Correction of13C Mass Isotopomer Distributions for Natural Stable Isotope Abundance

Fernandez, C. A.; Rosiers, Christine Des; Previs, Stephen F.; David, F.; Brunengraber, Henri

doi:10.1002/(sici)1096-9888(199603)31:3<255::aid-jms290>3.0.co;2-3

Cited by 368 publications

(227 citation statements)

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“…Calculations-Correction of measured mass isotopomer distributions for natural enrichment was performed using the CORMAT software (30). The labeling of the C-1ϩ2 acetyl of BHB, a proxy of mitochondrial acetyl-CoA, was calculated using the mass isotopomer distributions of the whole BHB molecule and of the C-3ϩ4 fragment of BHB.…”

Section: Methodsmentioning

confidence: 99%

Catabolism of 4-Hydroxyacids and 4-Hydroxynonenal via 4-Hydroxy-4-phosphoacyl-CoAs

Zhang

Kombu

Kasumov

et al. 2009

Journal of Biological Chemistry

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4-Hydroxyacids are products of ubiquitously occurring lipid peroxidation (C 9 , C 6 ) or drugs of abuse (C 4 , C 5 ). We investigated the catabolism of these compounds using a combination of metabolomics and mass isotopomer analysis. Livers were perfused with various concentrations of unlabeled and labeled saturated 4-hydroxyacids (C 4 to C 11 ) or 4-hydroxynonenal. All the compounds tested form a new class of acyl-CoA esters, 4-hydroxy-4-phosphoacyl-CoAs, characterized by liquid chromatography-tandem mass spectrometry, accurate mass spectrometry, and 31 P-NMR. All 4-hydroxyacids with five or more carbons are metabolized by two new pathways. The first and major pathway, which involves 4-hydroxy-4-phosphoacylCoAs, leads in six steps to the isomerization of 4-hydroxyacylCoA to 3-hydroxyacyl-CoAs. The latter are intermediates of physiological ␤-oxidation. The second and minor pathway involves a sequence of ␤-oxidation, ␣-oxidation, and ␤-oxidation steps. In mice deficient in succinic semialdehyde dehydrogenase, high plasma concentrations of 4-hydroxybutyrate result in high concentrations of 4-hydroxy-4-phospho-butyryl-CoA in brain and liver. The high concentration of 4-hydroxy-4-phospho-butyryl-CoA may be related to the cerebral dysfunction of subjects ingesting 4-hydroxybutyrate and to the mental retardation of patients with 4-hydroxybutyric aciduria. Our data illustrate the potential of the combination of metabolomics and mass isotopomer analysis for pathway discovery.4-Hydroxy-n-acids are involved in different areas of mammalian metabolism. Some unsaturated 4-hydroxyacids are derived from 4-hydroxynonenal and 4-hydroxyhexenal, which are products of lipid peroxidation (1). The metabolism of 4-hydroxynonenal has been extensively studied, especially its conjugation with glutathione (2), covalent modification of proteins (3, 4), and conversion to 4-hydroxynonenoate, 4-hydroxynonanoate and 1,4-dihydroxynonene, as well as its role in inflammatory processes (1, 5-11). However, the catabolism of its carbon skeleton has not been unraveled. The four-carbon 4-hydroxybutyrate is a physiological neurotransmitter derived from ␥-aminobutyrate. Humans with inborn disorder of succinic semialdehyde dehydrogenase have high 4-hydroxybutyrate concentrations in body fluids, mental retardation, and seizures (12). 4-Hydroxybutyrate is also a drug of abuse that impairs the capacity to exercise judgment for unknown reasons. 4-Hydroxybutyrate is used for the treatment of narcolepsy (13). Its known metabolism (14, 15) proceeds via oxidation to succinic semialdehyde and then to succinate, an intermediate of the citric acid cycle. The five-carbon 4-hydroxypentanoate is also a drug of abuse (16). The calcium salt of a compound closely related to 4-hydroxypentanoate, levulinate (4-ketopentanoate, 4-ketovalerate), is used as an oral or intravenous source of calcium in humans.We conducted a study on the catabolism of C 4 to C 11 4-hydroxyacids in perfused rat livers using a combination of metabolomics (17,18) and mass isotopomer analysis 2 (19)....

