Pyrimidine regulation

The biosynthesis of purines and pyrimidines is stringently regulated and coordinated by feedback mechanisms that ensure their production in quantities and at times appropriate to varying physiologic demand. Genetic diseases of purine metabolism include gout, Lesch-Nyhan syndrome, adenosine deaminase deficiency, and purine nucleoside phosphorylase deficiency. By contrast, apart from the orotic acidurias, there are few clinically significant disorders of pyrimidine catabolism. 

Figure 34-6. Regulation of the reduction of purine and pyrimidine ribonucleotides to their respective 2 -deoxyribonucleotides. Solid lines represent chemical flow. Broken lines show negative ( ) or positive ( ) feedback 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. 

Similarly, Dang and co-workers reported the displacement of one chloride from pyrimidine 44 with various amines to give diaminopyrimidines 45 <00TL6559>. These compounds were then subjected to a FeCb-SiOz-promoted cyclocondensation with various aldehydes to produce trisubstituted purines 46 in moderate to good yields as potential adenosine regulating agents. 

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). 

Regulation of the balance of the concentrations of the four deoxyribonucleotides depends on the properties of only two enzymes, the ribonucleotide reductase complex and deoxy-CMP deaminase. The balance between pyrimidine deoxynucleotides is brought about by the properties of the deoxy-CMP deaminase, which is inhibited by deoxy-TTP and stimulated by deoxy-CTP. The ribonucleotide reductase also possesses allosteric sites which bind all four deoxynucleotide triphosphates, the effect of which is to maintain approximately similar concentrations of all the triphosphates. 

The regulation of bacterial aspartate carbamoyltransferase by ATP and CTP has been particularly well studied, and is discussed on p. 116. In animals, in contrast to prokaryotes, it is not ACTase but carbamoyl-phosphate synthase that is the key enzyme in pyrimidine synthesis. It is activated by ATP and PRPP and inhibited by UTP. 

For the regulation of metabolic pathways metabolites are often used which are a product of that pathway. The basic strategy for the regulation is exemplified in the mechanisms employed in the biosynthetic and degradation pathways of amino acids, purines, pyrimidines, as well as in glycolysis. In most cases a metabolite (or similar molecule) of the pathway is utilized as the effector for the activation or inhibition of enzymes in that pathway. 

The purine and pyrimidine bases play an important role in the metabolic processes of cells through their involvement in the regulation of protein synthesis. Thus, several synthetic analogues of these compounds are used to interrupt the cancer cell growth. One such example is an adenine mimic, 6-mercaptopurine, which is a well known anticancer drug. 

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... 

Figure 25-23 Schematic representation of configuration of DNA, showing the relationship between the axes of hydrogen-bonded purine and pyrimidine bases and the deoxyribosephosphate strands. There are 10 pairs of bases per complete 360° twist of the chain. The spacing between the strands is such that there is a wide and a narrow helical groove around the molecule. Proteins known as histones coordinate with DNA by winding around the helix, filling one of the other of the grooves. The histone-DNA combination is important in regulating the action of DNA.

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