THE IMPORTANCE OF INHIBITORS FOR THE SIMULATION OF METABOLIC PROCESSES: IN SILICO Zn2+ INHIBITION OF m-ACONITASE FROM ANALYSIS OF GLYCOLYSIS AND KREBS CYCLE KINETIC MODELS

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DOIResolve DOI: http://doi.org/10.1142/S0219720010004872
AuthorSearch for:
TypeArticle
Journal titleJournal of Bioinformatics and Computational Biology
Volume8
Issue4
Pages703715; # of pages: 12
SubjectInhibition; pathway modeling; Krebs cycle; glycolysis; prostate metabolism; metal inhibition; prostate cancer; cancer metabolism; TCA; energy metabolism
AbstractMetal ions have a major effect on the metabolic processes in cells either as inhibitors or as integral components of enzymes. The inhibition of enzymes can take place either through the inhibition of gene expression or through inhibition of protein function. A particularly interesting example of the effect of a metal ion on metabolism is the observed inhibition of Krebs cycle and alteration of energy metabolism by zinc (II) cations. In this particular case metal ion inhibition of enzyme is linked to one of the major functions of prostate cells of accumulation and excretion of citrate. Experimental results have shown that increase in concentration of zinc (II) in prostate cells effectively blocks progression of a part of the Krebs cycle leading to change in the concentration of several metabolites with largest effect in the accumulation of citrate. Based on previously reported experimental results, several distinct mechanisms for zinc (II) inhibition of Krebs cycle were proposed. In order to determine the precise mechanism of inhibition in this system, a mathematical model of glycolysis and Krebs cycle was constructed. Three different types of inhibition were analyzed, including competitive and uncompetitive inhibition as well as inhibition through the alteration of the expression level of m-aconitase. The effects of different inhibition models on metabolite concentrations were investigated as a time course simulation of the system of reactions. Several kinetic parameters in the model were optimized in order to best resemble experimental measurements. The simulation shows that only competitive inhibition leads to an agreement with experimental data.
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LanguageEnglish
AffiliationNRC Institute for Information Technology; National Research Council Canada
Peer reviewedYes
NPARC number17791454
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Record identifierc7d88137-c0c9-4da1-9b0a-da6b6fc96202
Record created2011-04-27
Record modified2016-05-09
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