Carbamoyl phosphate CPS

Figure 8.19. Sequence reactions from aspartic acid (AA) and carbamoyl phosphate (CP) to the end product, cytidine triphosphate (CTP). The first reaction is catalyzed by ATCase. The intermediary compounds are N-carbamoyl aspartic acid (N-CAA), L-dihydroorotic acid (L-DHOA), orotic acid (OA), orotidine 5 -phosphate (0-5 -P), uridine 5 -phosphate (U-5 -P), uridine diphosphate (UDP), and uridine triphosphate (UTP).

Carbamoyl Phosphate CPS-1 deificiency CPS1 2q35 Liver Citrulline i ... 

Carbamoyl phosphate (CP) serves as a substrate for two separate transcarbamylase enzymes. One of these, in a reaction with aspartic acid, yields carbamoyl aspartate, the first specific precursor in the UMP pathway the other, in a similar reaction with ornithine, has a similar role for the eventual synthesis of arginine. Thus, CP serves as a common precursor for both UMP and arginine, and special regulation of its formation must be obtained to assure a balanced supply of both end products. The problem is handled in a variety of ways by different organisms. 

The enzyme carbamoyl phosphate synthase (CPS) is a control point in the process. Stage 3. The urea cycle (Figure 6.7)... 

The carbamoyl phosphate synthetase (abbreviated to CPS-I) that is involved in the ornithine cycle differs from the enzyme that is involved in pyrimidine synthesis (carbamoyl phosphate synthetase-ll). The latter enzyme is cytosolic, requires glutamine for provision of nitrogen, rather than ammonia, and is regulated by different factors (Chapter 20). 

CPS-I carbamoyl phosphate synthetase IRS insulin-receptor substrate... 

PRPP H Orotate derived from glutamine. CPS-II, carbamoyl phosphate synthetase Asp,... 

Table 2.1.9 Changes of blood amino acids in various primary inherited defects and as a result of secondary changes. ASA Argininosuccinic acid, CPS carbamoyl phosphate synthase, LPI Lysinuric protein intolerance, MAD multiple acyl-CoA dehydrogenation, MSUD maple syrup urine disease, NAGS N-acetylglutamate synthase, NKH nonketotic hyperglycinemia, NTBC 2-(2-nitro-4-3 trifluoro-methylbenzoyl)-1,3-cyclohexanedione, OCT Ornithine carbamoyltransferase,...

The regulated step of this pathway in mammalian cells is the synthesis of carbamoyl phosphate from glutamine and C02, catalyzed by carbamoyl phosphate synthetase II (CPS U). CPS II is inhibited... 

Summary of the differences between carbamoyl phosphate synthetase (CPS) I and II. 

The first step in de novo pyrimidine biosynthesis is the synthesis of carbamoyl phosphate from bicarbonate and ammonia in a multistep process, requiring the cleavage of two molecules of ATP. This reaction is catalyzed by carbamoyl phosphate synthetase (CPS) (Section 23.4.1). Analysis of the structure of CPS reveals two homologous domains, each of which catalyzes an ATP-dependent step (Figure 25.3). 

The active site for this reaction lies in a domain formed by the aminoterminal third of CPS. This domain forms a structure, called an ATP-grasp fold, that surrounds ATP and holds it in an orientation suitable for nucleophilic attack at the Y phosphoryl group. Proteins containing ATP-grasp folds catalyze the formation of carbon-nitrogen bonds through acyl-phosphate intermediates and are widely used in nucleotide biosynthesis. In the final step catalyzed by carbamoyl phosphate synthetase, carbamic acid is phosphorylated by another molecule of ATP to form carbamoyl phosphate. 

Carbamoyl Phosphate Synthetase 11 (CPS-11) differs in several ways from its isoform (CPS-I), the enzyme which provides carbamoyl phosphate for the Urea cycle (see "Protein Turnover / Ammonia Metabolism"). 

The primary site of regulation is Carbamoyl Phosphate Synthetase II (glutamine) which is allosterically inhibited by UTP. Elevated PRPP increases the CPS-II activity to help control PRPP levels. Feedback inhibition (control) is provided by TDP inhibition of PRPP synthesis and UMP inhibition of OMP Decarboxylase. 

Carbamoyl Phosphate Synthetase I (CPS I) provides the substrate, carbamoyl phosphate, for the urea cycle. 

The metabolic interrelationship between mitochondrial carbamoyl phosphate synthesis to urea formation and to cytosolic carbamoyl phosphate channeled into pyrimidine biosynthesis. In ornithine transcarbamoyiase (OTC) deficiency, mitochondrial carbamoyl phosphate diffuses into the cytosol and stimulates pyrimidine biosynthesis, leading to orotidinuria. Administration of allopurinol augments orotidinuria by increasing the flux in the pyrimidine biosynthetic pathway. CPS = Carbamoyl phosphate synthase, AT = aspartate transcarbamoyiase, D = dihydroorotase, DH = dihydroorotate dehydrogenase, OPRT = orotate phosphoribosyltransferase, XO = xanthine oxida.se,... 

In eukaryotic cells, two separate pools of carbamoyl phosphate are synthesized by different enzymes located at different sites. Carbamoyl phosphate synthetase I (CPS I) is located in the inner membrane of mitochondria in the liver and, to lesser extent, in the kidneys and small intestine. It supplies carbamoyl phosphate for the urea cycle. CPS 1 is specific for ammonia as nitrogen donor and requires N-acetylglutamate as activator. Carbamoyl phosphate synthetase II (CPS II) is present in the cytosol. It supplies carbamoyl phosphate for pyrimidine nucleotide biosynthesis and uses the amido group of glutamine as nitrogen donor. The presence of physically separated CPSs in eukaryotes probably reflects the need for independent regulation of pyrimidine biosynthesis and urea formation, despite the fact that both pathways require carbamoyl phosphate. In prokaryotes, one CPS serves both pathways. 

These substrates are different than those with the carbamoyl phosphate used for urea synthesis. The enzyme for the glutamine-dependent carbamoyl phosphate synthetase (CPS II) is in the cytosol, whereas that for urea synthesis (CPS I) is in the mitochondrion. The glutamine-dependent carbamoyl phosphate synthetase is present in most cells, whereas the mitochondrial carbamoyl phosphate synthetase is present primarily in the liver, kidney, and intestines (Fig. 20.6). 

---