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Syntactic Model of Metabolic Pathways

Syntactic Model of Metabolic Pathways. Positional Isotopomers of Pyruvate. Citric Acid Cycle, Illustrating Flow of Atoms from Acetyl CoA. Isotopomers of Citric Acid Cycle Intermediates Produced from [2- 13 C]acetate. glucose. pyruvate. phosphoenolpyruvate. acetyl -CoA. oxaloacetate.

nissim-franklin
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Syntactic Model of Metabolic Pathways

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  1. Syntactic Model of Metabolic Pathways

  2. Positional Isotopomers of Pyruvate

  3. Citric Acid Cycle, IllustratingFlow of Atoms from Acetyl CoA

  4. Isotopomers of Citric Acid Cycle Intermediates Produced from [2-13C]acetate glucose pyruvate phosphoenolpyruvate acetyl-CoA oxaloacetate malate citrate fumarate alpha-ketoglutarate succinate

  5. Isotopomers of Citrate Produced By Successive Turns of the Citric Acid Cycle (substrate: [2-13C]acetate) One turn Two Turns [3,4-13C]citrate [2,4-13C]citrate [4-13C]citrate Three Turns [2,3,4-13C]citrate [1,3,4-13C]citrate [2,4,6-13C]citrate

  6. Multiplets of Carbon C2 of Citrate Produced by 13C-Labeling

  7. 13C-NMR Spectrum of [U-13C]glutamate C5 C1 C2 C4 C3

  8. Computer Simulation of Fractional Enrichment of Carbons of Glutamate in Heart (substrate: [2-13C]acetate)

  9. [---] [4-13C]- [3,4-13C] [2,4-13C] [2,3,4-13C] 1.00 0.80 0.60 Mole Fraction 0.40 0.20 0.00 0.00 1.07 2.14 3.20 4.27 5.34 Time (min) Computer Simulation of Isotopomers of Glutamate Present in Perfused Heart During Administration of [2-13C]acetate [1,3,4-13C] [1,2,3,4-13C]-

  10. [--] [4-13C] [3,4-13C] [2,4-13C] [2,3,4-13C] 1.00 0.80 0.60 Mole Fraction 0.40 0.20 0.00 0 11 21 32 43 54 Time (min) Computer Simulation of Isotopomers of Glutamate Present in Perfused Heart During Administration of [2-13C]acetate [1,3,4-13C] [1,2,3,4-13C]

  11. Syntactic Model of Metabolic Pathways • Problem • Writing differential equations for positional isotopomers of metabolic intermediates is time-consuming, complicated and error-prone • Response • Description of metabolic transformations by means of “syntactic rules” • Stochastic simulation of a Poisson process model of chemical kinetics • Outcome • Monte Carlo simulation of time-dependent concentrations of all positional isotopomers of each metabolic pool • Predicts multiplets and fractional enrichments observed with NMR spectroscopy

  12. Simulation of the Citric Acid Cyclewith the Syntactic Model

  13. Syntactic Model: Details • Variables of Model • Concentration of each positional isotopomer of each metabolite • Simulation of Elapsed Time • Mean time of occurrence of next chemical reaction is calculated from current rates of reactions • Uses a stochastic model of enzyme kinetics, equivalent to integration of the Michaelis-Menten equation for each enzyme.

  14. Flowchart of Syntactic Simulation

  15. Syntactic Rule for Citrate Synthase

  16. Syntactic Rule for Transaldolase sedoheptulose glyceraldehyde erythrose fructose 7-phosphate 3-phosphate 4-phosphate 6-phosphate

  17. Transaldolase: Syntactic Rule and Differential Equation for One Isotopomer

  18. Comparison: Syntactic Approach versus Conventional Approach Syntactic Differential Rules Equations Citric Acid Cycle 35 180 Pentose Phosphate Pathway 69 504 Transaldolase 10 80

  19. Comparison of Conventional and Syntactic Approaches to Prediction of Positional Isotopomers of the Citric Acid Cycle Isotopic Syntactic Differential Labels Rules Equations 1 35 180 2 35 359 3 35 6288

  20. An Application of the Syntactic Model • Testing and verification of formulas for estimating anaplerosis from isotopomer distributions • Anaplerosis: Chemical reactions that increase the mass of the chemical intermediates of the citric acid cycle • Detection of underestimation in current formulas for relative anaplerosis • Proposal of alternate formulas involving isotopomer fractions • Testing of new formulas, using computer simulation • Cohen and Bergman, Amer. J. Physiol, 273:E1228-42, 1997

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