Inhibition of Arginine-glycine Amidinotransferase by Ornithine. A Possible Mechanism for the Muscular and Chorioretinal Atrophies in Gyrate Atrophy of the Choroid and Retina with Hyperornithinemia

The inhibitory effect of ornithine on L-arginine:glycine amidinotransferase (EC 2.1.4.1) was studied in crude rat kidney homogenates. The enzyme activity was linear with time up to 45 min and with protein up to 200 microgram. The apparent Km and V of amidinotransferase were 9.21 mM and 1.53 mu mol/g protein per min, respectively. The enzyme was competitively inhibited by ornithine, with a Ki of 0.253 mM. Kidney arginase was inhibited only slightly and non-competitively. The inhibition of amidinotransferase by ornithine may thus be important in creatine biosynthesis. In gyrate atrophy of the choroid and retina with hyperornithinemia, a human autosomal recessive disease caused by decreased ornithine aminotransferase activity, plasma ornithine concentrations are elevated 10-20-fold (0.65-1.35 mM during fasting). In consequence endogenous creatine production probably is severely decreased because of inhibition of the rate-limiting transamidination step by ornithine. The deficiency of creatine and further of readily available energy in the form of phosphocreatine is suggested to be involved in the pathogenesis of the choroidal, retinal and type II muscle fiver atrophies in gyrate atrophy.