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Mathematical Model of Methionine Cycle: A Comprehensive Analysis

Explore a mathematical model of methionine cycle, detailing reactions and biological consequences. Compare predictions with experimental data. Discover the significance of methionine in nutrition, metabolism, and molecular pathways. Uncover unique implications of AdoMet in liver function and diseases. Delve into the complexities of enzyme interactions and non-linear responses. Gain insights into methionine flux and homeostatic control mechanisms.

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Mathematical Model of Methionine Cycle: A Comprehensive Analysis

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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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