Effect of alpha-ketoisocaproate and leucine on the in vivo oxidation of glutamate and glutamine in the rat brain.
Leucine and alpha-ketoisocaproate (alpha-KIC) were perfused at increasing concentrations into rat brain hippocampus by microdialysis to mimic the conditions of maple syrup urine disease. The effects of elevated leucine or alpha-KIC on the oxidation of L-[U-14C]glutamate and L-[U-14C]glutamine in the brain were determined in the non-anesthetized rat. 14CO2 generated by the metabolic oxidation of [14C]glutamate and [14C]glutamine in brain was measured following its diffusion into the eluant during the microdialysis. Leucine and alpha-KIC exhibited differential effects on 14CO2 generation from radioactive glutamate on glutamine. Infusion of 0.5 mM alpha-KIC increased [14C]glutamate oxidation approximately 2-fold; higher concentrations of alpha-KIC did not further stimulate [14C]glutamate oxidation. The enhanced oxidation of [14C]glutamate may be attributed to the function of alpha-KIC as a nitrogen acceptor from [14C]glutamate yielding [14C]alpha-ketoglutarate, an intermediate of the tricarboxylic acid cycle. [14C]glutamine oxidation was not stimulated as much as [14C]glutamate oxidation and only increased at 10 mM alpha-KIC reflecting the extra metabolic step required for its oxidative metabolism. In contrast, leucine had no effect on the oxidation of either [14C]glutamate or [14C]glutamine. In maple syrup urine disease elevated alpha-KIC may play a significant role in altered energy metabolism in brain while leucine may contribute to clinical manifestations of this disease in other ways.
Zielke
H R
HR
Department of Pediatrics, University of Maryland at Baltimore 21201-1559, USA. rzielke@umabnet.ab.umd.edu
Huang
Y
Y
Baab
P J
PJ
Collins
R M
RM
Zielke
C L
CL
Tildon
J T
JT
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002208:Caproates; D018698:Glutamic Acid / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D007651:Keto Acids / Q000494:pharmacology*; D007930:Leucine / Q000494:pharmacology*; D008297:Male; D008375:Maple Syrup Urine Disease / Q000378:metabolism; D017551:Microdialysis; D010084:Oxidation-Reduction; D051381:Rats
D002208:Caproates; D007651:Keto Acids; D005973:Glutamine; D018698:Glutamic Acid; C013082:alpha-ketoisocaproic acid; D007930:Leucine