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Santos SS, Gibson GE, Cooper AJ, Denton TT, Thompson CM, Bunik VI, Alves PM, Sonnewald U: Inhibitors of the alpha-ketoglutarate dehydrogenase complex alter [1-13C] glucose and [U-13C] glutamate metabolism in cerebellar granule neurons. J Neurosci Res. 2006 Feb 15;83(3):450-8.
Diminished activity of the alpha-ketoglutarate dehydrogenase complex (KGDHC), an important component of the tricarboxylic acid (TCA) cycle, occurs in several neurological diseases. The effect of specific KGDHC inhibitors [phosphonoethyl ester of succinyl phosphonate (PESP) and the carboxy ethyl ester of succinyl phosphonate (CESP)] on [1-13C] glucose and [U-13C] glutamate metabolism in intact cerebellar granule neurons was investigated. Both inhibitors decreased formation of [4-13C] glutamate from [1-13C] glucose, a reduction in label in glutamate derived from [1-13C] glucose/[U-13C] glutamate through a second turn of the TCA cycle and a decline in the amounts of gamma-aminobutyric acid (GABA), aspartate, and alanine. PESP decreased formation of [U-13C] aspartate and total glutathione, whereas CESP decreased concentrations of valine and leucine. The findings are consistent with decreased KGDHC activity; increased alpha-ketoglutarate formation; increased transamination of alpha-ketoglutarate with valine, leucine, and GABA; and new equilibrium position of the aspartate aminotransferase reaction. Overall, the findings also suggest that some carbon derived from alpha-ketoglutarate may bypass the block in the TCA cycle at KGDHC by means of the GABA shunt and/or conversion of valine to succinate. The results suggest the potential of succinyl phosphonate esters for modeling the biochemical and pathophysiological consequences of reduced KGDHC activity in brain diseases. |
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