Reed, Nijhout, Sparks, Ulrich, 2004

Model Status

This is the original unchecked version of the model imported from the previous CellML model repository, 24-Jan-2006.

Model Structure

The methionine cycle 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 cycle 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 cycle in order to try to better understand the molecular mechanisms underlying the complexity of the methionine cycle. (This model can be seen in more detail at: Martinov et al., A Substrate Switch: A New Mode of Regulation in the Methionine Metabolic Pathway, 2000).

In the 2004 publication described here in CellML, Reed et al. have further developed the Martinov et al. model by closing the cycle and by taking into account the influence of S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy) on the fates of homocysteine (Hcy), (see the figure below). The authors use the model to better understand the temporal variations in methionine and folate input on the other metabolite concentrations. In addition they looked to understand the mechanisms by which dietary deficiencies (protein, vitamins B6, B12) and genetic abnormalities cause changes in the metabolite concentrations and affect the operation of the cycle as a whole.

The complete original paper reference is cited below:

A mathematical model of the methionine cycle, Michael C. Reed, H. Frederik Nijhout, Rachel Sparks, and Cornelia M. Ulrich, 2004, Journal of Theoretical Biology , 226, 33-43. (Full text (HTML) and PDF versions of the article are available on the Journal of Theoretical Biology website.) PubMed ID: 14637052

Components of the methionine metabolism modelled by Reed et al.. The main metabolites are shown in blue boxes and the enzymes in red boxes.

Model simulations revealed that the methionine cycle is surprisingly complex. Several steps in the pathway are catalysed by multiple enzymes, many of which have complicated kinetics. In addition, AdoMet and AdoHcy not only influence the enzymes that catalyse their own synthesis, they also inhibit and activate several other enzymes in the pathway. These interactions are essential for the regulatory properties of the network.