Substrate competition in the respiration of animal tissues. The metabolic interactions of pyruvate and α-oxoglutarate in rat-liver homogenates

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Abstract
The addition of pyruvate or of [alpha]-oxoglutarate in-creased the rate of respiration of rat-liver homogenates by about 20-30% but the O2 uptake in the presence of both substrates was not additive. The addition of a-oxoglutarate decreased the removal of pyruvate by 50-65%, and the addition of pyruvate decreased that of a-oxoglutarate by 12-35%. Experiments with [l-Cl4]-pyruvate showed that pyruvate was metabolized by 3 main reactions: 50-75% of the pyruvate removed was oxidized to acetyl- CoA, which was partly con-verted into ketone bodies and partly entered the tricarboxylic acid cycle; 15-40% was carboxylated to dicarboxylic acids; 10-15% was converted into alanine. The proportion of (b) was increased within the above range by the addition of 7.75 m[image]-bicarbonate, and this was associated with a decreased accumulation of ketone bodies. While pyruvate remained in the homogenate little was completely oxidized and the main products of pyruvate metabolism were intermediates of the tricarboxylic acid cycle, ketone bodies and alanine. The addition of a-oxoglutarate inhibited all 3 primary reactions of pyruvate although to different degrees: 10 m[image]-[alpha]-oxoglutarate inhibited the oxidative decarboxylation of 10 m[image]-pyruvate by 50-65%, the carboxylation by about 80% and alanine formation by about 20%. When a-oxoglutarate was the sole added substrate, 55-90% of the a-oxoglutarate removed underwent decarboxylation, followed by a further oxidation of the suc-cinate formed, and 10-20% was.converted into glutamate plus glutamine. Apart from CO2, malate, fumarate, glutamate and glutamine were the main end products. The existence of other minor pathways was demonstrated by experiments with [alpha]-oxo[l-Cl4]glutarate, which formed 2 radioactive products tentatively identified as a-hydroxyglutarate and citrate. The inhibition of the removal of [alpha]-oxoglutarate by pyruvate was due to 3 factors. About 25-50% of the effect resulted from a decreased yield of glutamate owing to transamination of glutamate with pyruvate. The second factor was the roughly 10% inhibition by pyruvate of the decarboxylation of a-oxoglutarate, which accounted for not more than 25% of the effect of pyruvate on the removal of a-oxoglutarate. The third factor accounting for the remainder of the effect was the conversion of pyruvate into a-oxoglutarate. Phyruvate (10 m[image]) suppressed the oxidation of endogenous substrates by roughly 50%.