Uracil catabolism

The biosynthetic source of the pyridone ring of 87 was investigated [260]. Thymine was found to inhibit uracil catabolism and 87 biosynthesis by Nocardia lactamdurans this inhibition was reversed by uracil catabolites. Both [5,6-3H]-uracil and [4,5-13c]-uracil were incorporated, with both labelled carbons of the latter being incorporated as a unit at C(4) and C(5) of 87. The proposed biosynthetic pathway (Scheme 2) involved catabolism of uracil to p-alanine, which was then incorporated into the pyridone ring of 87 [260]. 

Write a mechanism for the oxidation of malonic semialdehyde to give malonyl GoA, one of the steps in uracil catabolism. The process is similar to what occurs in step 6 of glycolysis. 

Uracil was degraded similarly via dihydrouracil and 8-ureidopropionic acid to 9-alanine (Fig. 26). These findings have also been demonstrated under a variety of experimental conditions, using isotopes in vivo and in vitro (415-419) and in studies with isolated enzyme systems (430, 431)-In support of the importance of reduced pyrimidines, dihydrouracil has been foimd in beef spleen (433). A similar reductive pathway for uracil catabolism was found in bacteria (43S 43B) and in Neurospora crasaa (436). 

Studies on isolated enzymes have revealed some differences between various systems. For example, the first step in uracil catabolism by Clostridium uraeUicum involved a DPNH-dependent conversion of uracil to dihydrouracil 432), while the corresponding reductions of uracil and thymine to dihydropyrimidines in acetone powder extracts of rat liver were TPNH-dependent reactions 416). Dihydropyrimidine dehydrogenase and dihydrouracil hydrases have been purified from animal 421, 433) and bacterial sources 432, 434). It was found that the hydrase enzyme from... 

In the majority of DPD defective patients experiencing severe 5-FU toxicity, abnormally high levels of natural pyrimidines are present in plasma and/or urine [62]. Moreover, endogenous dihydrouracil/uracil ratio in plasma has been proposed as a measure of 5-FU catabolic deficiency in cancer patients [63], and screening of cancer patients for these simple markers should be prospectively evaluated. 

Dihydropyrimidine dehydrogenase is the first and the rate-limiting enzyme in the three-step metabolic pathway involved in the degradation of the pyrimidine bases uracil and thymine. In addition, this catabolic pathway is the only route for the synthesis of p-alanine in mammals. 

In a study of the catabolic pathway of pyrimidines, it was found that the reduction of uracil was blocked almost completely by 5-cyanouracil (XXXV) in an in vitro test with the rat enzyme dihydropyrimidine dehydrogenase [303]. 5-Halogenated uracils and thymine are weakly active in this regard, and 5-acetyluracil and 5-trifluoromethyluracil are completely inert. 

The recent availability of oral formulations of 5-FU involving the ability to modulate the anabolic and catabolic metabolism of 5-FU with LV and dihydropyrimidine dehydrogenase (DPD) inhibitors has provided a substantial improvement in the ease of administration and may probably improve the efficacy of fluoropyrimidine-induced radiosensitization. Such oral fluoropyrimidines include UFT (uracil tegafur) plus oral LV (Orzel ), an oral DPD-inhibitory fluoropyrimidine (DIF), and capecitabine (Xeloda Roche). 

Enzymes present in mammalian liver are capable of the catabolism of both uracil and thymine. The first reduces uracil and thymine to the corresponding 5,6-dihydro derivatives. This hepatic enzyme uses NADPH as the reductant, whereas a similar bacterial enzyme is specific for NADH. Similar enzymes are apparently present in yeast and plants. Hydropyrimidine hydrase then opens the reduced pyrimidine ring, and finally the carbamoyl group is hydrolyzed off from the product to yield /3-alanine or /3-aminoisobutyric acid, respectively, from uracil and thymine (see fig. 23.23). 

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

In mammalian systems, catabolism of uracil and thymine proceeds in parallel steps, catalyzed by the same enzymes (Figure 27-31). The rate-determining step is reduction to a 5,6-dihydroderivative by dihydropyrimidine dehydrogenase. In the second step, dihydropyrimidinase hydrolyzes cleavage of the dihydropyrimidine rings to -ureido compounds. In the third step, /1-ureidopropionase hydrolyzes the j3-ureido compounds to -alanine or fi-aminoisobutyrate (BAIB), with release of ammonia and carbon dioxide. Thus, the major end product of the catabolism of cytosine and uracil is /i-alanine, whereas that of thymine is BAIB. 

West, T.P. 1997. Reductive catabolism of uracil and thymine by Burkholderia cepacia. Arch. Microbiol. 168 237-239. 

Pyrimidine catabolism. The steps in the catabolism of cytosine and uracil are shown with corresponding structures the steps for thymine are shown only in... 

Pathways for pyrimidine catabolism are shown in Figure 22.11. Pyrimidine bases are broken down through a common uracil intermediate, which is subsequently converted to dihydrouracil, followed by / -ureidopropionic acid, and finally / -alanine, ammonia and C02. ... 

Dihydrouracil is an intermediate in catabolism of pyrimidines (Figure 22.11). It is formed by reduction of uracil (Figure 22.11) and then... 

