Paper
Cyclical C7‐CoA esters derived from calcium levulinate, a pro‐drug of abuse
Published Apr 1, 2012 · DOI · Stephanie R. Harris, Guo-fang Zhang, Sushabhan Sadhukhan
The FASEB Journal
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Abstract
Calcium levulinate (4‐ketopentanoate, LEV) is a dietary calcium supplement. We previously showed that (i) LEV is reduced in liver to γ‐hydroxypentanoate (GHP), a drug of abuse, analog of γ‐hydroxybutyrate, (ii) the reduction of LEV to GHP is enhanced by ethanol oxidation, and (iii) the metabolism of LEV and GHP result in substantial accumulation of LEV‐derived C5‐acyl‐CoAs in liver and brain, leading to CoA trapping. We also identified new C7‐CoA esters in rat livers perfused with LEV and in liver and brain of rats gavaged with Ca‐LEV. The C7‐CoA esters derive from the elongation of LEV‐CoA by acetyl‐CoA to 3,6‐diketoheptanoyl‐CoA, a γ‐diketo compound. The latter is converted to two cyclical CoA esters (one with a cyclopentane ring, and one with a pyrrole ring). We traced the origin of the C7‐CoA esters with labeled substrates. Both cyclical C7‐CoAs include five 13C from [13C5]LEV and two 13C from [13C2]acetyl‐CoA (derived from LEV or other [13C]substrates). The pyrrolic C7‐CoA ester contains one N derived from the N on C‐6 of [6‐15N]lysine. The C7‐CoA esters were identified in rat livers and hearts perfused with 6‐ketoheptanoate, the beta‐oxidation of which passes by 3,6‐diketoheptanoyl‐CoA. The formation of cyclical C7‐CoA esters may contribute to the toxicity of LEV by binding to the ε‐N of lysine residues of proteins in liver, heart or brain. Supported by NIDDK RoadMap + training grant, and by NIEHS.
Cyclical C7-CoA esters, formed from calcium levulinate, may contribute to the toxicity of LEV by binding to lysine residues in liver, heart, or brain.
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