Mathematical modelling of the urea cycle. A numerical investigation into substrate channelling.

Metabolite channelling, the process in which consecutive enzymes have confined substrate transfer in metabolic pathways, has been proposed as a biochemical mechanism that has evolved because it enhances catalytic rates and protects unstable intermediates. Results from experiments on the synthesis of radioactive urea [Cheung, C., Cohen, N.S. & Raijman, L (1989) J. Biol. Chem.264, 4038-4044] have been interpreted as implying channelling of arginine between argininosuccinate lyase and arginase in permeabilized hepatocytes. To investigate this interpretation further, a mathematical model of the urea cycle was written, using Mathematica it simulates time courses of the reactions. The model includes all relevant intermediates, peripheral metabolites, and subcellular compartmentalization. Analysis of the output from the simulations supports the argument for a high degree of, but not absolute, channelling and offers insights for future experiments that could shed more light on the quantitative aspects of this phenomenon in the urea cycle and other pathways.