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Metabolomics and mass isotopomer analysis as a strategy for pathway discovery: pyrrolyl and cyclopentenyl derivatives of the pro-drug of abuse, levulinate.

Publication ,  Journal Article
Harris, SR; Zhang, G-F; Sadhukhan, S; Wang, H; Shi, C; Puchowicz, MA; Anderson, VE; Salomon, RG; Tochtrop, GP; Brunengraber, H
Published in: Chem Res Toxicol
February 18, 2013

We recently reported that levulinate (4-ketopentanoate) is converted in the liver to 4-hydroxypentanoate, a drug of abuse, and that the formation of 4-hydroxypentanoate is stimulated by ethanol oxidation. We also identified 3 parallel β-oxidation pathways by which levulinate and 4-hydroxypentanoate are catabolized to propionyl-CoA and acetyl-CoA. We now report that levulinate forms three seven-carbon cyclical CoA esters by processes starting with the elongation of levulinyl-CoA by acetyl-CoA to 3,6-diketoheptanoyl-CoA. The latter γ-diketo CoA ester undergoes two parallel cyclization processes. One process yields a mixture of tautomers, i.e., cyclopentenyl- and cyclopentadienyl-acyl-CoAs. The second cyclization process yields a methyl-pyrrolyl-acetyl-CoA containing a nitrogen atom derived from the ε-nitrogen of lysine but without carbons from lysine. The cyclic CoA esters were identified in rat livers perfused with levulinate and in livers and brains from rats gavaged with calcium levulinate ± ethanol. Lastly, 3,6-diketoheptanoyl-CoA, like 2,5-diketohexane, pyrrolates free lysine and, presumably, lysine residues from proteins. This may represent a new pathway for protein pyrrolation. The cyclic CoA esters and related pyrrolation processes may play a role in the toxic effects of 4-hydroxypentanoate.

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Published In

Chem Res Toxicol

DOI

EISSN

1520-5010

Publication Date

February 18, 2013

Volume

26

Issue

2

Start / End Page

213 / 220

Location

United States

Related Subject Headings

  • Toxicology
  • Rats, Sprague-Dawley
  • Rats
  • Prodrugs
  • Metabolomics
  • Male
  • Liver
  • Levulinic Acids
  • Enzyme Inhibitors
  • Cyclization
 

Citation

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Harris, S. R., Zhang, G.-F., Sadhukhan, S., Wang, H., Shi, C., Puchowicz, M. A., … Brunengraber, H. (2013). Metabolomics and mass isotopomer analysis as a strategy for pathway discovery: pyrrolyl and cyclopentenyl derivatives of the pro-drug of abuse, levulinate. Chem Res Toxicol, 26(2), 213–220. https://doi.org/10.1021/tx3003643
Harris, Stephanie R., Guo-Fang Zhang, Sushabhan Sadhukhan, Hua Wang, Chuan Shi, Michelle A. Puchowicz, Vernon E. Anderson, Robert G. Salomon, Gregory P. Tochtrop, and Henri Brunengraber. “Metabolomics and mass isotopomer analysis as a strategy for pathway discovery: pyrrolyl and cyclopentenyl derivatives of the pro-drug of abuse, levulinate.Chem Res Toxicol 26, no. 2 (February 18, 2013): 213–20. https://doi.org/10.1021/tx3003643.
Harris SR, Zhang G-F, Sadhukhan S, Wang H, Shi C, Puchowicz MA, et al. Metabolomics and mass isotopomer analysis as a strategy for pathway discovery: pyrrolyl and cyclopentenyl derivatives of the pro-drug of abuse, levulinate. Chem Res Toxicol. 2013 Feb 18;26(2):213–20.
Harris, Stephanie R., et al. “Metabolomics and mass isotopomer analysis as a strategy for pathway discovery: pyrrolyl and cyclopentenyl derivatives of the pro-drug of abuse, levulinate.Chem Res Toxicol, vol. 26, no. 2, Feb. 2013, pp. 213–20. Pubmed, doi:10.1021/tx3003643.
Harris SR, Zhang G-F, Sadhukhan S, Wang H, Shi C, Puchowicz MA, Anderson VE, Salomon RG, Tochtrop GP, Brunengraber H. Metabolomics and mass isotopomer analysis as a strategy for pathway discovery: pyrrolyl and cyclopentenyl derivatives of the pro-drug of abuse, levulinate. Chem Res Toxicol. 2013 Feb 18;26(2):213–220.
Journal cover image

Published In

Chem Res Toxicol

DOI

EISSN

1520-5010

Publication Date

February 18, 2013

Volume

26

Issue

2

Start / End Page

213 / 220

Location

United States

Related Subject Headings

  • Toxicology
  • Rats, Sprague-Dawley
  • Rats
  • Prodrugs
  • Metabolomics
  • Male
  • Liver
  • Levulinic Acids
  • Enzyme Inhibitors
  • Cyclization