Catabolism of pyrimidine nucleotides

Pathways for pyrimidine catabolism. The major end product from cytosine and uracil is y6-alanine, from thymine it is jS-aminoisobutyrate. 

Coordination of synthesis of purine and pyrimidine nucleotides is affected by activation of CPS II by ATP. 

Cultured mammalian cells (e.g., human lymphocytes) fail to grow when exposed to adenosine and have increased pools of ADP, ATP, and GTP, decreased pools of UDP, UTP, and CTP, and decreased 

Pyrimidine catabolism occurs mainly in the liver. In contrast to purine catabolism, pyrimidine catabolism yields highly soluble end products. Pyrimidine nucleotides are converted to nucleosides by 5 -nucleotidase. 

Cytidine so formed is converted to uridine by cy-tidine aminohydrolase, while uridine and thymidine are converted to free bases by pyrimidine nucleoside phosphorylase. 

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The catabolism of pyrimidine nucleotides, like that of purine nucleotides (Chapter 10), involves dephosphorylation, deamination, and glycosidic bond cleavage. In contrast to purine catabolism, however, the pyrimidine bases are most commonly subjected to reduction rather than to oxidation. An oxidative pathway is found in some bacteria however. 

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. 

The six-membered ring systems 5,6-dihydropyrimidine, 5,6-dihydrouracil and 5,6-dihydrothymine can be hydrolyzed by the enzyme dihydropyrimidinase (E.C. 3.5.2.2), which is involved in the degradation of pyrimidine nucleotides. This widely spread, inducible catabolic enzyme is strictly D-selective in contrast to the L-selective dihydroorotase (E. C. 3.5.2.3), which is involved in the opposite anabolic pathway (see above). Another name often used in the literature for the dihydropyrimidinase is d-hydantoinase, because it is also able to hydrolyze D,L-5-monosubstituted hydantoin derivatives with high activity. Both reactions are shown in Fig. 12.4-7. 

Since the early 1950s it has been known that the inducible catabolic enzyme dihydropyrimidinase (E.C. 3.5.2.2) plays an important role in pyrimidine metabolism123, 31, 33, 39, 64-661 and is widespread in nature. The natural substrates of this enzyme, which were also reported to be inducers, are 5,6-dihydrouracil and 5,6-dihy-drothymine. Both compounds are important intermediates in the degradation of pyrimidine nucleotides. The dihydropyrimidinase-reaction is described to be strictly D-specific and to have a wide substrate specificity (see Fig. 12.4-11). In 1970 and... 

All organisms synthesize, interconvert, and catabolize various purine and pyrimidine nucleotides. However, cells of different types, or even the same cells in different stages of development, differ greatly in their ability to carry out some of the reactions involved, with some cells favoring one set of reactions and others another. In the rest of the chapter we deal with the details of these reactions. 

Degradation of pyrimidine bases. Parts of this pathway are widely distributed in nature. The entire pathway is found in mammalian liver. As in purine nucleotide catabolism, no ATP results from catabolism, and the ribose-1-phosphate is released during catabolism before destruction of the base. 

In humans the purine ring cannot be degraded. This is not true for the pyrimidine ring. An outline of the pathway for pyrimidine nucleotide catabolism is illustrated in Figure 15.14. 

The chemistry and metabolism of purines, pyrimidines, and their nucleosides and nucleotides constitute one of the oldest subjects of biochemistry, beginning as it does with the identification of uric acid in 1776. It is ironic that it has taken longer to work out the pathways of the synthesis, interconversion, and catabolism of these compounds than those of many other metabolites. 

In summary, the biochemical function of folate coenzymes is to transfer and use these one-carbon units in a variety of essential reactions (Figure 2), including de novo purine biosynthesis (formylation of glycinamide ribonucleotide and 5-amino-4-imidazole carboxamide ribonucleotide), pyrimidine nucleotide biosynthesis (methylation of deoxyuridylic acid to thy-midylic acid), amino-acid interconversions (the interconversion of serine to glycine, catabolism of histidine to glutamic acid, and conversion of homocysteine to methionine (which also requires vitamin B12)), and the generation and use of formate. 

Nucleotides are synthesized by two types of metabolic pathways de novo synthesis and salvage pathways. The former refers to synthesis of purines and pyrimidines from precursor molecules the latter refers to the conversion of preformed purines and pyrimidines—derived from dietary sources, the surrounding medium, or nucleotide catabolism—to nucleotides, usually by addition of ribose-5-phosphate to the base. De novo synthesis of purines is based on the metabolism of one-carbon compounds. 

Several examples of prodrugs are found in the purine and pyrimidine analogs that substitute for natural nucleotides and inhibit nucleic acid formation. For example, 5-fluorouracil is essentially harmless to mammalian host and tumor cells. Upon administration, the drug is subject to one of two opposingmetabolicfates (10). Inactivation and elimination are accomplished by catabolism (about 80% of the dose) and by urinary excretion of unchanged drug... 

The purine and pyrimidine bases are the building blocks of DNA and RNA, in which they are incorporated as nucleotides. All purines and pyrimidines are produced by de novo synthesis there is a continuous turnover. The majority of the purine and pyrimidine bases (and their nucleosides) has a strong UV-absorbance, facilitating their detection by HPLC. Humans produce uric acid as the end product of purine catabolism, its concentration may serve as an indicator of purine metabolism. 

In addition to their role as components of nucleoproteins, purines and pyrimidines are vital to the proper functioning of the cell. The bases are constituents of various coenzymes, such as coenzyme A (CoA), adenosine triphosphate (ATP), guanosine triphosphate (GTP), cytidine triphosphate (CTP), diphosphopyridine nucleotide (DPN), triphosphopyridine nucleotide (TPN), and flavin adenine dinucleotide (FAD). A pyrimidine derivative, cytidine diphosphate choline, is involved in phospholipid synthe another pyrimidine compound, uridine diphosphate glucose, is an important substance in carbohydrate metabolism. Cytidine diphosphate ribitol functions in the biosynthesis of a new group of bacterial cell-wall components, the teichoic acids. While mammals excrete nitrogen derived from protein catabolism in the form of urea, birds eliminate their nitrogen by synthesizing it into the purine compound, uric acid. 

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