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Studies on the metabolic pathway of the acetyl group for acetylcholine synthesis

1980; Elsevier BV; Volume: 29; Issue: 2 Linguagem: Inglês

10.1016/0006-2952(80)90325-1

1873-2968

Gary E. Gibson, Masahisa Shimada,

Mitochondrial Function and Pathology

Glucose and pyruvate are the most effective precursors of the acetyl moiety of acetylcholine in mammalian brain; the metabolic intermediates between pyruvate and acetylcholine, however, are unknown. The following data suggest that citrate is not the sole intermediate of the acetyl group for acetylcholine synthesis in rat brain slices or synaptosomes: (1) 2.5 mM (−)-hydroxycitrate decreased acetylcholine synthesis from [U-14C]glucose by only 25 per cent; (2) inhibition of citrate transport out of mitochondria by n-butylmalonate or 1,2,3-benzenetricarboxylate variably affected acetylcholine synthesis; and (3) high concentrations of nonradioactive citrate decreased the synthesis of acetylcholine but did not decrease the specific activity of the acetylcholine synthesized from [U-14C]glucose. even though the uptake of citrate into the synaptosomes under these experimental conditions was approximately five times greater than the uptake of glucose. Other possible acetyl donors altered acetylcholine synthesis. Acetylcarnitine stimulated synthesis in brain slices, and carnitine stimulated synthesis by synaptosomes.The specificactivity of the acetylcholine synthesized from [U-14Cglucose by synaptosomes was decreased by N-acetyl-l-aspartate (10mM), acetyl CoA (1 mM), and acetyl phosphate (10mM) which is consistent with these compounds acting as direct acetyl donors. Acetate (10 mM) did not affect either the amount or specific activity of the acetylcholine synthesized. Further evidence of compartmentation of cytoplasmic acetyl CoA is presented. The cytoplasmic acetyl CoA for acetylcholine synthesis is distinguishable from the cytoplasmic acetyl CoA for lipid synthesis. (−)-Hydroxycitrate inhibited acetylcholine synthesis without inhibiting lipid synthesis from [U-14C]glucose. However, when 3-hydroxy[3-14C]butyrate was used as substrate, (−)-hydroxycitrate inhibited incorporation into lipids twice as much as incorporation into acetylcholine. [U-14C]Glucose metabolism by infant brain slices was more sensitive than adult brain slices to (−)-hydroxycitrate. However, the response to the other compounds which interfere with citrate metabolism was similar in slices from adult and infant brains.