Metabolic isotopomer labeling systems: Part I: global dynamic behavior

In the last few years metabolic flux analysis (MFA) using carbon labeling experiments (CLE) has become a major diagnostic tool in metabolic engineering. The mathematical centerpiece of MFA is the solution of isotopomer labeling systems (ILS). An ILS is a high-dimensional nonlinear differential equation system that describes the distribution of isotopomers over a metabolic network during a carbon labeling experiment. This contribution presents a global analysis of the dynamic behavior of general ILSs. It is proven that an ILS is globally stable under very weak conditions that are always satisfied in practice. In particular it is shown that in some sense ILSs are a nonlinear extension to the classical theory of compartmental systems. The central stability condition for compartmental systems, i.e., the non-existence of traps in linear compartmental networks, is also the major stability condition for ILSs. As an important side result of the proof, it is shown that ILSs can be transformed to a cascade of linear systems with time-dependent inhomogeneous terms. This cascade structure has considerable consequences for the development of efficient numerical algorithms for the solution of ILSs and thus for MFA.