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A mathematical model of the methionine cycle Michael C. Reeda,*, H. Frederik Nijhoutb, Rachel Sparksc, Cornelia M. Ulrichc Journal of Theoretical Biology.

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Presentation on theme: "A mathematical model of the methionine cycle Michael C. Reeda,*, H. Frederik Nijhoutb, Rachel Sparksc, Cornelia M. Ulrichc Journal of Theoretical Biology."— Presentation transcript:

1 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

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 amino acidamino acid containing sulphur*. It is essential in human nutrition. Symbol met m Molecular formula C5H11NO2S Molecular weight 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) Chemically diverse biochemical (cf ATP) Involvement in a multitude of metabolic pathways Involvement in a multitude of metabolic pathways Alkylation, methylation, free radical formation reactions Alkylation, methylation, free radical formation reactions Sulphur, amino acid, nucleotide metabolism Sulphur, amino acid, nucleotide metabolism Polyamine biosynthesis (cell proliferation…) Polyamine biosynthesis (cell proliferation…) signalling 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) Chemically diverse biochemical (cf ATP) Involvement in a multitude of metabolic pathways Involvement in a multitude of metabolic pathways Alkylation, methylation, free radical formation reactions Alkylation, methylation, free radical formation reactions Sulphur, amino acid, nucleotide metabolism Sulphur, amino acid, nucleotide metabolism Polyamine biosynthesis (cell proliferation…) Polyamine biosynthesis (cell proliferation…) signalling 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 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) 7gms/day synthesized (liver) Implicated in cancer, cardiovascular and liver disease Implicated in cancer, cardiovascular and liver disease Reported to ameliorate arthritis, liver cirrhosis, depression Reported to ameliorate arthritis, liver cirrhosis, depression

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

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

10 Overall rates

11 met Adomet

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

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

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

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


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