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Section: Methodsmentioning

confidence: 99%

Catabolism of 4-Hydroxyacids and 4-Hydroxynonenal via 4-Hydroxy-4-phosphoacyl-CoAs

Zhang

Kombu

Kasumov

et al. 2009

Journal of Biological Chemistry

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“…However, as Brauman pointed out in his method 10 , we can make a square matrix by multiplying by the transpose of A, denoted by A T : (7) The matrix A T A is a square matrix, and its inverse, (A T A) −1 , can be found. Multiplying both sides by (A T A) −1 gives the solution for x: (8) Note that the above discussion assumes we can measure the mass spectra of the labeled isotopomers shown in the left-side spectra of Figure 2. This assumption poses a problem: we never have a pure labeled isotopomer available to measure.…”

Section: Definitions Of Terms and Key Equations Of The Methodsmentioning

confidence: 99%

Determination of Complex Isotopomer Patterns in Isotopically Labeled Compounds by Mass Spectrometry

Jennings

Matthews

2005

Anal. Chem.

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A classic problem in analytical chemistry has been determination of individual components in a mixture without availability of the pure individual components. Measurement of the distribution of isotopomers in a labeled compound or mixture of labeled compounds is an example of this problem that is commonly encountered when stable isotopically labeled metabolites are used to determine in vivo kinetics and metabolism. We present a method that uses the measured mass spectral data of the unlabeled material to represent any and all combinations of isotopomer variations of that material and to determine abundances of these isotopomers. Although examples of the method are presented for gas chromatography-mass spectrometry, the method is applicable to any type of mass spectrometry data. The method also accounts for errors induced by mass spectrometer ionization and resolution effects. To demonstrate this method, we determined the isotopomer distributions of samples of 13 C-labeled leucine and glucose for both highly enriched isotopomers and labeled isotopomers present in low abundance against a natural isotopic abundance background. The method accurately and precisely determined isotopomer identity and abundance in the labeled materials without adding noise or error that was not inherent in the original mass spectral data. In examples shown here isotopomer uncertainties were calculated with relative standard errors of <1% from good quality mass spectral data.

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“…[23][24][25] Correction of measured mass isotopomer distributions for natural enrichment was performed using the CORMAT software. 26 …”

Section: Gc-ms/lc-ms Analysismentioning

confidence: 99%

Heptanoate as a Neural Fuel: Energetic and Neurotransmitter Precursors in Normal and Glucose Transporter I-Deficient (G1D) Brain

Marin‐Valencia

Good

Qian

et al. 2012

J Cereb Blood Flow Metab

128

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It has been postulated that triheptanoin can ameliorate seizures by supplying the tricarboxylic acid cycle with both acetyl-CoA for energy production and propionyl-CoA to replenish cycle intermediates. These potential effects may also be important in other disorders associated with impaired glucose metabolism because glucose supplies, in addition to acetyl-CoA, pyruvate, which fulfills biosynthetic demands via carboxylation. In patients with glucose transporter type I deficiency (G1D), ketogenic diet fat (a source only of acetyl-CoA) reduces seizures, but other symptoms persist, providing the motivation for studying heptanoate metabolism. In this work, metabolism of infused [5,6,[7][8][9][10][11][12][13] C 3 ]heptanoate was examined in the normal mouse brain and in G1D by 13 C-nuclear magnetic resonance spectroscopy, gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-mass spectrometry (LC-MS). In both groups, plasma glucose was enriched in 13 C, confirming gluconeogenesis from heptanoate. Acetyl-CoA and glutamine levels became significantly higher in the brain of G1D mice relative to normal mice. In addition, brain glutamine concentration and 13 C enrichment were also greater when compared with glutamate in both animal groups, suggesting that heptanoate and/or C5 ketones are primarily metabolized by glia. These results enlighten the mechanism of heptanoate metabolism in the normal and glucosedeficient brain and encourage further studies to elucidate its potential antiepileptic effects in disorders of energy metabolism.

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Correction of13C Mass Isotopomer Distributions for Natural Stable Isotope Abundance

Cited by 368 publications

References 1 publication

Catabolism of 4-Hydroxyacids and 4-Hydroxynonenal via 4-Hydroxy-4-phosphoacyl-CoAs

Catabolism of 4-Hydroxyacids and 4-Hydroxynonenal via 4-Hydroxy-4-phosphoacyl-CoAs

Determination of Complex Isotopomer Patterns in Isotopically Labeled Compounds by Mass Spectrometry

Heptanoate as a Neural Fuel: Energetic and Neurotransmitter Precursors in Normal and Glucose Transporter I-Deficient (G1D) Brain

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