SYNTAX: a rule-based stochastic simulation of the time-varying concentrations of positional isotopomers of metabolic...

We present a new approach to simulation of metabolic pathways. The syntactic approach combines a rule-based description of biochemical reactions with a stochastic model of chemical kinetics. Each syntactic rule describes the location in a product molecule to which a particular carbon of a reactant molecule will be transferred. Using specifically labeled substrates and known rates of chemical reactions, our simulation predicts the time-dependent changes in concentration of positional isotopomers of metabolic intermediates. (A positional isotopomer of a compound is an isomer that is determined by the positions of isotopes within the molecule, e.g., [1,2-13C]glucose and [1,3,5-13C]glucose). For the simulation of the 13C-positional isotopomers of the citric acid cycle in heart cells we require only 39 syntactic rules, compared to the 176 ordinary differential equations required by the traditional approach. Addition of chemical reactions to the simulation does not require changing the program code for the existing reactions. In comparison, addition of a reaction to a system described by differential equations requires altering the equations for all isotopomers of all reactants and products of the new chemical reaction.