Inhibition of Glutamate Dehydrogenase in Brain Mitochondria and Synaptosomes by Mg2+ and Polyamines: A Possible Cause for Its Low In Vivo Activity

Abstract: Magnesium and the polyamines putrescine, spermidine, and spermine inhibited the activity of glutamate dehydrogenase in permeabilized rat brain mitochondria in a concentration-dependent manner. The inhibitory effect was observed on both the reductive amination of 2-oxoglutarate and oxidative deamination of glutamate, as well as in the presence and absence of ADP and leucine, the allosteric activators of the enzyme. Kinetic studies at various concentrations of substrates showed that inhibition by magnesium and spermine was very pronounced at 2-oxoglutarate concentrations less than 0.5 m M and NADH levels less than 0.08 m M . The presence of the former compounds also accentuated the inhibitory effect of high concentrations of 2-oxoglutarate (>2.0 m M ) and NADH (>0.32 m M ). Addition of magnesium and spermine to suspensions of synaptosomes decreased the amount of ammonia produced from glutamate. It is suggested that polyamines and magnesium, normal constituents of mammalian brain, are responsible, at least in part, for the low glutamate dehydrogenase activity in vivo.