A Substrate Switch: A New Mode of Regulation in the Methionine Metabolic Pathway |  PDF |
Catherine Lloyd (Bioengineering Institute, University of Auckland)
Table of Contents
The methionine pathway serves three important functions in cellular metabolism:
It regulates between the amino acids methionine and cysteine for protein synthesis;
It provides the substrate for polyamine synthesis; and
It provides the mechanism by which methyl groups are transferred from 5-methyltetrahydrofolate to a wide range of substrates, and it represents the main mechanism for transmethylation reactions in mammals.
Abnormalities in methionine metabolism are associated with cardiovascular disease, liver disease, neural tube defects, and cancer.
Due to its essential role in cellular metabolism, the methionine pathway has been the subject of many experimental studies. These studies have revealed a high complexity of the cycle, in part due to the fact that enzymes in the cycle are activated and inhibited by intermediates of the cycle. In 2000, Martinov et al. developed a mathematical model of the methionine pathway in order to try to better understand the molecular mechanisms underlying the complexity of the methionine cycle. This model has been described in CellML and can be downloaded in various formats as explained in the section “Download This Model” below. The model structure is also outlined in Figure 1 below.
The complete original paper reference is cited below:
A Substrate Switch: A New Mode of Regulation in the Methionine Metabolic Pathway, Michael V. Martinov, Victor M. Vitvitsky, Eugene V. Mosharov, Ruma Banerjee, and Fazoil I. Ataullakhanov, 2000, Journal of Theoretical Biology, 204, 521-532. (A PDF version of the article is available on the Journal of Theoretical Biology website.) PubMed ID: 10833353
Model simulations revealed that S-adenosylmethionine (AdoMet) metabolism can operate under two different modes:
The first, with a low metabolic rate and a low AdoMet concentration, serves predominantly to supply the cell with AdoMet, the substrate for various methylation reactions.
The second, with a high metabolic rate and high AdoMet concentration serves as an opportunity for cleavage of excess methionine and can also serve as a source of cysteine when its increased synthesis is necessary.
The switch that triggers interconversion between the two modes is methionine concentration. This kinetic behaviour results from the kinetic properties of i) the two isozymes of AdoMet synthetase, MATI and MATIII; one is inhibited by AdoMet, while the other is activated by it, and ii) glycine-N-methyltransferase (GNMT) that displays highly cooperative kinetics.
Finally, the authors concluded that their mathematical model provides an explanation for how different cellular needs are met by regulation of the methionine pathway. In addition, the model also identifies a critical role for GNMT in depleting excess methionine in the high rate, high concentration mode, thus avoiding the toxicity associated with accumulation of this amino acid.
martinov_model_2000.xml — the raw XML.
martinov_model_2000.html — an HTML version for browsing online.
martinov_model_2000.pdf — a PDF version suitable for printing.
cellml_martinov_model_2000.tar.gz — a gzipped tarball with the XML and this documentation.
martinov_model_2000_maths.pdf — a PDF of the equations described in the model generated directly from the CellML description using the MathML Renderer.
