title: Decreased erythrocyte phosphoribosylpyrophosphate synthetase activity and impaired formation in thalassemia minor: a mechanism for decreased adenine nucleotide content.
abstract: Adenosine triphosphate (ATP) and adenosine diphosphate levels are decreased in erythrocytes from individuals with beta-thalassemia minor. Because 5-phosphoribosyl-1-pyrophosphate (PRPP) is an essential precurosr of adenine nucleotides, we tested the hypothesis that impaired PRPP synthesis is a mechanism for the decreased adenine nucleotide content. Erythrocyte PRPP synthetase activity was significantly decreased, and the Michaelis-Menten constant (Km) for ribose-5-phosphate (R5P) was significantly increased in individuals with alpha-thalassemia minor and those with beta-thalassemia minor. Intact erythrocytes from individuals with alpha-thalassemia and those with beta-thalassemia minor also had an impaired rate of PRPP formation. Both the decrease in PRPP synthetase activity and the impaired PRPP formation were also found in erythrocytes with microcytosis resulting from iron deficiency, indicating that these phenomena may not be specific to thalassemia minor. In all individuals examined, the rate of PRPP formation correlated with ATP content, suggesting that either (1) PRPP synthetase activity is a determinant of ATP content or (2) ATP content is a determinant of PRPP synthetase activity. The depletion of ATP from normal erythrocytes did not affect PRPP synthetase activity, suggesting that ATP content is not a determinant of PRPP synthetase activity. However, a decrease in PRPP synthetase activity did cause an impairment in the rate of adenine nucleotide synthesis, suggesting that PRPP synthetase activity is a determinant of ATP content. Taken together, our results suggest that the decrease in PRPP synthetase activity and the resulting impairment in the rate of PRPP formation are mechanisms for the decreased adenine nucleotide content in thalassemic erythrocytes.
authors.affiliation: Department of Medicine, Harbor-UCLA Medical Center, University of California, Los Angeles School of Medicine.
authors.forename: C R
authors.initials: CR
authors.lastname: Zerez
authors.forename: N A
authors.initials: NA
authors.lastname: Lachant
authors.forename: K R
authors.initials: KR
authors.lastname: Tanaka
mesh_terms: D000227:Adenine Nucleotides / Q000097:blood*; D000244:Adenosine Diphosphate / Q000097:blood; D000255:Adenosine Triphosphate / Q000097:blood; D000740:Anemia / Q000097:blood; D004912:Erythrocytes / Q000201:enzymology*; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D066298:In Vitro Techniques; D000090463:Iron Deficiencies; D007700:Kinetics; D010770:Phosphotransferases / Q000097:blood*; D012016:Reference Values; D012156:Reticulocytes / Q000378:metabolism; D012268:Ribose-Phosphate Pyrophosphokinase / Q000097:blood* / Q000302:isolation & purification; D013789:Thalassemia / Q000097:blood* / Q000201:enzymology
chemical_list: D000227:Adenine Nucleotides; D006454:Hemoglobins; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D010770:Phosphotransferases; D012268:Ribose-Phosphate Pyrophosphokinase