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

Zhang, Guofang; Kombu, Rajan S.; Kasumov, Takhar; Han, Yong; Sadhukhan, Sushabhan; Zhang, Jianye; Sayre, Lawrence M.; Ray, Dale G.; Gibson, K. Michael; Anderson, Vernon A.; Tochtrop, Gregory P.; Brunengraber, Henri

doi:10.1074/jbc.m109.055665

Cited by 60 publications

(104 citation statements)

References 48 publications

(80 reference statements)

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“…Although challenges of profi ling acyl-CoAs exist, common fragmentation patterns of acyl-CoAs in LC-MS/MS were found by us and others ( 4,6,23,24 ), and these common fragmentation patterns enable broad profi ling. In this work, a novel MRM method was developed to quantitatively scan acyl-CoAs in different rat organs according to the characteristic fragmentation pattern of acyl-CoAs in MS/MS.…”

Section: Lc-ms/ms Is the Most Sensitive Methods To Analyze Acylcoas Anmentioning

confidence: 70%

Novel approach in LC-MS/MS using MRM to generate a full profile of acyl-CoAs: discovery of acyl-dephospho-CoAs

Zhang

Berthiaume

et al. 2014

Journal of Lipid Research

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This article is available online at http://www.jlr.org Acyl-CoAs are a class of important molecules that play essential roles in many physiological processes ( 1 ), such as fatty acid oxidation, lipid synthesis/remodeling, ketone body synthesis, xenobiotic metabolism, and signaling pathways. Classically, acyl-CoAs such as free CoA, acetyl-CoA, and malonyl-CoA are recognized as regulators of metabolic fl ux. The ratio of acetyl-CoA versus free CoA tightly regulates glycolysis and fatty acid oxidation. Malonyl-CoA attenuates fatty acid oxidation by inhibiting acyl-CoA transport into the mitochondrion for oxidation and is utilized in fatty acid synthesis when its concentration is elevated ( 2 ). Many proteins and genes are dynamically regulated by deacylation and acylation via various acyl-CoAs, such as acetyl-CoA, succinyl-CoA, palmitoyl-CoA, etc. ( 3 ). However, acyl-CoAs present in the cell are diverse and may involve molecules beyond fatty acids and their oxidized derivatives. The metabolism of xenobiotics can also lead to the formation of acyl-CoAs, as demonstrated in our previous work on the metabolism of 4-hydroxy acids from C 4 to C 11 in perfused rat liver. The identifi cation of these novel acyl-CoAs extends our understanding of the new catabolic pathways involved in the disposal of 4-hydroxy acids including drugs of abuse and lipid peroxidation products ( 4-8 ).Acyl-CoAs are exclusive to the intracellular metabolites, and the profi le of these biomolecules is indicative of the local metabolic status. Each organ has its specifi c physiological roles with different energetic demands, and therefore, would be expected to exhibit a unique acyl-CoA profi le. The heart preferentially utilizes fatty acids to meet the ATP demand of mechanical contraction. Glucose and/or ketone bodies serve as the primary substrate of the brain for energy

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Section: Lc-ms/ms Is the Most Sensitive Methods To Analyze Acylcoas Anmentioning

confidence: 70%

Novel approach in LC-MS/MS using MRM to generate a full profile of acyl-CoAs: discovery of acyl-dephospho-CoAs

Zhang

Berthiaume

et al. 2014

Journal of Lipid Research

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“…21,22 Plasma samples were assayed for the mass distribution of glucose as previously reported. [23][24][25] Correction of measured mass isotopomer distributions for natural enrichment was performed using the CORMAT software.…”

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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“…The concentrations and mass isotopomer distributions of acylCoA esters were assayed as in Ref. 5. The chromatographic conditions optimize the separation of short-and mediumchain acyl-CoAs.…”

