1. Modelling of Metabolic Networks Case Study: Martinov model of the methionine cycle

2. The methionine cycle Methinione combined with ATP to form S-adenosylmethionine (AdoMet) AdoMet donates a methyl group (CH 3 ) to various acceptors (lumped as A) S-adenosylhomocysteine (AdoHcy) converted to homocysteine Homocysteine converted to methionine or to cysteine

3. The methionine cycle Model constructed to address three aspects of behaviour:  AdoMet is produced by two distinct enyzmes: MATI and MATIII. MATI inhibited by AdoMet MATIII activated by AdoMet  GNMT transfers CH3 to glycine, forming non-functional sarcosine  As methinoine input rises, [methionine] steady; [AdoMet] and [AdoHcy] steady, then jump at a threshold

4. Model Network Two key assumptions:  [methionine], [ATP], [glycine], [A], fixed  Hcy AdoHcy in rapid equilibrium

5. Model Network Model equations:

6. Rates:

7. Behaviour: low [Met] Separation of time-scales: AdoHcy fast, AdoMet slow

8. Behaviour Bistability caused by positive feedback of AdoMet on MATIII low [Met] high [Met]

9. Behaviour low [Met] high [Met] standard operation “shunt” active to avoid increased methylation (V MET ) rates

10. Behaviour: bifurcation diagram AdoMet levels steady (lower branch) for low [Met], jumps to high values at threshold (edge of bistable region)