Modeling the Role of Negative Cooperativity in Metabolic Regulation and Homeostasis

Abstract

A significant proportion of enzymes display cooperativity in binding ligand molecules, and such effects have an important impact on metabolic regulation. This is easiest to understand in the case of positive cooperativity. Sharp responses to changes in metabolite concentrations can allow organisms to better respond to environmental changes and maintain metabolic homeostasis. However, despite the fact that negative cooperativity is almost as common as positive, it has been harder to imagine what advantages it provides. Here we use computational models to explore the utility of negative cooperativity in one particular context: that of an inhibitor binding to an enzyme. We identify several factors which may contribute, and show that acting together they can make negative cooperativity advantageous.

Modulation of Global Low-Frequency Motions Underlies Allosteric Regulation: Demonstration in CRP/FNR Family Transcription Factors

“…It is proposed that negative cooperativity reduces the sensitivity of a system and extends the concentration range over which a response can be observed [50]. In metabolism, recent modelling suggests that there is a significant overall advantage for metabolic pathway flux with components showing negative cooperativity [51],[52]. In transcriptional regulation, negative cooperativity in the binding of D-camphor to the CamR repressor of Pseudomonas putida is proposed to enable coupling of high specificity for D-camphor with a physiological response to high concentrations of the metabolite [53].…”

Chloroplast Glutamine Synthetase, the Key Regulator of Nitrogen Metabolism in Wheat, Performs Its Role by Fine Regulation of Enzyme Activity via Negative Cooperativity of Its Subunits

“…The intracellular level of such key molecules must be carefully controlled for mediating adequate cellular and physiological responses. Consequently at critical steps of cyclical processes or at branch points connecting pathways, key enzymes, act as finely tuned switches, allowing homeostasis in rapidly changing biochemical environments (Bush et al, 2012 ). These enzymes typically exhibit allosteric behavior.…”

“…Several mathematical models were constructed to describe allosteric cooperativity Monod-Wyman-Changeux (Monod et al, 1965 ) and Koshland-Némethy-Filmer models (Koshland et al, 1966 ; Levitzki and Koshland, 1969 ). Enzymes exhibiting allosteric cooperativity occupy key positions in interconnected metabolic networks (LaPorte et al, 1984 ; Kurganov, 2000 ; Bush et al, 2012 ).…”

The Role of Strong Electrostatic Interactions at the Dimer Interface of Human Glutathione Synthetase

“…The enzyme is negatively cooperative towards its γ-glutamyl substrate; thus, when the first γ-GC substrate binds, the substrate affinity of the second subunit of hGS decreases [13]. The allostery of hGS likely mediates the flux of γ-GC, while maintaining cellular levels of GSH [14, 15]. Communication between the active sites of hGS may pass through the dimer interface.…”