Purine nucleotide catabolism pathways

Bios5mthetic pathways of naturally occurring cytokinins are illustrated in Fig. 29.5. The first step of cytokinin biosynthesis is the formation of A -(A -isopentenyl) adenine nucleotides catalyzed by adenylate isopentenyltransferase (EC 2.5.1.27). In higher plants, A -(A -isopentenyl)adenine riboside 5 -triphosphate or A -(A -isopentenyl)adenine riboside 5 -diphosphate are formed preferentially. In Arabidopsis, A -(A -isopentenyl)adenine nucleotides are converted into fraws-zeatin nucleotides by cytochrome P450 monooxygenases. Bioactive cytokinins are base forms. Cytokinin nucleotides are converted to nucleobases by 5 -nucleotidase and nucleosidase as shown in the conventional purine nucleotide catabolism pathway. However, a novel enzyme, cytokinin nucleoside 5 -monophosphate phosphoribo-hydrolase, named LOG, has recently been identified. Therefore, it is likely that at least two pathways convert inactive nucleotide forms of cytokinin to the active freebase forms that occur in plants [27, 42]. The reverse reactions, the conversion of the active to inactive structures, seem to be catalyzed by adenine phosphoiibosyl-transferase [43] and/or adenosine kinase [44]. In addition, biosynthesis of c/s-zeatin from tRNAs in plants has been demonstrated using Arabidopsis mutants with defective tRNA isopentenyltransferases [45]. 

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. 

Purine nucleotide catabolism is outlined in Figure 15.12. There is some variation in the specific pathways used by different organisms or tissues to degrade AMP. In muscle, for example, AMP is initially converted to IMP by AMP deaminase (also referred to as adenylate aminohydrolase). IMP is subsequently hydrolyzed to inosine by 5 -nucleotidase. In most tissues, however, AMP is hydrolyzed by 5 -nucleotidase to form adenosine. Adenosine is then deaminated by adenosine deaminase (also called adenosine aminohydrolase) to form inosine. 

B. Purine nucleotides can be synthesized de novo from amphibolic or dual-purpose intermediates, which may be derived either from anabolic or catabolic pathways. 

Uric acid is the excreted end product of purine catabolism in primates, birds, and some other animals. A healthy adult human excretes uric acid at a rate of about 0.6 g/24 h the excreted product arises in part from ingested purines and in part from turnover of the purine nucleotides of nucleic acids. In most mammals and many other vertebrates, uric acid is further degraded to al-lantoin by the action of urate oxidase. In other organisms the pathway is further extended, as shown in Figure 22-45. 

Figure 25-18 Pathways of catabolism of purine nucleotides, nucleosides, and free bases. Spiders excrete xanthine while mammals and birds excrete uric acid. Spiders and birds convert all of their excess nitrogen via the de novo pathway of Fig. 25-15 into purines. Many animals excrete allantoin, urea, or NH4+. Some legumes utilize the pathway marked by green arrows in their nitrogen transport via ureides.

The detailed mechanism of myocardial protection via PC is not fully understood yet. Many pathways have been proposed and include myocardial stunning, synthesis of heat-shock proteins, involvement of G-proteins, and nitric oxide production [3-5]. The generally accepted model is that the ischemic phase leads to enhanced catabolism of purine nucleotides, resulting in a high level of adenosine. These activate PKC and a cascade of signaling steps leading to activation of MAP, MAPK and MAPKK, culminating in a marked effect on ATP-dependent channels [3,4,6, ]. 

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. 

Fig. 4. Possible pathways of purine nucleotide anabolism and catabolism. The heavy arrows indicate the normal routes of degradation in man. I = phosphoribosylpyrophosphate, II = phosphoribosylamine, III = inosinic acid, IV = xanthylic acid, V = adenyhc acid, VI = guanyhc acid VII = hypoxanthine, VIII = xanthine, IX — uric acid, and X = adenosine.

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. 