Section: Methodsmentioning

confidence: 99%

“…Our interest in levulinate arose from our recent study of the metabolism of 4-hydroxyacids, which are products of lipid peroxidation (C 9 , C 6 ) or drugs of abuse (C 4 , C 5 ) (5,6). We showed that 4-hydroxyacids with 5 or more carbons are metabolized by two new pathways.…”

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confidence: 99%

Metabolism of Levulinate in Perfused Rat Livers and Live Rats

Harris¹,

Zhang²,

Sadhukhan³

et al. 2011

Journal of Biological Chemistry

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Calcium levulinate (4-ketopentanoate) is used as an oral and parenteral source of calcium. We hypothesized that levulinate is converted in the liver to 4-hydroxypentanoate, a new drug of abuse, and that this conversion is accelerated by ethanol oxidation. We confirmed these hypotheses in live rats, perfused rat livers, and liver subcellular preparations. Levulinate is reduced to (R)-4-hydroxypentanoate by a cytosolic and a mitochondrial dehydrogenase, which are NADPH-and NADH-dependent, respectively. A mitochondrial dehydrogenase or racemase system also forms (S)-4-hydroxypentanoate. In livers perfused with [ 13 C 5 ]levulinate, there was substantial CoA trapping in levulinyl-CoA, 4-hydroxypentanoyl-CoA, and 4-phosphopentanoyl-CoA. This CoA trapping was increased by ethanol, with a 6-fold increase in the concentration of 4-phosphopentanoylCoA. Levulinate is catabolized by 3 parallel pathways to propionyl-CoA, acetyl-CoA, and lactate. Most intermediates of the 3 pathways were identified by mass isotopomer analysis and metabolomics. The production of 4-hydroxypentanoate from levulinate and its stimulation by ethanol is a potential public health concern.Levulinate (4-ketopentanoate) is a food additive allowed by the Food and Drug Administration. As a calcium salt, it has been used for many years as an oral and intravenous form of calcium administration (1, 2). It is listed in the pharmacopeias of a number of countries (USA, Europe, India, China, Japan, etc). It is also listed in quality control documents of the World Health Organization. The dry salt is sold on the internet as a non-prescription dietary supplement. To the best of our review of the literature, the catabolism of levulinate has not been investigated in mammalian cells. We found one report on the identification of the reduced form of levulinate, 4-hydroxypentanoate, in the urine of children with ␤-ketothiolase deficiency treated with intravenous calcium levulinate (3). We also found an unexplained report of induction of lactic acidosis in premature babies treated with oral calcium levulinate for hypocalcemia (4).Our interest in levulinate arose from our recent study of the metabolism of 4-hydroxyacids, which are products of lipid peroxidation (C 9 , C 6 ) or drugs of abuse (C 4 , C 5 ) (5, 6). We showed that 4-hydroxyacids with 5 or more carbons are metabolized by two new pathways. The first pathway involves the isomerization of 4-hydroxyacyl-CoAs to 3-hydroxyacylCoAs via 4-phosphoacyl-CoAs, a new class of acyl-CoA esters. After isomerization, the 3-hydroxyacyl-CoAs are catabolized via classical ␤-oxidation to acetyl-CoA and, in the case of odd-chain 4-hydroxyacids, to propionyl-CoA. The second pathway involves a sequence of ␤-, ␣-, and ␤-oxidation steps leading to acetyl-CoA, formate and, in the case of even chain 4-hydroxyacids, to propionyl-CoA.The five-carbon 4-hydroxypentanoate, as a racemic mixture, is a new drug of abuse used in lieu of 4-hydroxybutyrate, which is now a controlled substance in the United States (7-11). Based on our previous work...

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

Cited by 60 publications

References 48 publications

Novel approach in LC-MS/MS using MRM to generate a full profile of acyl-CoAs: discovery of acyl-dephospho-CoAs

Novel approach in LC-MS/MS using MRM to generate a full profile of acyl-CoAs: discovery of acyl-dephospho-CoAs

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

Metabolism of Levulinate in Perfused Rat Livers and Live Rats

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