Hemoglobin Milledgeville (alpha 44 (CD2) Pro leads to Leu): a new variant with increased oxygen affinity.
Hemoglobin Milledgeville, a new hemoglobin structural variant, was identified in three members of a black American family. The oxygen affinity of blood and hemoglobin samples from the affected individuals was markedly increased (p50 O2 of whole blood 11-15 mmHg at 37 degrees C, pH 7.4), and the abnormality was associated with mild erythrocytosis. The variant hemoglobin did not separate from Hb A by electrophoresis or by chromatography or isoelectric focusing, and efforts to isolate an abnormal globin chain were also unsuccessful. The Hb A2 fraction as well as Hb A from erythrocytes of affected individuals exhibited increased oxygen affinity, indicating that the altered oxygen equilibrium was the result of a hemoglobin alpha chain abnormality. Fractionation of trypsin and chymotrypsin digests of isolated alpha chains demonstrated a single abnormal peptide representing a Pro leads to Leu substitution at alpha 44 (CD2). Properties of Hb Milledgeville include low cooperativity (n = 1.1-1.4), a normal alkaline Bohr effect (delta logp50/delta pH = -0.62), and normal interaction with 2,3-diphosphoglycerate. The alpha CD2 proline residue normally participates in the formation of the alpha 1 beta 2 subunit interface in the deoxy quaternary conformation, but not in oxyhemoglobin; the leucine substitution may produce destabilization of the deoxy conformation with a resulting shift in equilibrium toward the oxy conformation.
D000595:Amino Acid Sequence; D002648:Child; D004163:Diphosphoglyceric Acids / Q000097:blood; D005260:Female; D006455:Hemoglobins, Abnormal / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D010100:Oxygen / Q000097:blood*; D010375:Pedigree; D011487:Protein Conformation
D004163:Diphosphoglyceric Acids; D006455:Hemoglobins, Abnormal; D010100:Oxygen