Abstract |
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-phosphoacyl-CoAs, leads in six steps to the isomerization of 4-hydroxyacyl-CoA to 3-hydroxyacyl-CoAs. The latter are intermediates of physiological beta-oxidation. The second and minor pathway involves a sequence of beta-oxidation, alpha-oxidation, and beta-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.
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Authors | Guo-Fang Zhang, Rajan S Kombu, Takhar Kasumov, Yong Han, Sushabhan Sadhukhan, Jianye Zhang, Lawrence M Sayre, Dale Ray, K Michael Gibson, Vernon A Anderson, Gregory P Tochtrop, Henri Brunengraber |
Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 284
Issue 48
Pg. 33521-34
(Nov 27 2009)
ISSN: 1083-351X [Electronic] United States |
PMID | 19759021
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Acyl Coenzyme A
- Aldehydes
- Hydroxy Acids
- 4-hydroxy-2-nonenal
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Topics |
- Acyl Coenzyme A
(metabolism)
- Aldehydes
(metabolism)
- Animals
- Chromatography, Liquid
- Hydroxy Acids
(metabolism)
- Liver
(metabolism)
- Magnetic Resonance Spectroscopy
- Male
- Metabolomics
(methods)
- Oxidation-Reduction
- Rats
- Rats, Sprague-Dawley
- Tandem Mass Spectrometry
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