Pyrimidines/pyrimidine nucleotides synthesis

While mammahan cells reutilize few free pyrimidines, salvage reactions convert the ribonucleosides uridine and cytidine and the deoxyribonucleosides thymidine and deoxycytidine to their respective nucleotides. ATP-dependent phosphoryltransferases (kinases) catalyze the phosphorylation of the nucleoside diphosphates 2 "-de-oxycytidine, 2 -deoxyguanosine, and 2 -deoxyadenosine to their corresponding nucleoside triphosphates. In addition, orotate phosphoribosyltransferase (reaction 5, Figure 34-7), an enzyme of pyrimidine nucleotide synthesis, salvages orotic acid by converting it to orotidine monophosphate (OMP). 

Another important vitamin is folate, which is required for purine and pyrimidine nucleotide synthesis. Since folate and its derivatives are generally lipo-phobic anions, they do not traverse biological membranes via simple diffusion but rather have to be taken up into the cells by specific transport processes... 

Reisner M, Carmeli S, Werman M, Sukenik A (2004) The cyanobacterial toxin cylindrospermopsin inhibits pyrimidine nucleotide synthesis and alters cholesterol distribution in mice. 

Figure 20.9 The positions in the pathway for de novo pyrimidine nucleotide synthesis where GLUCOSE provides the ribose molecule and GLUTAMINE provides nitrogen atoms. Glucose forms ribose 5-phosphate, via the pentose phosphate pathway (see chapter 6), which enters the pathway, after phosphorylation, as 5-phospho-ribosyl 1-pyrophosphate. Glutamine provides the nitrogen atom to synthesise carbamoylphos-phate (with formation of glutamate), and also to form cytidine triphosphate (CTP) from uridine triphosphate (UTP), catalysed by the enzyme CTP synthetase. It is the amide nitrogen of glutamine that is the nitrogen atom that is provided in these reactions.

Antimetabolites (inhibition of purine and pyrimidine nucleotide synthesis) Methotrexate Folic acid antagonist, inhibits tetrahydrofolate reductase and therefore dTMP synthesis 6-Mercaptopurine Interferes with purine synthesis 5-Fluorouracil Inhibits dTMP synthesis ... 

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... 

Two activities of the immunosuppressive metabolite of Leflimomide, A77 1 726. Inhibition of pyrimidine nucleotide synthesis and protein tyrosine phosphorylation. Biochem. Pharmacol. 52,... 

Figure 25.2. de Novo Pathway for Pyrimidine Nucleotide Synthesis. The C-2 and N-3 atoms in the pyrimidine ring come from carbamoyl phosphate, whereas the other atoms of the ring come from aspartate. 

As a component of pyrimidine nucleotide synthesis leading to liver cell regeneration... 

Immune system dysfunction in ADA deficiency has also been ascribed to the inhibition of pyrimidine nucleotide synthesis by adenosine, known as pyrimidine starvation. This may arise from inhibition of conversion of orotic acid to orotidine 5 -monophosphate or from inhibition of PRPP synthesis by excessive synthesis of adenine nucleotides. 

Feedback inhibition of pyrimidine nucleotide synthesis can occur by which of the following means ... 

TSH also increased pyrimidine nucleotide synthesis in the bovine thyroid (H2, L6). Hall and Tubman postulated that increases in nucleotide synthesis may be mediated by increased ribose generated from the hexose monophosphate shunt. Incorporation of labeled formate and adenine into nuclear, cytoplasmic, or whole RNA was not inhibited by puromycin at a time when protein synthesis was inhibited as measured... 

L6. Lindsay, R. H., Cash, A. G., and Hill, J. B., Thyrotropin stimulation of pyrimidine nucleotide synthesis in the bovine thyroid. Biochem. Biophys. Res. Commun. 29, 850-855 (1967). 

In pyrimidine nucleotide synthesis, the carbon and nitrogen atoms are derived from bicarbonate, aspartate, and glutamine. Devise a simple experiment to prove the source of the nitrogen... 

The synthesis of deoxyuridine, cytidine, deoxycytidine and thymidine nucleotides from UMP (Fig. 6.13) involves three reactions CTP synthetase, ribonucleotide reductase, and thymidylate synthase (80). The first enzyme converts UTP into CTP and the second catalyzes the conversion of CDP, UDP, ADP and GDP into their respective deoxyribonucleotides. The last enzyme, thymidylate synthase, catalyzes the reductive methylation of deoxyUMP at the C-5 position giving deoxyTMP. The human enzyme has been extensively studied as it is a target enzyme in cancer chemotherapy. Besides these three enzymes, two other enzymes are involved in pyrimidine nucleotide synthesis and interconversion. DeoxyCMP deaminase converts deoxyCMP into deoxyUMP and deoxyUTP triphosphatase converts deoxyUTP into deoxyUMP. Giardia lamblia, and Trichomonas vaginalis lack both ribonucleotide reductase and thymidylate synthase and... 

In addition to the requirement for pyrimidine nucleotide synthesis, carbamyl phosphate is required for synthesis of arginine and urea. Carbamyl phosphate synthesis is a prominent activity in ureotelic liver and is aimed primarily at the formation of urea the process of urea synthesis is served by a special carbamyl phosphate synthetase which is quite distinct from the enzymes responsible for carbamyl phosphate synthesis in extrahepatic tissues and in the livers of uricotelic animals. A third mechanism for synthesis of carbamyl phosphate is found in bacteria. 

Hartman, S.C., Buchanan, J.M. Nucleic acids, purines, pyrimidines (nucleotide synthesis). Annu. Rev. Biochem. 28, 365-410 (1959)... 

Leflxmomide is a disease-modifying antirheumatic drug which was approved in August 1998 by the US FDA for the treatment of rheumatoid arthritis. It inhibits dihydroorotate dehydrogenase (DHODH) and as a consequence it blocks the de novo pathway of pyrimidine nucleotide synthesis, which is crucial for T cell activation and proliferation. The tolerability of leflxmomide is rather poor, as up to 50% of rheumatoid arthritis patients withdrew from leflxmomide xvithin the first year mostly due to adverse effects such as GI disorders (dyspepsia, diarrhoea, nausea and vomiting or abdominal pain), increased level of liver enzymes, alopecia, skin rashes, infections and hypertension. 

Pnrine, pyrimidine, nucleotide synthesis (amine gronp)... 

Figure 34-7 summarizes the roles of the intermediates and enzymes of pyrimidine nucleotide biosynthesis. The catalyst for the initial reaction is cytosolic carbamoyl phosphate synthase II, a different enzyme from the mitochondrial carbamoyl phosphate synthase I of urea synthesis (Figure 29-9). Compartmentation thus provides two independent pools of carbamoyl phosphate. PRPP, an early participant in purine nucleotide synthesis (Figure 34-2), is a much later participant in pyrimidine biosynthesis.

Since the end products of pyrimidine catabolism are highly water-soluble, pyrimidine overproduction results in few clinical signs or symptoms. In hypemricemia associated with severe overproduction of PRPP, there is overproduction of pyrimidine nucleotides and increased excretion of p-alanine. Since A, A -methyl-ene-tetrahydrofolate is required for thymidylate synthesis, disorders of folate and vitamin Bjj metabofism result in deficiencies of TMP. 

Twenty different amino acids are required for the synthesis of the cellular complement of proteins thus, there must be at least 20 distinct codons that make up the genetic code. Since there are only four different nucleotides in mRNA, each codon must consist of more than a single purine or pyrimidine nucleotide. Codons consisting of two nucleotides each could provide for only 16 (4 ) specific codons, whereas codons of three nucleotides could provide 64 4 ) specific codons. 

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