title: CD73 and AMPD3 deficiency enhance metabolic performance via erythrocyte ATP that decreases hemoglobin oxygen affinity.
abstract: Erythrocytes are the key target in 5'-AMP induced hypometabolism. To understand how regulation of endogenous erythrocyte AMP levels modulates systemic metabolism, we generated mice deficient in both CD73 and AMPD3, the key catabolic enzymes for extracellular and intra-erythrocyte AMP, respectively. Under physiological conditions, these mice displayed enhanced capacity for physical activity accompanied by significantly higher food and oxygen consumption, compared to wild type mice. Erythrocytes from Ampd3(-/-) mice exhibited higher half-saturation pressure of oxygen (p50) and about 3-fold higher levels of ATP and ADP, while they maintained normal 2,3-bisphosphoglycerate (2,3-BPG), methemoglobin levels and intracellular pH. The affinity of mammalian hemoglobin for oxygen is thought to be regulated primarily by 2,3-BPG levels and pH (the Bohr effect). However, our results show that increased endogenous levels of ATP and ADP, but not AMP, directly increase the p50 value of hemoglobin. Additionally, the rise in erythrocyte p50 directly correlates with an enhanced capability of systemic metabolism.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, Texas, USA 77030.
authors.forename: William G
authors.initials: WG
authors.lastname: O'Brien
authors.affiliation: Division of Hematology, Department of Internal Medicine, University of Texas Health Science Center, Houston, Texas, USA 77030.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Berka
authors.affiliation: Division of Hematology, Department of Internal Medicine, University of Texas Health Science Center, Houston, Texas, USA 77030.
authors.forename: Ah-Lim
authors.initials: AL
authors.lastname: Tsai
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, Texas, USA 77030.
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, Texas, USA 77030.
authors.forename: Cheng Chi
authors.initials: CC
authors.lastname: Lee
mesh_terms: D019794:2,3-Diphosphoglycerate / Q000378:metabolism; D015720:5'-Nucleotidase / Q000172:deficiency*; D000659:AMP Deaminase / Q000172:deficiency*; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001669:Biochemical Phenomena / Q000502:physiology; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D006454:Hemoglobins / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D008297:Male; D051379:Mice; D010100:Oxygen / Q000378:metabolism*
chemical_list: D006454:Hemoglobins; D019794:2,3-Diphosphoglycerate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D015720:5'-Nucleotidase; D000659:AMP Deaminase; C579174:AMPD3 protein, mouse; D010100:Oxygen