Inhibition of bovine liver lysine-ketoglutarate reductase by urea cycle metabolites and saccharopine.

Lysine-ketoglutarate reductase was purified 675-fold from bovine liver mitochondria. Product inhibition studies gave results similar to those reported for this enzyme extracted from other sources. Inhibition studies with L-citrulline exhibited mixed inhibition patterns. No inhibition of the partially-purified enzyme by ammonium salts was detected; in contrast, marked inhibition of the enzyme by ammonium was apparently observed in crude liver homogenates. This was probably due to depletion of NADPH and/or 2-oxoglutarate in the assay mixture as a result of conversion of ammonium to glutamate by glutamate dehydrogenase. A similar explanation could account for the high levels of lysine observed in humans with urea cycle disorders.