the hydrophobic   one.  The  nonconservative   substitution   of the valine  for glutamate  provides  HbS a sticky  hydrophobic  patch  on outside  of each  of its  β-chains.  In corner between helices E and F of β-chain of deoxy-HbS  is hydrophobic  site which is complementary  to sticky patch.

Thus the complementary site on one deoxy-HbS molecule is bind to the sticky patch on the other deoxy-HbS molecule, resulting in formation of long ?bers of hemoglobin molecules which distort the erythrocyte. Electron microscopy has  revealed  that  ?bers  have  diameter  of  21.5  nm  and consist of 14-stranded  helix. Multiple polar interactions, in addition to critical interaction between sticky patches, stabilize the ?ber.  In oxy-HbS complementary site is masked, so the formation of long ?bers occurs when there is high concentration of deoxygenated form of HbS.

Sickle-cell anemia is genetically transmitted, hemolytic disease. The sickled cells are much fragile than normal erythrocytes, lysing much easily and having a shorter half-life, which leads to severe anemia.  As sickle-cell anemia is transmitted genetically, homozygotes have two copies of abnormal gene while heterozygotes have  one  abnormal  and  normal  copy.  Homozygotes

    Figure:Molecular basis for the aggregation of deoxyhemoglobin molecules in sickle-cell anemia.

have a reduced life-span often as a result of renal failure, infection,  cardiac failure or thrombosis,  because of the  sickled  cells  becoming  trapped  in small  blood  vessels leading  to  tissue  damage.  On the contrary, heterozygotes are not symptomatic usually as only approximately 1 percent of their erythrocytes are sickled, compared with approximately  50 percent in a homozygote.  The frequency  of the sickle gene is high  in  certain  parts  of  Africa  and  correlates   with  incidence   of malaria. The reason for this is that the heterozygotes are protected against most lethal form of malaria, while normal homozygotes are vulnerable to the disease. Inheritance of abnormal hemoglobin gene can now be monitored by recombinant DNA methods.