Irreversible reactions in metabolic simulations : how reversible is irreversible ?

Mathematically and thermodynamically there are no irreversible reactions in chemistry, and all enzymes catalyse reversible reactions. All reactions have finite standard Gibbs energies, which is just another way of saying that they all have finite equilibrium constants. Nonetheless, for an enzyme like pyruvate kinase, with an equilibrium constant of the order of 105, one may feel that this is just a mathematical nicety and that the thermodynamic necessity for the reverse reaction to be possible has no practical consequences for cell physiology, and in practice many metabolic reactions are conventionally regarded as irreversible. This typically means that they have equilibrium constants of the order of 1000 or more, though when the mass action ratio in the cell also strongly favours the forward direction a reaction with a substantially smaller equilibrium constant than this can be regarded as irreversible. For example, the hexokinase reaction has an equilibrium constant that is less than 250 at pH 6.5 (Gregoriou et al., 1981), but the reaction is still considered irreversible because in normal physiological conditions the concentration of glucose is always much greater than that of glucose 6-phosphate and the concentration of ATP is usually greater than that of ADP. In metabolic simulations the difficulty and inconvenience of using complete reversible rate equations for all the enzymes is aggravated by the fact that for nearly all “irreversible” enzymes virtually no kinetic measurements of the rates of the reverse reactions, or even of the effects of products on the rates of the forward reactions, have ever been reported. In the absence of any data, therefore, one is forced to choose between ignoring the reverse reaction altogether or guessing what its kinetic parameters might be on the basis of the values of the equilibrium constant and of the kinetic parameters for the forward direction. It would hardly be surprising if many simulators faced with such an unappealing choice preferred the easier option of ignoring reverse reactions, apparently safe and no worse than just guessing the parameter values. Our view is that it is always best to use reversible equations in metabolic sim-