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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Harris, SR; Zhang, G-F; Sadhukhan, S; Wang, H; Shi, C; Puchowicz, MA; Anderson, VE; Salomon, RG; Tochtrop, GP; Brunengraber, H

Published Date

  • February 18, 2013

Published In

Volume / Issue

  • 26 / 2

Start / End Page

  • 213 - 220

PubMed ID

  • 23171137

Pubmed Central ID

  • PMC3997259

Electronic International Standard Serial Number (EISSN)

  • 1520-5010

Digital Object Identifier (DOI)

  • 10.1021/tx3003643


  • eng

Conference Location

  • United States