Thymine catabolism

Pyrimidines are metabolized largely as shown in Figure 10.15. /3-Aminoiso-butyric acid, the product of thymine catabolism, is excreted in the urine in some individuals. In others it is further catabolized to C02 and HzO. 

Recent studies by Fink, Henderson, and Fink postulate a pathway of thymine catabolism that is markedly different from that suggested by... 

The essential difference between the findings of Fink and collaborators and the bacterial studies reported above with thymine is that, in the former instance, an initial reduction at Ce to yield )8-aminoisobutyric acid was postulated, while to produce 5-methylbarbituric acid in bacteria, an oxidation must be postulated as the initial step. The possibility should not be overlooked that several degradative pathways may exist. The two pathways of thymine catabolism discussed above are shown in Fig. 15. 

A pathway of thymine catabolism has been demonstrated that differed markedly from that suggested by microbiolo cal studies presented in the previous section (41S, 41S). It was found first that diets contmnir lai e amounts of thynune or DNA caused normal rats to excrete a new amino acid, whereas diets containing RNA failed to produce this effect. This amino acid was (8-aminoisobutyric acid (Fig. 25), and it was established that only thymine, thymine-containing DNA, and dihydrothymine re-... 

Additional studies substantiated the I ole of dihydropyrimidines and 3-amino acids in pyrimidine catabolism. In the rat, thymine catabolism proceeded by reduction to dihydrothymine with the subsequent formation of j8-ureidoisobutyric acid (413, 4H) (Fig. 25). The fate of /3-aminoiso-butyric acid was uncertmn. 

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 pathways for degradation of pyrimidines generally lead to NH4 production and thus to urea synthesis. Thymine, for example, is degraded to methyl-malonylsemialdehyde (Fig. 22-46), an intermediate of valine catabolism. It is further degraded through propionyl-CoA and methylmalonyl-CoA to succinyl-CoA (see Fig. 18-27). 

RGURE 22-46 Catabolism of a pyrimidine. Shown here is the pathway for thymine. The methylmalonylsemialdehyde is further degraded to succinyl-CoA. 

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. 

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]. 

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

The main source of C, units is the hydroxymethyl group of serine, which is transferred to THF by serine hydroxymethyltransferase (EC 2.1.2.1), forming fV -hydroxymethyl-THF (activated form dehyde). Production of C, units during histidine catabolism and in the anaerobic degradation of purines is of particular importance. C, units are incorporated during purine biosynthesis, and they provide the S-methyl group of thymine. C units are interconverted while attached to THF (Hg.2). For other metabolic sources and uses of C units, see legend to Fig.2. 

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. 

Propionic acid fermentation is not limited to propionibacteria it functions in vertebrates, in many species of arthropods, in some invertebrates imder anaerobic conditions (Halanker and Blomquist, 1989). In eukaryotes the propionic acid fermentation operates in reverse, providing a pathway for the catabolism of propionate formed via p-oxidation of odd-numbered fatty acids, by degradation of branched-chain amino acids (valine, isoleucine) and also produced from the carbon backbones of methionine, threonine, thymine and cholesterol (Rosenberg, 1983). The key reaction of propionic acid fermentation is the transformation of L-methylmalonyl-CoA(b) to succinyl-CoA, which requires coenzyme B12 (AdoCbl). In humans vitamin B deficit provokes a disease called pernicious anemia. 

Medicine. In humans and animals AdoCbl is the coenzyme of methylmalonyl CoA-mutase that catalyzes the isomerization of methyl-malonyl-CoA into succinyl-CoA (in propionibacteria this reaction runs in the opposite direction). The reaction is linked with the catabolism of amino acids and lipids. If the activity of methylmalonyl CoA-mutase is blocked, the catabolism of some amino acids, fatty acids and thymine is inhibited (Fig. 7.1). Intracellular levels of methylmalonyl-CoA and propionyl-CoA are increased and may affect fatty acids synthesis. In some cases, an increase in the content of C15 and Cn odd-numbered fatty acids and branched-chain fatty acids in glycolipids of the nervous system is observed (Kishimoto et al., 1973). 

Figure 7.1. Dependence of catabolism of some amino acids, fatty acids and thymine upon methylmalonyl-CoA mutase. Reprinted with pennission from A. Stroinski, Medical aspects of vitamin B12, pp. 335-370 in Z. Schneider and A. Stroinski (eds.) Comprehensive B12 Chemistry. Biochemistry. Nutrition. Ecology. Medicine. 1987 Walter de Gruyter.

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. 

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... 

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