title: Dynamic simulation and metabolome analysis of long-term erythrocyte storage in adenine-guanosine solution.
abstract: Although intraerythrocytic ATP and 2,3-bisphophoglycerate (2,3-BPG) are known as direct indicators of the viability of preserved red blood cells and the efficiency of post-transfusion oxygen delivery, no current blood storage method in practical use has succeeded in maintaining both these metabolites at high levels for long periods. In this study, we constructed a mathematical kinetic model of comprehensive metabolism in red blood cells stored in a recently developed blood storage solution containing adenine and guanosine, which can maintain both ATP and 2,3-BPG. The predicted dynamics of metabolic intermediates in glycolysis, the pentose phosphate pathway, and purine salvage pathway were consistent with time-series metabolome data measured with capillary electrophoresis time-of-flight mass spectrometry over 5 weeks of storage. From the analysis of the simulation model, the metabolic roles and fates of the 2 major additives were illustrated: (1) adenine could enlarge the adenylate pool, which maintains constant ATP levels throughout the storage period and leads to production of metabolic waste, including hypoxanthine; (2) adenine also induces the consumption of ribose phosphates, which results in 2,3-BPG reduction, while (3) guanosine is converted to ribose phosphates, which can boost the activity of upper glycolysis and result in the efficient production of ATP and 2,3-BPG. This is the first attempt to clarify the underlying metabolic mechanism for maintaining levels of both ATP and 2,3-BPG in stored red blood cells with in silico analysis, as well as to analyze the trade-off and the interlock phenomena between the benefits and possible side effects of the storage-solution additives.
authors.affiliation: Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan ; Systems Biology Program, Graduate School of Media and Governance, Keio University, Fujisawa, Kanagawa, Japan.
authors.forename: Taiko
authors.initials: T
authors.lastname: Nishino
authors.forename: Ayako
authors.initials: A
authors.lastname: Yachie-Kinoshita
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Hirayama
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Soga
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.forename: Masaru
authors.initials: M
authors.lastname: Tomita
mesh_terms: D019794:2,3-Diphosphoglycerate / Q000378:metabolism; D000225:Adenine / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D001793:Blood Preservation / Q000379:methods*; D003198:Computer Simulation; D004912:Erythrocytes / Q000378:metabolism*; D006019:Glycolysis; D006151:Guanosine / Q000378:metabolism*; D006801:Humans; D055442:Metabolome; D008954:Models, Biological; D010427:Pentose Phosphate Pathway
chemical_list: D006151:Guanosine; D019794:2,3-Diphosphoglycerate; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D000225:Adenine