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The Influence of Excess Lysine on Urea Cycle Operation and Pyrimidine Biosynthesis^1,2,

Department of Food Science, University of Illinois, Urbana, IL 61801

Rats fed a purified L-amino acid diet with 0.72, 1.50, 2.9 or 4.3% lysine excreted 117, 124, 237 and 628 µg/day orotic acid, respectively. Dietary arginine supplementation prevented the orotic aciduria induced by excess dietary lysine. Increased orotic acid excretion was accompanied by a significant depression in urinary urea in rats fed a diet containing 4.3% lysine compared to those fed a diet containing 0.72% lysine. As measured by incorporation of [¹⁴C]HCO₃, lysine addition to liver slices or isolated hepatocytes resulted in a progressive increase in the rate of orotic acid biosynthesis. The minimum quantity of lysine tested that significantly increased the rate of orotic acid biosynthesis was 0.5 mM or 1 mM for studies with slices and hepatocytes, respectively. Ammonia at concentrations of 0, 0.75, or 5.0 mM NH₄Cl linearly increased orotate and urea synthesis. Inhibition of urea biosynthesis resulting from lysine supplementation coincided with an increase in pyrimidine biosynthesis. Addition of 1 mM arginine to the liver incubation media prevented the increased rate of orotic acid biosynthesis caused by lysine. Arginine addition may overcome an approximate 90% competitive inhibition of arginase by excess lysine.

KEY WORDS: • lysine • orotic aciduria • urea • arginine

¹ Supported in part by Public Health Service 2 RO1 AM19294.

² Presented in part at the annual meeting of the Federation of American Societies for Experimental Biology, Atlanta, CA; Fed. Proc. 40, 849 (abs.).

³ Abdelmonem S. Hassan, P.O. Box 1158, Khartoum, Sudan.

Manuscript received 5 February 1982.