GHB (γ-hydroxybutyrate) is both a neurotransmitter and a drug of abuse (date-rape drug). We investigated the catabolism of this compound in perfused rat livers. Using a combination of metabolomics and mass isotopomer analysis, we showed that GHB is metabolized by multiple processes, in addition to its previously reported metabolism in the citric acid cycle via oxidation to succinate. A substrate cycle operates between GHB and γ-aminobutyrate via succinic semialdehyde. Also, GHB undergoes (i) β-oxidation to glycolyl-CoA+acetyl-CoA, (ii) two parallel processes which remove C-1 or C-4 of GHB and form 3-hydroxypropionate from C-2+C-3+C-4 or from C-1+C-2+C-3 of GHB, and (iii) degradation to acetyl-CoA via 4-phosphobutyryl-CoA. The present study illustrates the potential of the combination of metabolomics and mass isotopomer analysis for pathway discovery.
The syntheses, X-ray structures of three novel low-dimensional assemblies, the molecules [Cu 2 (dmpzpo) 2 ][Ag(CN) 2 ] 2 (1),The temperature-dependent susceptibility of 2 · 2CH 3 OH and 2 · DMF · 3H 2 O is determined. The structure of compound 1 consists of one dicopper(II) moiety and two Ag(CN) 2 Ϫ units, each being coordinated to different copper atoms of the dicopper(II) moiety with trans arrangement. Compound 1 has an inversion center located the middle of the Cu 2 O 2 plane. The structures of
The goal of the study was to investigate the metabolism of levulinate (4‐ketopentanoate, LEV) which as a calcium salt, is used as an oral or intravenous source of calcium. We hypothesized that (i) levulinate is converted to gamma‐hydroxypentanoate (GHP), a new drug of abuse, analog of gamma‐hydroxybutyrate, and (ii) the formation of GHP from LEV is enhanced by ethanol. We investigated the metabolism of LEV and GHP in perfused rat livers and live rats. In both models, LEV was converted to GHP, and GHP was converted to LEV. This interconversion involves a cytosolic NADP‐dehydrogenase. Ethanol decreases the uptake of LEV and increases the formation of GHP from LEV, without affecting the [GHP]/[LEV] ratio. Thus, ethanol appears to inhibit both LEV and GHP catabolism, presumably at the level of 3‐hydroxyacyl‐CoA dehydrogenase. In livers perfused with LEV there was substantial accumulation of LEV‐CoA, GHP‐CoA and 4‐phospho‐GHP‐CoA. In parallel, the concentrations of acetyl‐CoA, malonyl‐CoA, HMG‐CoA methylmalonyl‐CoA and succinyl‐CoA markedly decreased. Thus, the metabolism of LEV and GHP result in substantial CoA trapping which can affect a number of processes. The conversion of LEV to GHP, a drug of abuse, and the stimulation of GHP formation by ethanol is a public health concern since calcium‐LEV is freely available. Supported by NIDDK RoadMap and by NIEHS.
Enolization of acetyl‐CoA on CS had been identified in Eggerer¡s experiments with [3H]acetyl‐CoA (Biochem. Z. 343: 111, 1965). To test whether CS catalyzes sequential cycles of acetyl‐CoA enolization, we incubated [2H3, 13C2]acetyl‐CoA with pig heart CS + oxaloacetate (OAA) (added as either a bolus, a bolus of OAA/malate, or malate + NAD + malate dehydrogenase). We measured the mass isotopomer distribution (MID) of acetyl‐CoA and citrate. The productions of M4 + M3 + M2 acetyl‐CoA, and of M4 + M3 + M2 citrate revealed up to 3 cycles of acetyl‐CoA enolization. This was confirmed when condensation of unlabeled acetyl‐CoA + OAA was conducted in 50% D2O. Acetyl‐CoA was up to M3 labeled and citrate was M1 labeled. Thus, up to 3 cycles of acetyl‐CoA enolization were catalyzed by CS.We hypothesized that ACL could also catalyze enolization of acetyl‐CoA. We incubated [2,2,4,4‐2H4]citrate + Mg++, CoA, ATP and rat liver ACL. The production of M2 + M1 + M acetyl‐ CoA, and the progressive de‐labeling of acetyl‐CoA demonstrated multiple cycles of enolization of acetyl‐CoA on ACL. This was confirmed when cleavage of unlabeled citrate was conducted in 50% D2O, by the accumulation of M1 + M2 + M3 acetyl‐CoA. Thus, multiple cycles of acetyl‐CoA enolization were catalyzed by ACL.(Supported by the NIDDK Metabolomic Initiative grant R33DK070291).
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