title: On the dynamics of the adenylate energy system: homeorhesis vs homeostasis.
abstract: Biochemical energy is the fundamental element that maintains both the adequate turnover of the biomolecular structures and the functional metabolic viability of unicellular organisms. The levels of ATP, ADP and AMP reflect roughly the energetic status of the cell, and a precise ratio relating them was proposed by Atkinson as the adenylate energy charge (AEC). Under growth-phase conditions, cells maintain the AEC within narrow physiological values, despite extremely large fluctuations in the adenine nucleotides concentration. Intensive experimental studies have shown that these AEC values are preserved in a wide variety of organisms, both eukaryotes and prokaryotes. Here, to understand some of the functional elements involved in the cellular energy status, we present a computational model conformed by some key essential parts of the adenylate energy system. Specifically, we have considered (I) the main synthesis process of ATP from ADP, (II) the main catalyzed phosphotransfer reaction for interconversion of ATP, ADP and AMP, (III) the enzymatic hydrolysis of ATP yielding ADP, and (IV) the enzymatic hydrolysis of ATP providing AMP. This leads to a dynamic metabolic model (with the form of a delayed differential system) in which the enzymatic rate equations and all the physiological kinetic parameters have been explicitly considered and experimentally tested in vitro. Our central hypothesis is that cells are characterized by changing energy dynamics (homeorhesis). The results show that the AEC presents stable transitions between steady states and periodic oscillations and, in agreement with experimental data these oscillations range within the narrow AEC window. Furthermore, the model shows sustained oscillations in the Gibbs free energy and in the total nucleotide pool. The present study provides a step forward towards the understanding of the fundamental principles and quantitative laws governing the adenylate energy system, which is a fundamental element for unveiling the dynamics of cellular life.
authors.affiliation: Institute of Parasitology and Biomedicine "López-Neyra", CSIC, Granada, Spain; Department of Mathematics, University of the Basque Country UPV/EHU, Leioa, Spain; Unit of Biophysics (CSIC, UPV/EHU), and Department of Biochemistry and Molecular Biology University of the Basque Country, Bilbao, Spain; Biocruces Health Research Institute, Hospital Universitario de Cruces, Barakaldo, Spain.
authors.forename: Ildefonso M
authors.initials: IM
authors.lastname: De la Fuente
authors.affiliation: Biocruces Health Research Institute, Hospital Universitario de Cruces, Barakaldo, Spain; Ikerbasque: The Basque Foundation for Science, Bilbao, Basque Country, Spain.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Cortés
authors.affiliation: Department of Physical Chemistry, School of Industrial Engineering, University of Castilla-La Mancha, Albacete, Spain.
authors.forename: Edelmira
authors.initials: E
authors.lastname: Valero
authors.affiliation: INRIA Paris-Rocquencourt Centre, Paris, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Desroches
authors.affiliation: School of Computing and Mathematics, University of Plymouth, Plymouth, United Kingdom.
authors.forename: Serafim
authors.initials: S
authors.lastname: Rodrigues
authors.affiliation: Department of Physiology, University of the Basque Country UPV/EHU, Bilbao, Spain; Biocruces Health Research Institute, Hospital Universitario de Cruces, Barakaldo, Spain.
authors.forename: Iker
authors.initials: I
authors.lastname: Malaina
authors.affiliation: Department of Mathematics, University of the Basque Country UPV/EHU, Leioa, Spain; Biocruces Health Research Institute, Hospital Universitario de Cruces, Barakaldo, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Martínez
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D003198:Computer Simulation; D004734:Energy Metabolism; D006706:Homeostasis; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D010507:Periodicity
chemical_list: D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate