Question

Why does it make metabolic sense for UTP to inhibit carbamoyl phosphate synthetase II, whereas ATP activates the enzyme?

Answer 1

N-acetylglutamate, which stimulates the mitochondrial form of carbamoyl phosphate synthetase (urea cycle), is not an allosteric activator of the cytoplasmic form (pyrimidine synthesis).

Carbamoyl Phosphate Formation

Mitochondrial carbamoyl phosphate formation, the first and also rate-limiting reaction in the urea cycle, is catalyzed by carbamoyl phosphate synthetase-1 (CPS-1). A CPS-2 exists in the cytoplasm; however, it uses a different nitrogen source, and participates in pyrimidine nucleotide rather than urea biosynthesis (see Chapter 14). N-Acetylglutamate, whose steady-state level is determined by the rates of its synthesis from acetyl-CoA and Glu, is a cofactor required as an allosteric activator of CPS-1. Under the influence of CPS-1, HCO₃⁻, NH₄⁺, 2ATP and H₂O are condensed in the formation of carbamoyl phosphate, 2ADP, and an inorganic phosphate (Pi).

In prokaryotic cells aspartate transcarbamoylase, an allosteric protein, is inhibited by the end product CTP and activated by ATP. In mammals, carbamoyl phosphate synthetase II (CPS II) activity of the trimeric multifunctional protein (Pyr 1–3) is the primary regulatory site. CPS II allosteric ligand UTP inhibits, whereas PRPP and ATP activate, the enzyme activity. Activation by ATP may be important in achieving a balanced synthesis of purine and pyrimidine nucleotides. During rapid proliferation of cells, either as a normal physiological process or in pathological processes (e.g., tumor growth), there is an increased demand for nucleotides required for nucleic acid synthesis. In those periods of cellular growth, CPS II activity is altered by phosphorylation at its regulatory site, leading to relief of UTP inhibition and enhancement in the stimulation of PRPP activation. The phosphorylation is mediated by mitogen-activated protein (MAP) kinase. The MAP kinase cascade is activated in response to growth factors (e.g., epidermal growth factor). PRPP is also an essential (and probably a rate-limiting) substrate for the orotate phosphoribosyltransferase reaction (reaction 5 in Figure 25.16) promoting de novo pyrimidine nucleotide synthesis by induction of Pyr 1–3. Another potential site of regulation is orotidine-5-phosphate decarboxylase, which is inhibited by UMP, CMP, allopurinol nucleotide, and oxypurinol.

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Amino Acid and Heme Metabolism

Carbamoyl phosphate synthetase I (CPS I): Ammonium ions are joined with carbon dioxide and adenosine triphosphate to produce carbamoyl phosphate