Analysis of pathological defects in methionine metabolism using a simple mathematical model.
Derangements in methionine metabolism are a hallmark of cancers and homocystinuria, an inborn error of metabolism. In this study, the metabolic consequences of the pathological changes associated with the key pathway enzymes, methionine adenosyl transferase (MAT), glycine N-methyl transferase (GNMT) and cystathionine beta-synthase (CBS) as well as an activation of polyamine metabolism, were analyzed using a simple mathematical model describing methionine metabolism in liver. The model predicts that the mere loss of allosteric regulation of CBS by adenosylmethionine (AdoMet) leads to an increase in homocysteine concentration. This is consistent with the experimental data on the corresponding genetic defects, which specifically impair allosteric activation but not basal enzyme activity. Application of the characteristics of transformed hepatocytes to our model, i.e., substitution of the MAT I/III isozyme by MAT II, loss of GNMT activity and activation of polyamine biosynthesis, leads to the prediction of a significantly different dependence of methionine metabolism on methionine concentrations. The theoretical predictions were found to be in good agreement with experimental data obtained with the human hepatoma cell line, HepG2.
Prudova
Anna
A
Department of Biochemistry, University of Nebraska, Lincoln, NE 68588-0664, USA.
Martinov
Mikhail V
MV
Vitvitsky
Victor M
VM
Ataullakhanov
Fazoil I
FI
Banerjee
Ruma
R
D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism; D050938:Glycine N-Methyltransferase / Q000378:metabolism; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008715:Methionine / Q000378:metabolism*; D008716:Methionine Adenosyltransferase / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation / Q000235:genetics
D006710:Homocysteine; D008715:Methionine; C494510:GNMT protein, human; D050938:Glycine N-Methyltransferase; D008716:Methionine Adenosyltransferase; D003541:Cystathionine beta-Synthase