IX. GENETICS AND HUMAN HEMOGLOBIN CHEMISTRY 431 



tlie abnormal hemoglobins have been found to lie on the surface of the 

 tridimensional structure of the hemoglobin peptide chains. Few notable 

 exceptions to this rule are represented by the amino acid residues 

 involved in substitutions in the Hb-M's (Gerald and Efron, 1961). 



The characteristic abnormality of this group of Hb-A variants is an 

 unusual difficulty in reducing the ferric form of the iron atom in the heme 

 group to the ferrous form. The Hb-M genes are responsible for the 

 dominant hereditary form of methemoglobinemia; the recessive heredi- 

 tary form of this disease is due to the absence or alteration of the enzyme 

 diphosphopyridine nucleotide diaphorase (Scott and Griffith, 1959). 

 The presence of Hb-M is associated with chronic cyanosis, since this 

 hemoglobin is normally in the oxidized form as methemoglobin. Five 

 samples of Hb-M from unrelated individuals have been examined by 

 Gerald and Efron (1961). In three of these hemoglobins the amino acid 

 substitution has been detected and localized along the hemoglobin 

 chains. 



Tyrosine has been found to substitute for histidine in homologous 

 regions of the a chain in Hb-Muoston (Fig. 6), and of the /3 chain in 

 Hb-Msaskatoon (Fig. 7). Ou tho basis of the similarities with the tertiaiy 

 structure of the sperm whale myoglobin, Watson and Kendrew (1961) 

 have suggested that these regions of the human hemoglobin chains are 

 situated immediately opposite the sixth coordination position of the iron 

 atom in the heme. The heme is known to be located in the inner part of 

 each folded chain, between the folds of the chain; it is most likely 

 attached to a portion of the peptide chains opposite the one altered in 

 Hb-MBoston and Hb-M saskatoon- If, because of a gene mutation, an amino 

 acid with a reactive side chain is substituted for an amino acid with no 

 such side chain in the vicinity of the heme group, then the reactive side 

 chain may complex with the oxidized heme group to give a stable 

 complex. This is an internal complex in which the reactive group of the 

 amino acid acts as a ligand. The complex is quite stable and for this 

 reason the Hb-M remains in the ferric form as methemoglobin (Gerald 

 and Efron, 1961). 



That part of the hemoglobin chains where the amino acid substitu- 

 tions leading to Hb-M have been found is presumably in helical con- 

 figuration (Watson and Kendrew, 1961). The pitch of the helix is about 

 100° per residue, so that the side chains of two adjacent amino acids 

 point toward different directions at a 100° angle. Only residues four 

 positions apart have their side chains pointing toward the same side at 

 a 40° angle. 



Other amino acid substitutions have been observed in the same region 

 of the peptide chains where the Hb-Mnoston and Hb-Msaskatoon substitu- 



