Network-level allosteric effects are elucidated by detailing how ligand-binding events modulate utilization of catalytic potentials
| Autor: | Zachary B. Haiman, Bernhard O. Palsson, Miguel A. Alcantar, James T. Yurkovich |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Metabolic Processes Physiology Phosphofructokinase-1 Enzyme Metabolism Ligands Biochemistry chemistry.chemical_compound Hexokinase Medicine and Health Sciences Homeostasis Glycolysis Enzyme Chemistry lcsh:QH301-705.5 chemistry.chemical_classification Ecology biology Enzymes Computational Theory and Mathematics Modeling and Simulation Thermodynamics Network Analysis Phosphofructokinase Protein Binding Research Article Computer and Information Sciences Allosteric regulation Pyruvate Kinase Computational biology Biophysical Phenomena Catalysis Enzyme Regulation 03 medical and health sciences Cellular and Molecular Neuroscience Metabolic Networks Allosteric Regulation Genetics Humans Computer Simulation Enzyme kinetics Molecular Biology Ecology Evolution Behavior and Systematics Enzyme Kinetics Biology and Life Sciences Proteins Kinetics 030104 developmental biology Enzyme Metabolism lcsh:Biology (General) Allosteric enzyme chemistry biology.protein Enzymology Physiological Processes Pyruvate kinase |
| Zdroj: | PLoS Computational Biology PLoS Computational Biology, Vol 14, Iss 8, p e1006356 (2018) |
| ISSN: | 1553-7358 |
| Popis: | Allosteric regulation has traditionally been described by mathematically-complex allosteric rate laws in the form of ratios of polynomials derived from the application of simplifying kinetic assumptions. Alternatively, an approach that explicitly describes all known ligand-binding events requires no simplifying assumptions while allowing for the computation of enzymatic states. Here, we employ such a modeling approach to examine the “catalytic potential” of an enzyme—an enzyme’s capacity to catalyze a biochemical reaction. The catalytic potential is the fundamental result of multiple ligand-binding events that represents a “tug of war” among the various regulators and substrates within the network. This formalism allows for the assessment of interacting allosteric enzymes and development of a network-level understanding of regulation. We first define the catalytic potential and use it to characterize the response of three key kinases (hexokinase, phosphofructokinase, and pyruvate kinase) in human red blood cell glycolysis to perturbations in ATP utilization. Next, we examine the sensitivity of the catalytic potential by using existing personalized models, finding that the catalytic potential allows for the identification of subtle but important differences in how individuals respond to such perturbations. Finally, we explore how the catalytic potential can help to elucidate how enzymes work in tandem to maintain a homeostatic state. Taken together, this work provides an interpretation and visualization of the dynamic interactions and network-level effects of interacting allosteric enzymes. Author summary Enzymatic rate laws have historically been used to simulate the dynamics of complex metabolic networks with regulated reactions represented by allosteric rate laws. Here, we use detailed elementary reaction descriptions of regulatory enzymes that allow for the explicit computation of the fraction of the enzymes that are in a catalytically-active state. The fraction of the enzyme that is in the active state represents the time-dependent utilization of the enzyme’s “catalytic potential,” its capacity to catalyze a reaction. We apply this interpretation to red blood cell glycolysis, examining how three key kinases with allosteric regulation modulate their utilization of their catalytic potential based on ligand-binding events throughout the network in order to maintain a homeostatic state. We then examine how an enzyme modulates its utilization of its catalytic potential using personalized data as a case study, visualizing the systems-level properties of a kinetic model. |
| Databáze: | OpenAIRE |
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