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Abstract
A pervasive issue in stable isotope tracing and metabolic flux analysis is the presence of naturally occurring isotopes such as 13C. For mass isotopomer distributions (MIDs) measured by mass spectrometry, it is common practice to correct for natural occurrence of isotopes within metabolites of interest using a linear transform based on binomial distributions. The resulting corrected MIDs are often used to fit metabolic network models and infer metabolic fluxes, which implicitly assumes that corrected MIDs will yield the same flux solution as the actual observed MIDs. Although this assumption can be empirically verified in special cases by simulation studies, there seems to be no published proof of this important property for the general case. In this paper, we prove that this property holds for the case of noise-free MID data obtained at steady state. On the other hand, for noisy MID data, the flux solution will generally differ between the two representations. These results provide a theoretical foundation for the common practice of MID correction in metabolic flux analysis.
Highlights
When analyzing data from stable isotope tracing experiments, the presence of naturally occurring isotopes can be problematic
We have provided a self-contained derivation of the linear transform T n commonly used for isotope correction, and explored the effects of T n for metabolic flux analysis
We hope that this contribution will help clarify the role of isotope correction in analysis of mass spectrometry data from 13C tracing experiments
Summary
When analyzing data from stable isotope tracing experiments, the presence of naturally occurring isotopes can be problematic. Several methods and software packages have been developed for MID correction [Millard et al, 2012, Jungreuthmayer et al, 2015, Su et al, 2017, Millard et al, 2019], providing various features such as support for multiple isotopes and compound fragmentation. They are all based on a particular class of linear transforms T n, n = 1, 2, . We provide such a proof for the case of noise-free data at isotopic steady-state in section 4, and conclude by discussing some remaining open questions
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