Pyrimidines/pyrimidine nucleotides regulation

Purine Pyrimidine Nucleotide Biosynthesis Are Coordinately Regulated... 

Purine and pyrimidine biosynthesis parallel one another mole for mole, suggesting coordinated control of their biosynthesis. Several sites of cross-regulation characterize purine and pyrimidine nucleotide biosynthesis. The PRPP synthase reaction (reaction 1, Figure 34-2), which forms a precursor essential for both processes, is feedback-inhibited by both purine and pyrimidine nucleotides. 

Goordinated regulation of purine and pyrimidine nucleotide biosynthesis ensures their presence in proportions appropriate for nucleic acid biosynthesis and other metabolic needs. 

We examine here the biosynthetic pathways of purine and pyrimidine nucleotides and their regulation, the formation of the deoxynucleotides, and the degradation of purines and pyrimidines to uric acid and urea. We end with a discussion of chemotherapeutic agents that affect nucleotide synthesis. 

Pyrimidine Nucleotide Biosynthesis Is Regulated by Feedback Inhibition... 

Regulation of the rate of pyrimidine nucleotide synthesis in bacteria occurs in large part through aspartate transcarbamoylase (ATCase), which catalyzes the first reaction in the sequence and is inhibited by CTP, the end product of the sequence (Fig. 22-36). The bacterial ATCase molecule consists of six catalytic subunits and six regulatory subunits (see Fig. 6-27). The catalytic subunits bind the substrate molecules, and the allosteric subunits bind the allosteric inhibitor, CTP. The entire ATCase molecule, as well as its subunits, exists in two conformations, active and inactive. When CTP is... 

FIGURE 26-8 Common sequences in promoters recognized by eukaryotic RNA polymerase II. The TATA box is the major assembly point for the proteins of the preinitiation complexes of Pol II. The DNA is unwound at the initiator sequence (Inr), and the transcription start site is usually within or very near this sequence. In the Inr consensus sequence shown here, N represents any nucleotide Y, a pyrimidine nucleotide. Many additional sequences serve as binding sites for a wide variety of proteins that affect the activity of Pol II. These sequences are important in regulating Pol II promoters and vary greatly in type and... 

Jones, M. E., Pyrimidine nucleotide biosynthesis in animals Genes, enzymes and regulation of UMP biosynthesis. Ann. Rev. Biochem. 49 253-279, 1980. Authoritative outline of the regulatory properties of the two multifunctional proteins responsible for pyrimidine nucleotide synthesis in animals. 

Carbamyl-L-aspartate is the key precursor in the biosynthesis of pyrimidines. The enzyme aspartate transcarbamylase is inhibited by several pyrimidine nucleotides, notably cytidine triphosphate, and is activated by ATP, a purine nucleotide. Thus the enzyme is under feedback regulation, and controls the relative concentration of pyrimidine and purine nucleotides. 

Aspartate transcarbamoylase catalyzes the first step in the biosynthesis of pyrimidines, bases that are components of nucleic acids. The reaction catalyzed by this enzyme is the condensation of aspartate and carbamoyl phosphate to form A-carbamoylaspartate and orthophosphate (Figure 10.1). ATCase catalyzes the committed step in the pathway that will ultimately yield pyrimidine nucleotides such as cytidine triphosphate (CTP). How is this enzyme regulated to generate precisely the amount of CTP needed by the cell ... 

The utilization of ammonia resulting from the combination of carbamyl phosphate with aspartic acid, the initial reaction for the synthesis of the pyrimidine nucleotides, continues only as long as there is a requirement for them (Fig. 3). Regulation of this biosynthetic pathway is probably by way of feedback inhibition of aspartate transcarbamylase. The rat liver enzyme is inhibited by uridine, cytidine or thymidine or such derivatives as CMP, UTP, or TMP, all intermediates or products of this pathway (B8). This is not the only enzyme of the pathway which may be subject to feedback regulation. Dihydroorotase from rat liver is also inhibited by some pyrimidines and purines (B9). 

This amide of glutamic acid has properties similar to those of asparagine. The y-amido nitrogen, derived from ammonia, can be used in the synthesis of purine and pyrimidine nucleotides (Chapter 27), converted to urea in the liver (Chapter 17), or released as NH3 in the kidney tubular epithelial cells. The last reaction, catalyzed by the enzyme glutaminase, functions in acid-base regulation by neutralizing H+ ions in the urine (Chapter 39). 

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. 

Nucleotides are the building blocks of the nucleic acids. They also regulate metabolism and transfer energy. The purine and pyrimidine nucleotides are synthesized in both de novo and salvage pathways. 

See also Regulation of Enzyme Activity, Pyrimidine Nucleotide Metabolism (from Chapter 22), Figure 22.10... 

Purine and pyrimidine nucleotides are fundamental to life as they are involved in nearly all biochemical processes. Purine and pyrimidine nucleotides are the monomeric units of both DNA and RNA, ATP serves as the universal cellular energy source, adenine nucleotides are components of three key coenzymes (NAC", FAD and Co A), they are used to form activated intermediates, such as UDP-glucose, and they serve as metabolic regulators. 

ATCase catalyzes the committed step in the pathway that will ultimately yield pyrimidine nucleotides such as cytidine triphosphate (GTP). How is this enzyme regulated to generate precisely the amount of CTP needed by the cell ... 

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