The biosynthesis of human hemoglobin A1c. Slow glycosylation of hemoglobin in vivo.

A B S T R A C T Hemoglobin A1e, the most abundant mi- nor hemoglobin component in human erythrocytes, is formed by the condensation of glucose with the N-termi- nal amino groups of the fl-chains of Hb A. The biosyn- thesis of this glycosylated hemoglobin was studied in vitro by incubating suspensions of reticulocytes and bone marrow cells with 'Hleucine or Fe-bound transferrin. In all experiments, the specific activity of Hb A1. was significantly lower than that of Hb A, suggesting that the formation of Hb A,. is a posttranslational modifica- tion. The formation of Hb Ai. in vivo was determined in two individuals who were given an infusion of 'Felabeled transferrin. As expected, the specific activity of Hb A rose promptly to a maximum during the 1st week and remained nearly constant thereafter. In contrast, the specific activity of Hb A1. and also of Hbs Ai. and Alb rose slowly, reaching that of Hb A by about day 60. These results indicate that Hb Ai. is slowly formed dur- ing the 120-day life-span of the erythrocyte, probably by a nonenzymatic process. Patients with shortened erythrocyte life-span due to hemolysis had markedly de- creased levels of Hb Ale. INTRODUCTION The diverse biological functions of many proteins de- pend upon posttranslational modifications (1). Because the biosynthesis and structure of human hemoglobin are so well understood, this protein is ideally suited for the study of such structural alteration. Fortunately, human hemoglobin is less heterogeneous than that of other mammals. About 90% of hemoglobin of adults and children above the age of 6 mo is Hb A (a2#s). Hb A2 (a285) and