Purine nucleosides, catabolism

The biosynthesis of purines and pyrimidines is stringently regulated and coordinated by feedback mechanisms that ensure their production in quantities and at times appropriate to varying physiologic demand. Genetic diseases of purine metabolism include gout, Lesch-Nyhan syndrome, adenosine deaminase deficiency, and purine nucleoside phosphorylase deficiency. By contrast, apart from the orotic acidurias, there are few clinically significant disorders of pyrimidine catabolism. 

Figure 34-8. Formation of uric acid from purine nucleosides byway of the purine bases hypoxanthine, xanthine, and guanine. Purine deoxyribonucleosides are degraded by the same catabolic pathwayand enzymes,all of which existin the mucosa of the mammalian gastrointestinal tract.

Although purine nucleosides are intermediates in the catabolism of nucleotides and nucleic acids in higher animals and humans, these nucleosides do not accumulate and are normally present in blood and tissues only in trace amounts. Nevertheless, cells of many vertebrate tissues contain kinases capable of converting purine nucleosides to nucleotides. Typical of these is adenosine kinase, which catalyzes the reaction... 

Such a catabolic reaction is indeed excluded in 6 alkyl purine derivatives. The parent compound of this group, 6-methylpurine, is known for its cytotoxicity its libera tion from the 2 -deoxyribonucleoside by purine nucleo side phosphorylases is used for detection of mycoplasma in cell cultures.19 It is highly potent and toxic to nonproliferating and proliferating tumor cells. Recently, the use of cytotoxic bases liberated by purine nucleoside phosphorylases such as 6-methylpurine was proposed as a novel principle in the gene therapy of cancer.20... 

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... 

Uric acid is a primary end product of urine metabohsm in the kidney. Uric acid levels in human urine are like creatinine as an important parameter of renal function and a marker for renal failure as well as toxicity. As shown in Fig. 3, uric acid is the final product of catabolization of the purine nucleosides, adenosine, and guanosine. ... 

Uric acid (UA) is the primary end product of catabolism of purine nucleosides adenosine and guanosine and has often been regarded as a key biomarker in evaluation of physiological wellbeing [157,158], In healthy human, UA is filtered and removed from the blood by the kidneys and excreted through urine and hence kidney diseases are known to affect uric acid... 

In humans, uric acid (2,6,8-trihydroxypurine) is the major product of the catabolism of the purine nucleosides adenosine and guanosine (Figure 24-3), Purines from catabolism of dietary nucleic acid are converted to uric acid directly. The bulk of purines excreted as uric acid arise from degradation of endogenous nucleic acids. The daily synthesis rate of uric acid is approximately 400 mg dietary sources contribute... 

Catabolism of the nucleotides (Figure 24-3, B) begins with removal of their ribose-linked phosphate, a process catalyzed by purine 5 -nucleotidase. Removal of the ribose moiety of inosine and guanosine by the action of purine-nucleoside phosphorylase forms hypoxanthine and guanine, both of which are converted to xanthme. Xanthine is converted to uric acid through the action of xanthine oxidase. 

Reactions catalyzed by adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP). ADA and PNP participate in the purine catabolic pathway, and deficiency of either leads to immunodeficiency disease. [Slightly modified and reproduced, with permission, from N. M. Kredich and M. S. Hershfield, Immunodeficiency diseases caused by adenosine deaminase and purine nucleoside phosphorylase deficiency. In The Metabolic Basis of Inherited Disease, 6th ed., C. S. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle, Eds. New York McGraw-Hill (1989).]... 

An increased production of uric acid can result from clinical conditions in which there is a rapid increase in the rate of degradation of purine nucleotides. This degradation occurs as a result of the turnover or breakdown of nucleic acids and soluble nucleotides in the cell often associated with breakdown of the cell itself. Examples of this would include the acute leukemias and hemolytic anemias (2). In addition, the degradation of purine nucleotides can occur as a result of alterations in the energy of the cell which enhance the breakdown of ATP. Examples of this might include starvation, muscular exertion, and hypoxia. In some of these latter conditions related to the catabolism of purine nucleoside triphosphates, there may also be compensatory increase in the rate or purine biosynthesis de novo related to the release of feedback inhibition at the level of PRPP synthetase and/or PRPP amidotransferase. 

Fig. 14-1. Catabolism of deoxyribonucleosides (1) cytidine deaminase (2) adenosine deaminase (3) thymidine phosphotylase (4) purine nucleoside phosphorylase (5) phosphoribomutase (6) deoxyriboaldolase.

Thymidine phosphorylase can also use deoxyuridine as substrate [161-163], and the purine nucleoside enzyme can use either the ribonu-cleoside or the deoxyribonucleoside forms of adenine or guanine [115,164], Uridine phosphorylase (EC 2.4.2.3) is a separate entity and will not be considered here, since its regulation is not clearly understood. The four enzymes under consideration are interrelated in function and operate in concert in the regulation of nucleoside catabolism. The mechanisms of their regulation evolved from a number of independent and seemingly devious observations and events, the essence of which may be summarized as follows. 

IMP v/hich was always the main labeled compound present within erythrocytes). After the lag time, the rate of hypoxanthine release was about the same of that observed in the absence of formycin B (fig. 2). Since, at the concentration employed, formycin B is known to inhibit purine nucleoside phosphorylase in intact human erythrocytes, these results confirm that the cells sequentially degrade the intracellular IMP to inosine and hypoxanthine and suggest that the phosphory-lase-catalyzed formation of hypoxanthine from its nucleoside is not the rate limiting step in this catabolic path. 

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]. 

Using a purine requiring mutant, defective in nucleoside catabolism (lacking nucleoside phosphorylase... 

Excess purine nucleotides or those released from DNA and RNA by nucleases are catabolized first to nucleosides (loss of P.) and then to free purine bases (release of ribose or deoxyribose). Excess nucleoside monophosphates may accumulate when ... 

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... 

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.

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. 

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). 

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