Bruce Lippert

Biochemical consequences of reactions catalyzed by GAD and GABA-T

Abstract GABA-T abstracts the pro-4-S proton from GABA. The enzyme abstracts the analogous protons from (+)-γ-acetylenic GABA and (+)-γ-vinyl GABA in each case precipitating its own inactivation. (+)-γ-Acetylenic GABA also irreversibly inhibits GAD indicating a transamination capability of the decarboxylase on this synthetic GABA analogue. γ-Vinyl GABA has no effect on this enzyme in vitro . Administration of either γ-acetylenic or γ-vinyl GABA to rats or mice results in a dose-dependent increase in brain GABA levels. At any given level of GABA-T inhibition the concentrations of GABA are higher after γ-vinyl GABA due to its smaller effect on GAD. Nevertheless, after a dose of γ-vinyl GABA sufficient to raise brain GABA levels to over 300% of control levels for 48 hours, there is a slow decrease in brain GAD activity to 75% and 65% of control levels at 24 and 48 hours respectively. This diminution of GAD activity after administration of γ-vinyl GABA is consistent with a feedback effect of sustained elevated GABA levels on the synthesis of GAD.

Enzyme-activated irreversible inhibition of rat and mouse brain 4-aminobutyric acid-α-ketoglutarate transaminase by 5-fluoro-4-oxo-pentanoic acid

Abstract γ-Aminobutyric acid-α-ketoglutarate aminotransferase from rat and mouse brain was irreversibly inhibited by 5-fluoro-4-oxo-pentanoic acid, an analogue of succinic semi-aldehyde. The inhibition was concentration and temperature-dependent, and was initiated solely with the pyridoxamine form of the enzyme. All of the results to date are consistent with a catalytic mechanism for the inhibition. Intraperitoneal administration of 5-fluoro-4-oxo-pentanoic acid to rats or mice produced a dose-dependent, irreversible inhibition of brain γ-aminobutyric acid-α-ketoglutarate aminotransferase and elevation of brain GABA levels. No inhibition of glutamate decarboxylase, aspartate aminotransferase or alanine aminotransferase was observed.

α-Trifluoromethylhistamine: A mechanism-based inhibitor of mammalian histidine decarboxylase

Abstract α-Trifluoromethylhistamine (1), proposed as a suicide inhibitor of histidine decarboxylase, has been prepared from β-trifluoromethyl-β-alanine. Histidine decarboxylase from hamster placenta is inhibited in a time-dependent manner by 1; however, the adduct formed between inhibitor and enzyme is labile. 1 inhibits stomach histidine decarboxylase activity in vivo in rats, but has no antisecretory effect in the pyloric-ligated stomach of the mouse.