Comparison of kinetic models for analysis of pyruvate-to-lactate exchange by hyperpolarized 13C NMR

Crystal Harrison, Chendong Yang, Ashish Jindal, Ralph J. Deberardinis, M. A. Hooshyar, Matthew Merritt, A. Dean Sherry, Craig R. Malloy

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

The activity of specific enzyme-catalyzed reactions may be detected in vivo by 13C NMR of hyperpolarized (HP) substrates. The signals from HP substrates and products, acquired over time, have been fitted to a number of different mathematical models to determine fluxes, but these models have not been critically compared. In this study, two-pool and three-pool first-order models were constructed to measure flux through lactate dehydrogenase in isolated glioblastoma cells by NMR detection of lactate and pyruvate following the addition of HP [1-13C]pyruvate. Mass spectrometry (MS) was used to independently monitor 13C enrichment in intra- and extracellular lactate. Six models were evaluated using time-dependent pyruvate C2 and lactate C1 HP NMR data acquired by the use of selective excitation pulses, plus 13C enrichment data from intracellular and extracellular lactate measured by MS. A three-pool bidirectional model provided the most accurate description of pyruvate metabolism in these cells. With computed values for T1 of pyruvate and lactate, as well as the effect of pulsing, the initial flux through lactate dehydrogenase was well determined by both the two-pool bidirectional and unidirectional models when only HP data were available. The three-pool model was necessary to fit the combined data from both MS and HP, but the simpler two-pool exchange model was sufficient to determine the 13C lactate concentration when the lactate appearance was measured only by HP.

Original languageEnglish (US)
Pages (from-to)1286-1294
Number of pages9
JournalNMR in Biomedicine
Volume25
Issue number11
DOIs
StatePublished - Nov 2012

Fingerprint

Pyruvic Acid
Lactic Acid
Nuclear magnetic resonance
Kinetics
Mass spectrometry
Mass Spectrometry
Fluxes
L-Lactate Dehydrogenase
Substrates
Glioblastoma
Carbon-13 Magnetic Resonance Spectroscopy
Metabolism
Theoretical Models
Mathematical models
Enzymes

Keywords

  • Dynamic nuclear polarization
  • Glioblastoma
  • Hyperpolarized carbon-13
  • Kinetics
  • Lactate
  • Lactate dehydrogenase
  • Pyruvate

ASJC Scopus subject areas

  • Spectroscopy
  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging

Cite this

Comparison of kinetic models for analysis of pyruvate-to-lactate exchange by hyperpolarized 13C NMR. / Harrison, Crystal; Yang, Chendong; Jindal, Ashish; Deberardinis, Ralph J.; Hooshyar, M. A.; Merritt, Matthew; Dean Sherry, A.; Malloy, Craig R.

In: NMR in Biomedicine, Vol. 25, No. 11, 11.2012, p. 1286-1294.

Research output: Contribution to journalArticle

Harrison, Crystal ; Yang, Chendong ; Jindal, Ashish ; Deberardinis, Ralph J. ; Hooshyar, M. A. ; Merritt, Matthew ; Dean Sherry, A. ; Malloy, Craig R. / Comparison of kinetic models for analysis of pyruvate-to-lactate exchange by hyperpolarized 13C NMR. In: NMR in Biomedicine. 2012 ; Vol. 25, No. 11. pp. 1286-1294.
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