Purine nucleotides stimulate while carbamoyl phosphate protects inactivation of ornithine transcarbamoylase by disrupted lysosomes

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Abstract
Ornithine transcarbamoylase (OTC) is inactivated by liver lysosomes. Carbamoyl phosphate prevents the inactivation of OTC by lysosomes, while ATP, ADP, GTP, GDP 1,N6-ethenoadenosine 5′-triphosphate and particularly ɛ-ATP stimulate it. Both stimulation and protection occur at concentrations within the physiological range of ATP and carbamoyl phosphate. Inactivation of OTC is followed by extensive proteolysis. Since the inactivation is prevented by leupeptin, antipain and L-(tosylamido-2-phenyl)ethylchloromethyl ketone, the proteolytic susceptibility of OTC to lysosomes could be due to thiol endopeptidase(s). 1,N6-Ethenoadenosine 5′-triphosphate also markedly increases OTC susceptibility to trypsin and elastase. ATP analogs had no stimulatory effect on OTC inactivation by lysosomes; none of the inhibitors of ATPases tested inhibited the ATP effect. The ATP stimulation does not require Mg2+. These findings indicate a new role for ATP, GTP and related nucleotides in protein breakdown. The ATP, ADP, GTP, GDP stimulation, together with the carbamoyl protection of OTC, agree well with the molecular plasticity hypothesis model.