There are thirty-three pyrimidine derivatives identified in tobacco and tobacco smoke. The vast majority of these compounds (67%) have been identified in tobacco. Only fourteen are known to exist in tobacco smoke. As previously mentioned, the naturally occurring derivatives of pyrimidine are components of nucleic acids cytosine, thymidine, and uracil. Free pyrimidine and functionalized pyrimidine compounds in tobacco are believed to be formed from the catabolism of various nucleosides (17B21). Several of the pyrimidine-containing compounds in tobacco are agronomic chemical residues while other compounds identified in tobacco smoke are formed from those agronomic residues. 

Fluorouracil is catabolized in an analogous manner to uracil, forming the following degradative products dihydrofluorouraci1, a-fluoro-6-ureidopropionic acid, a-fluoro-3-guanidopropionic acid, a-fluoro-3-alanine, urea, and CO2 (16). 

Pyrimidine ribonucleotides, like those of purines, may be synthesized de novo from amino acids and other small molecules (Chapter 11). Preformed pyrimidine bases and their ribonucleoside derivatives, derived from the diet of animals or found in the environment of cells, may be converted to ribonucleotides via nucleoside phosphorylases and nucleoside kinases. In some cells a more direct pyrimidine phosphoribosyltransferase pathway has also been recognized (Chapter 12). Ribonucleotides are catabolized by dephosphorylation, deamination, and cleavage of the glycosidic bond, to uracil. Uracil may be either oxidatively or reductively cleaved, depending on the organism involved, and can be converted to CO and NH (Chapter 13). 

The catabolism of uridine and cytidine by this route has value to the cell in that the ribose 1-phosphate produced may be degraded in energy-yielding reactions of the glycolytic pathway (see Chapter 6). Because of the ready reversibility of uridine phosphorolysis, this enzyme may contribute to the anabolism of uracil. 

In summary, a catabolic function for uridine phosphorylase is clear. However, this enzyme may also participate in the anabolism of uracil, which is the evident function of uracil phosphoribosyltransferase. The operation of these apparently alternative routes of uracil anabolism in living cells has not yet been evaluated. 

Rat liver catabolizes uracil at a high rate, and, as has been mentioned in Chapter 12, this base is consequently not readily incorporated into nucleic acids. However, as shown by the data in Table 13-1 (S), by increasing the concentration of uracil the catabolic enzyme system of rat liver slices can be saturated, and significant amounts are then incorporated into RNA. 

Effect of Concentration on the Relative Amount op Uracil Anabolized and Catabolized IN Rat Liver Slices ... 

Deoxyuridine and thymidine are substrates for pyrimidine nucleoside phosphorylases, but deoxycytidine (and cytidine) is generally regarded as being inert to phosphorolysis (7) Tarris demonstration of deoxycytidine formation from cytosine in extracts of fish milt is an exception to this generalization (8). Catabolism of C3rtosine nucleosides is initiated by deamination to form uracil nucleosides which can be phosphorolyzed. 

Experiments with animal cells have shown that the pyrimidine bases are much less effective DNA precursors than the corresponding deoxy-ribonucleosides, although the interpretation of such experiments is complicated by the rapid catabolism of uracil and thymine which takes place in liver. The incorporation of thymine into DNA in animals (14), or in in vitro systems (15) is slow and contrasts with the much more rapid incorporation of thymidine. 

Possible hypotheses for the defect in E.v.d.B. are 1. Decreased reutilisation of uracil at the level of uridine phosphorylase or uridine kinase. At low uracil levels reutilisation will predominate over catabolism via the diHPyDH reaction and at high uracil concentrations the reverse will be the case presumably. 2. Increased synthesis of pyrimidines due to a fluctuating regulation at the level of aspartate transcarbamylase and/or ornithine trans-carbamylase. It has to be presumed that attacks of periodic hyperammonemia have not occurred during the limited time of investigations, with the phenomena of patient A.G. in mind. 

In the above studies, cytosine and 5-methylcytosine were probably deaminated to uracil and thymine, respectively, by a single enzyme. That deamination was the first catabolic step is in accord with earlier studies on the degradation of aminopyrimidines in bacteria. " The cell-free extracts of Wang and Lampen, however, were unable to oxidize cytosine, since the extracts did not contain cytosine deaminase. Evidence was presented nonetheless that the intact bacterial cell did metabolize cytosine cytosine was not utilized, but was first deaminated to uracil, which was in turn oxidized. Chargaff and Kream have reported the... 

Enzymic hydrolysis of nucleic acids produced mononucleotides, which, in turn, were successively degraded to nucleosides and free purine and P3rrimidine bases. The metabolism of the bases, cytosine, uracil, and thymine (Fig. 18), will be discussed in this section. Since there is little known of the intermediates involved in the catabolism of pyrimidine mononucleotides to free bases, this area will not be discussed. 

The metabolism of several halogenated pyrimidines used in cancer chemotherapy has been investigated. In man (435) and other species 419, 436-440), 5-bromouracil was converted to urinary uracil which was then further degraded to jS-ureidopropionic acid. The reduction of 5-bromouracil to a dihydro compound 431, 436) and the loss of HBr to form uracil are shown in Fig. 28. The catabolism of uracil has been discussed previously (Section VII, B). 

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