METABOLIC MODELING OF CONVERGING METABOLIC PATHWAYS - Analysis of Non-steady State Stable Isotope-resolve Metabolism of UDP-GlcNAc and UDP-GalNAc

Hunter N. B. Moseley, Richard M. Higashi, Teresa W-M. Fan, Andrew N. Lane

2011

Abstract

We have developed a novel metabolic modeling methodology that traces the flow of functional moieties (chemical substructures) through metabolic pathways via the deconvolution of mass isotopologue data of specific metabolites. We have implemented a general simulated annealing/genetic algorithm for parameter optimization called Genetic Algorithm for Isotopologues in Metabolic Systems (GAIMS), with a model selection method developed from the Akaike information criterion. GAIMS is tailored for analysis of ultra-high resolution, high mass-accuracy isotopologue data from Fourier transform-ion cyclotron resonance mass spectrometry (FT-ICR-MS) for interpretation of non-steady state stable isotope-resolved metabolomics (SIRM) experiments. We applied GAIMS to a time-course of uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) and uridine diphospho-N-acetylgalactosamine (UDP-GalNAc) isotopologue data obtained from LNCaP-LN3 prostate cancer cells grown in [U-13C]-glucose. The best metabolic model was identified, which revealed the relative contribution of specific metabolic pathways to 13C incorporation from glucose into individual functional moieties of UDP-GlcNAc and UDP-GalNAc. Furthermore, this analysis allows direct comparison of MS isotopologue data with NMR positional isotopomer data for independent experimental cross-verification.

References

  1. Akaike, H., 1974. “A new look at the statistical model identification”, IEEE Transactions on Automatic Control, 19, 716-723.
  2. Edwards, J. S., Ibarra, R. U., Palsson, B. O., 2001. “In silico predictions of Escherichia coli metabolic capabilities are consistent with experimental data”, Nature Biotech, 19, 125-130.
  3. Fell, D. A., 1984. “Fat synthesis in adipose tissue. An examination of stoichiometric constraints”, J Biochem, 238, 781-786.
  4. Fell, D.A., 1997. Understanding the Control of Metabolism, London: Portland Press.
  5. Gambetta, M. C., Oktaba, K., & Müller, J., 2009. “Essential Role of the Glycosyltransferase Sxc/Ogt in Polycomb Repression”, Science, 325, 93-96.
  6. Harrigan, G. G., Goodacre, R. (Ed), 2003. Metabolic profiling: its role in biomarker discovery and gene function analysis, Boston: Kluwer Academic Publishers.
  7. Hart G. W., Housley M. P., Slawson C., 2007. "Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins", Nature, 446, 1017-1022.
  8. Hellerstein, M. K., 2003. “In vivo measurement of fluxes through metabolic pathways: the missing link in functional genomics and pharmaceutical research”, Annu Rev Nutr, 23, 379-402.
  9. Kauffman, K. J., Prakash, P., Edwards, J. S., 2003. “Advances in flux balance analysis”, Curr Opin Biotech, 14, 491-496.
  10. Lane A. N., Fan T. W-M., Higashi R. M., 2008. “Isotopomer-based metabolomic analysis by NMR and mass spectrometry". Methods in Cell Biology,Vol 84. Biophysical Tools for Biologists, Vol 1,ed. Correia JJ, Detrich HW. Elsevier Science & Technology Books Ch.18. 541-588.
  11. Lane, A. N., Fan, T. W-M., Xie, Z., Moseley, H. N. B., Higashi, R. M., 2009. “Stable isotope analysis of lipid biosynthesis by high resolution mass spectrometry and NMR.”, Anal Chim Acta, 651, 201-208.
  12. Moseley, H. N. B., 2010. “Correcting for the Effects of Natural Abundance in Stable Isotope Resolved Metabolomics Experiments Involving Ultra-High Resolution Mass Spectrometry”, BMC Bioinformatics, 11, 139-144.
  13. Savinell, J. M., Palsson, B. O., “Optimal selection of metabolic fluxes for in vivo measurement. I. Development of mathematical methods”, J Theor Biol, 155, 201-214.
  14. Sauer, U., Lasko, D. R., Fiaux, J., Hochuli, M., Glaser, R., Szyperski, T., Wuthrich, K., Bailey, J. E., 1999. “Metabolic Flux Ratio Analysis of Genetic and Environmental Modulations of Escherichia coli Central Carbon Metabolism”, J Bacteriol, 181, 6679- 6688.
  15. Sauer, U., 2006. “Metabolic networks in motion: 13Cbased flux analysis”, Mol Syst Biol, 2, 62.
  16. Schellenberger, J., Palsson, B. O., 2009. “Use of Randomized Sampling for Analysis of Metabolic Networks”, J Biol Chem, 284, 5457-5461.
  17. Selivanov, V. A., Marin, S., Lee, P. W. N., Cascante, M., 2006. “Software for dynamic analysis of tracer-based metabolomics data: estimation of metabolic fluxes and their statistical analysis”, Bioinformatics, 22, 2806- 2812.
  18. Stephanopoulos, G., “Metabolic fluxes and metabolic engineering”, Metab Eng, 1, 1-11.
  19. Wahl, S. A., Nöh, K., Wiechert, W., 2008. “13C labelling experiments at metabolic nonstationary conditions: An exploratory study”, BMC Bioinformatics, 9, 152-169.
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Paper Citation


in Harvard Style

N. B. Moseley H., M. Higashi R., W-M. Fan T. and N. Lane A. (2011). METABOLIC MODELING OF CONVERGING METABOLIC PATHWAYS - Analysis of Non-steady State Stable Isotope-resolve Metabolism of UDP-GlcNAc and UDP-GalNAc . In Proceedings of the International Conference on Bioinformatics Models, Methods and Algorithms - Volume 1: BIOINFORMATICS, (BIOSTEC 2011) ISBN 978-989-8425-36-2, pages 108-115. DOI: 10.5220/0003129401080115


in Bibtex Style

@conference{bioinformatics11,
author={Hunter N. B. Moseley and Richard M. Higashi and Teresa W-M. Fan and Andrew N. Lane},
title={METABOLIC MODELING OF CONVERGING METABOLIC PATHWAYS - Analysis of Non-steady State Stable Isotope-resolve Metabolism of UDP-GlcNAc and UDP-GalNAc},
booktitle={Proceedings of the International Conference on Bioinformatics Models, Methods and Algorithms - Volume 1: BIOINFORMATICS, (BIOSTEC 2011)},
year={2011},
pages={108-115},
publisher={SciTePress},
organization={INSTICC},
doi={10.5220/0003129401080115},
isbn={978-989-8425-36-2},
}


in EndNote Style

TY - CONF
JO - Proceedings of the International Conference on Bioinformatics Models, Methods and Algorithms - Volume 1: BIOINFORMATICS, (BIOSTEC 2011)
TI - METABOLIC MODELING OF CONVERGING METABOLIC PATHWAYS - Analysis of Non-steady State Stable Isotope-resolve Metabolism of UDP-GlcNAc and UDP-GalNAc
SN - 978-989-8425-36-2
AU - N. B. Moseley H.
AU - M. Higashi R.
AU - W-M. Fan T.
AU - N. Lane A.
PY - 2011
SP - 108
EP - 115
DO - 10.5220/0003129401080115