Catabolism of 4-hydroxyacids and 4-hydroxynonenal via 4-hydroxy-4-phosphoacyl-CoAs.
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.
Zhang
Guo-Fang
GF
Department of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Kombu
Rajan S
RS
Kasumov
Takhar
T
Han
Yong
Y
Sadhukhan
Sushabhan
S
Zhang
Jianye
J
Sayre
Lawrence M
LM
Ray
Dale
D
Gibson
K Michael
KM
Anderson
Vernon A
VA
Tochtrop
Gregory P
GP
Brunengraber
Henri
H
D000214:Acyl Coenzyme A / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D002853:Chromatography, Liquid; D006880:Hydroxy Acids / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055432:Metabolomics / Q000379:methods; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry
D000214:Acyl Coenzyme A; D000447:Aldehydes; D006880:Hydroxy Acids; C027576:4-hydroxy-2-nonenal