Control of the Formation of Uridine Diphospho-N-acetyl-hexosamine and Glycoprotein Synthesis in Rat Liver

Rats fed a purified diet containing 1% orotic acid for 2 days accumulate large amounts of uridine diphospho-N-acetylhexosamine in the liver. This accumulation is not the result of a block in utilization of uridine diphospho-N-acetylhexosamine, but probably results from increased synthesis de novo. These rats appear to suffer from a defect in the feedback control of l-glutamine-d-fructose 6-phosphate amidotransferase by uridine diphospho-N-acetylglucosamine. The injection of glucosamine into control animals greatly reduces the synthesis de novo of glucosamine as measured by the incorporation of fructose into the glucosamine of uridine diphospho-N-acetylglucosamine. Duazomycin A, a glutamine analogue, completely prevents the synthesis de novo of glucosamine derivatives in the liver by inhibiting the amidotransferase, and reduces liver uridine diphospho-N-acetylhexosamine levels by 85% in 4 hours. Duazomycin A does not significantly reduce either the conversion of glucosamine to uridine diphospho-N-acetylhexosamine or the utilization of available uridine diphospho-N-acetylhexosamine for glycoprotein synthesis. Duazomycin A does inhibit glycoprotein synthesis indirectly, however, by reducing the level of uridine diphospho-N-acetylhexosamine in the liver. This reduction can be prevented by the infusion of glucosamine.