Fast computation of gradient and sentitivity in 13C metabolic flux analysis instationary experiments using the adjoint method

Abstract: Metabolic flux analysis using 13C labeled substrates is an important tool for metabolic engineering. Although it has now been evolving for more than ten years, metabolic flux analysis has still not reached the limits of its application. First and foremost, there is only one reference software for the analysis and identification of metabolic fluxes using stationnary carbon labeling experiments, which is closed-source. Moreover, this software lacks connections with the new standards of systems biology community, for example the Systems Biology Markup Language, which allows to describe arbitrary large metabolic networks. The first part of this paper, after recalling all the mathematics involved in the mathematical problem of flux identification in the case of multiple experiments (state equations, regularized cost function, explicit computation of the gradient) concentrates on the problem of specific automatic generation of scripts (Matlab or Scilab) implementing the numerical resolution. To this purpose, we will describe the architecture of the software chain implementing the transformation from the XML file describing the metaboling network and the carbon transitions to the final collection of scripts computing, for example, the exact gradient of the regularized least-squares cost function and the output sensitivities. In the unstationnary case the adjoint state method is used to speed up computations.