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Effect of Substrate Number Fluctuations in Stochastic Enzyme Kinetics.

ABSTRACT: Conventional studies on enzyme kinetics assume that the substrate concentration remains constant. However, for catalytic reactions taking place in intracellular compartments, the substrate molecules are fed in and out of the compartment and are catalyzed into product molecules within the compartment. In this work, we use a chemical master equation approach to study the stochastic kinetics of a single enzyme for different reaction pathways with one or more intermediate states. We obtain velocity expressions that deviate from the Michaelis-Menten expression. We study the coefficient of variation, which is a measure of the noise strength as a function of the mean substrate concentration for systems where there is influx or/and outflux of substrate molecules. Our results show that the noise strength decreases with the increase in the substrate concentration and finally remains the same when the substrate is present in abundance.

SUBMITTER: Singh D

PROVIDER: S-EPMC6641702 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Effect of Substrate Number Fluctuations in Stochastic Enzyme Kinetics.

Singh Divya D Chaudhury Srabanti S

ACS omega 20180524 5

Conventional studies on enzyme kinetics assume that the substrate concentration remains constant. However, for catalytic reactions taking place in intracellular compartments, the substrate molecules are fed in and out of the compartment and are catalyzed into product molecules within the compartment. In this work, we use a chemical master equation approach to study the stochastic kinetics of a single enzyme for different reaction pathways with one or more intermediate states. We obtain velocity ...[more]

PMID: 31458761

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Project description:Enzymes are catalysts in biochemical reactions that, by definition, increase rates of reactions without being altered or destroyed. However, when that enzyme is a protease, a subclass of enzymes that hydrolyze other proteins, and that protease is in a multiprotease system, protease-as-substrate dynamics must be included, challenging assumptions of enzyme inertness, shifting kinetic predictions of that system. Protease-on-protease inactivating hydrolysis can alter predicted protease concentrations used to determine pharmaceutical dosing strategies. Cysteine cathepsins are proteases capable of cathepsin cannibalism, where one cathepsin hydrolyzes another with substrate present, and misunderstanding of these dynamics may cause miscalculations of multiple proteases working in one proteolytic network of interactions occurring in a defined compartment. Once rates for individual protease-on-protease binding and catalysis are determined, proteolytic network dynamics can be explored using computational models of cooperative/competitive degradation by multiple proteases in one system, while simultaneously incorporating substrate cleavage. During parameter optimization, it was revealed that additional distraction reactions, where inactivated proteases become competitive inhibitors to remaining, active proteases, occurred, introducing another network reaction node. Taken together, improved predictions of substrate degradation in a multiple protease network were achieved after including reaction terms of autodigestion, inactivation, cannibalism, and distraction, altering kinetic considerations from other enzymatic systems, since enzyme can be lost to proteolytic degradation. We compiled and encoded these dynamics into an online platform (https://plattlab.shinyapps.io/catKLS/) for individual users to test hypotheses of specific perturbations to multiple cathepsins, substrates, and inhibitors, and predict shifts in proteolytic network reactions and system dynamics.

Dataset Information

Effect of Substrate Number Fluctuations in Stochastic Enzyme Kinetics.

Publications

Effect of Substrate Number Fluctuations in Stochastic Enzyme Kinetics.

Similar Datasets

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