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Journal of Theoretical Biology 226 (2004) 33–43

A mathematical model of the methionine cycle Michael C. Reeda,*, H. Frederik Nijhoutb, Rachel Sparksc, Cornelia M. Ulrichc. Journal of Theoretical Biology 226 (2004) 33–43. Summary. Methionine cycle- individual reactions each expressed mathematically (and as a follow-on from a previous paper)

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Journal of Theoretical Biology 226 (2004) 33–43

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  1. A mathematical model of the methionine cycleMichael C. Reeda,*, H. Frederik Nijhoutb, Rachel Sparksc, Cornelia M. Ulrichc Journal of Theoretical Biology 226 (2004) 33–43

  2. Summary Methionine cycle- individual reactions each expressed mathematically (and as a follow-on from a previous paper) Using these equations to determine: -Conc. of reactants with differing rates of input of methionine -Dynamic changes in conc., testing regulatory control and biological consequences Comparison of model predictions with experimental results

  3. methionine • L-Methionine is a neutral, genetically coded amino acid • containing sulphur*. • It is essential in human nutrition. • Symbol • met m • Molecular formula • C5H11NO2S • Molecular weight • 149.21 • Isoelectric point (pH) • 5.74 The start codon AUG codes for methionine *Sulphur (methionine and cysteine): 0.25% body weight (esp. hair, nails, skin) Constituent of -mucopolysaccharides (cartilage, tendon, bones) -sulfolipids (liver, brain, kidneys, salivary glands)

  4. Methionine + ATP AdoMet • Chemically diverse biochemical (cf ATP) • Involvement in a multitude of metabolic pathways • Alkylation, methylation, free radical formation reactions • Sulphur, amino acid, nucleotide metabolism • Polyamine biosynthesis (cell proliferation…) • signalling e.g. Methylation: -DNA (replication and transcription, host recognition, heredity imprinting, X chromosome inactivation) -RNA (mRNA stability, nuclear export, tRNA modulation, RNA splicing) -protein (susceptibility to hydrolysis, signalling, chemotaxis, rescue of protein funtion, targeting, histone-gene expression and chromatin structure) -misc (cofactor, e- transport, secondary metabolites

  5. Methionine + ATP AdoMet • Chemically diverse biochemical (cf ATP) • Involvement in a multitude of metabolic pathways • Alkylation, methylation, free radical formation reactions • Sulphur, amino acid, nucleotide metabolism • Polyamine biosynthesis (cell proliferation…) • signalling e.g. Methylation: -DNA (replication and transcription, host recognition, heredity imprinting, X chromosome inactivation) -RNA (mRNA stability, nuclear export, tRNA modulation, RNA splicing) -protein (susceptibility to hydrolysis, signalling, chemotaxis, rescue of protein funtion, targeting, histone-gene expression and chromatin structure) -misc (cofactor, e- transport, secondary metabolites

  6. AdoMet • Due to unique expression in liver of metAdomet enzyme (MATIII), liver is able to respond to great changes in met conc. in diet • 7gms/day synthesized (liver) • Implicated in cancer, cardiovascular and liver disease • Reported to ameliorate arthritis, liver cirrhosis, depression

  7. Methionine cycle • Enzymes are activated and inhibited by several intermediates in cycle • Non-linearities in interactions among componentscontext dependent responses, unpredictable • Several steps catalysed by multiple enzymes

  8. V velocity of reaction Km rate constant to multiply kinetic equation (1st, 2nd, 3rd order kinetics…)

  9. Overall rates

  10. metAdomet

  11. Results • Conc. Reactants v rate of input of met (steady state) Input met =cystathionine production • [met] (MATIII) • [AdoHcy] & [homocysteine] (Vmeth at near saturation)

  12. Methionine flux in hepatocytes • Not well characterised • Metadomet  adohcy  hcy 400uM/h with about 200uM/h leaving cycle Therefore, staedy state 200uM/h input

  13. Biological phenomena • Sudden switch from low to high Adomet with gradual increase in methionine conc. (saturation of Vmeth reaction) • Homeostatic control of met conc. (MATIII) • Alterations in the fraction of [Hcy] which is transsulfurated independent of [Hcy] (regulation of enzymes by Adomet and AdoHcy)

  14. Discussion • Much observed phenomena explained by causal chain of events postulated • Great variation in observed phenomena • Many assumptions made in kinetic vaklues • Linear approximations used • Assumed methionine cycle in isolation-also affected by regulation of synthesis of enzymes e.g. adomet and 5mTHF • Localisation of cycle in cell/partitoning of components

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