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Analysis of the functional properties of the creatine kinase system using a multiscale ‘sloppy’ modeling approach
BMC Bioinformatics volume 11, Article number: O9 (2010)
Distinct functions have been hypothesized for the creatine kinase (CK) enzyme catalyzing the reversible transfer of the high-energy phosphate group of ATP to creatine. In muscle cells, two CK isoforms might mediate (i) temporal energy buffering to maintain ATP homeostasis and (ii) energy transport from mitochondria to myofibrils via the “phosphocreatine shuttle” mechanism. Here we investigate the relative importance of the two roles using a computational model . Model simulations predict a contribution of CK to the net transcytosolic energy transport of less than 1/3.
Materials and methods
The model is validated on experimental data from two scales: kinetic parameter measurements on the enzyme level and response times of oxidative phosphorylation in whole cardiac muscle.
To account for possible inaccuracies in the 22 model parameters, we sample a Bayesian ensemble of parameter sets which allows us to set confidence regions on model predictions. In this ‘sloppy’ modeling approach , the likelihood of a parameter combination to be included in the ensemble is proportional to its likelihood to predict the data. We use prior information on single parameter values from enzyme kinetic measurements to constrain them within their measurement errors.
From the ensemble, we predict a contribution of CK to the overall energy transport of 15±8% (mean±SD). The CK system damps the pulses of ATP hydrolysis of 3765 μM*s-1 during cardiac systole about 20 fold. CK inhibition by 98% increases the amplitude of ATP synthesis from 215±23 to 566±31 μM*s-1 (see Figure 1).
Our findings clearly support the hypothesis that CK acts as a high capacity temporal energy buffer damping energy peaks rather than being an essential energy transport system.
van Beek J: Adenine nucleotide-creatine-phosphate module in myocardial metabolic system explains fast phase of dynamic regulation of oxidative phosphorylation. Am J Physiol Cell Physiol 2007, 293: C815-C829. 10.1152/ajpcell.00355.2006
Gutenkunst RN, Waterfall JJ, Casey FP, et al.: Universally sloppy parameter sensitivities in systems biology models. PLoS Comput Biol 2007, 3: 1871–1878. 10.1371/journal.pcbi.0030189
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Hettling, H., Heringa, J. & van Beek, J.H. Analysis of the functional properties of the creatine kinase system using a multiscale ‘sloppy’ modeling approach. BMC Bioinformatics 11, O9 (2010). https://doi.org/10.1186/1471-2105-11-S10-O9
- Creatine Kinase
- Energy Transport
- Reversible Transfer
- Kinase System