Carbamoyl phosphate excess

Excess carbamoyl phosphate exits to the cytosol, where it stimulates pyrimidine nucleotide biosynthesis. The resulting mild orotic aciduria is increased by high-nitrogen foods. 

Since pyrimidine catabolites are water-soluble, their overproduction does not result in clinical abnormalities. Excretion of pyrimidine precursors can, however, result from a deficiency of ornithine transcar-bamoylase because excess carbamoyl phosphate is available for pyrimidine biosynthesis. 

Carbamoyl phosphate synthesis requires amino acid acetyltransferase (N-acetylglutamate synthase, mitochondrial) and carbamoyl-phosphate synthase I (CPSI). N-Acetylglutamate (NAG) is an obligatory positive effector of CPSI. NAG synthase is under positive allosteric modulation by arginine and product inhibition by NAG. Depletion of CoA-SH decreases NAG synthesis and ureage-nesis. This situation can occur in organic acidemias (e.g., propionic acidemia Chapter 18), in which organic acids produced in excess compete for CoA-SH for formation... 

The answer is e. (Murray, pp 30/-346. Sciivei, pp 1909-1964. Sack, pp 121—138. Wilson, pp 287-317.) In the liver, the urea cycle converts excess NH/ to a form amenable to excretion by the kidneys. Free NH/ condenses with CO2 to form carbamoyl phosphate in a reaction catalyzed by carbamoyl phosphate synthetase. This is an energy-expensive, essentially irreversible... 

The activity of ornithine transcarbamoylase, the next enzyme in the urea cycle, appears to be extremely high. In the case of excess ammonia, almost all of the ornithine present in the liver is converted to citrulline, indicating a sufficient activity of carbamoyl phosphate... 

When ornithine transcarbamoylase (OTC) is deficient, the carbamoyl phosphate that normally would enter the urea cycle accumulates and floods the pathway for pyrimidine biosynthesis. Under these conditions, excess orotic acid (orotate), an intermediate in pyrimidine biosynthesis, is excreted in the urine. It produces no ill effects but is indicative of a problem in the urea cycle. 

When ornithine transcarbamoylase is deficient (urea cycle disorder), excess carbamoyl phosphate from the mitochondria leaks into the cytoplasm. The elevated levels of cytoplasmic carbamoyl phosphate lead to pyrimidine production, as the regulated step of the pathway, the reaction catalyzed by carbamoyl synthetase II, is being bypassed. Thus, orotic aciduria results. 

If rats are injected with a mixture of amino acids, there is a rapid increase in the liver content of glutamate. This is followed by an increase in acetylglutamate, a consequent increase in carbamoyl phosphate synthase activity and an increase in urea production. If excess amino acids are injected, the liver carbamoyl phosphate synthase becomes saturated with acetylglutamate and ammonia appears in the circulation. Thus regulation of carbamoyl phosphate synthase by N-acetylglutamate appears to be an important factor in the control of nitrogen disposal by the liver. 

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