Two reactions that are required to form the precursors of DNA are described in detail ribonucleotide reductase converts ribonucleotides to deoxyribonucleotides, and thymidylate synthase methylates dUMP to form dTMP. The authors present the mechanisms and cofactors of these enzymes and explain how some anticancer drugs and antibiotics function by inhibition of dTMP synthesis and thus the growth of cells. Nucleotides also serve important roles as constituents of NAD", NADP, FAD, and coenzyme A (CoA), so the syntheses of these cofactors are described briefly. The chapter concludes with an explanation of how the purines are catabolized and some of the pathological conditions that arise from defects in the catabolic pathway of the purines. 

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. 

The conventional pathway for the formation of ALN and ALA in animals and microbes involves the oxidative catabolism of purine nucleotides [Eq. (1)]. 

In addition to the enzymes that catalyse the formation of nucleotides and polynucleotides, a large number of catabolic systems exist which operate at all levels of the internucleotide pathways. The ribonucleases and deoxyribonucleases that degrade polynucleotides are probably not significantly involved in purine analogue metabolism, but the enzymes which dephosphorylate nucleoside 5 -monophosphates are known to attack analogue nucleotides and may be of some importance to their in vivo activity. Phosphatases of low specificity are abundant in many tissues [38], particularly the intestine [29]. Purified mammalian 5-nucleotidases hydrolyse only the nucleoside 5 monophosphates [28] and... 

Allantoin is the excretory product in most mammals other than primates. Most fish hydrolyze allantoin to allantoic acid, and some excrete that compound as an end product. However, most continue the hydrolysis to form urea and glyoxylate using peroxisomal enzymes.336 In some invertebrates the urea may be hydrolyzed further to ammonia. In organisms that hydrolyze uric acid to urea or ammonia, this pathway is used only for degradation of purines from nucleotides. Excess nitrogen from catabolism of amino acids either is excreted directly as ammonia or is converted to urea by the urea cycle (Fig. 24-10). 

Most of the free purines derived from the breakdown of DNA, RNA, and nucleotides in the diet are catabolized to xanthine and then to uric acid in the gut mucosa. The AMP and GMP biosynthesized in the body can also be bmken down to free purines, such as adenine, guanine, and hypoxanthine. These purines, in contrast to those derived frcim the diet, are largely reused for the synthesis of ATP and GTP- They are first converted back to AMP or GMP in a pathway of reutiliza-lion called the purine salvage pathway. For example, adenine phosphoribosyl-transferase (PRPP) catalyzes the conversion of adenine to AMP. Here, PRPP serves as the source of the phosphoribose group. Pyrophosphate is a product of the reaction. 

Uric acid is the major product of catabolism of purine nucleosides adenosine and guanosine. Hypoxanthine and xanthine are intermediates along this pathway (Fig. 2). Under normal conditions, they reflect the balance between the synthesis and breakdown of nucleotides. Levels of these compounds change in various situations (e.g., they decrease in experimental tumors) when synthesis prevails over catabolism, and are enhanced during oxidative stress and hypoxia. Uric acid serves as a marker for tubular... 

Purine catabolism. The pathways to uric acid from guanine and adenine nucleotides are... 

See also Pathways in Nucleotide Metabolism, Nucleotide Salvage Synthesis, Purine Degradation, Pyrimidine Catabolism... 

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. 

Since there has been no evidence presented to support the hypothesis that free adenine can be formed de novo in biological systems from small molecule precursors, and furthermore, since purines have never been reported to have been essential dietary additions, the formation of nucleotides from free purines may be looked upon as a minor biosynthetic pathway. Undoubtedly, there is some utilization of free purines which are derived from the intestinal tract as well as from catabolic events within the cell. The term salvage pathway has been aptly applied to the reactions utilizing free bases for nucleic acid synthesis (206). 

Speaking about purine salvage it implies not only the pu-rine-PRT and its pathological appearance in human, but also includes all other possible reutilisation of nucleotide precursors derived from catabolic processes Gallo (1971) reports that a second pathway exists in human leucocytes ... 

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