Nucleoside catabolism

Munch-Petersen, A., Nygaard, P., Hammer-Jespersen, K. and Fill, N., Mutants constitutive for nucleoside-catabolizing enzymes in Escherichia coli K 12. Eur. J. Biochem., 1972, 27, 208-215. 

The potency of zebularine is about 10-fold lower than for the azacytosines [73]. Zebularine also inhibits cytidine deaminase [75] which is involved in nucleoside catabolism and deactivates also for example azacitidine and its desoxy analog [76]. Thus, it increases the concentrations of nucleoside triphosphates for incorporation into DNA, the efficacy of DNA methylation and ultimately the anticancer activity of for example azacitidine [77, 78[. Zebularine is metabolized by aldehyde oxidase and ithasbeen shovm that its activity can be increases if an inhibitor of that enzyme, for example raloxifene is given in combination [79]. One big question about all epigenetic drugs is the origin of the observed selectivity towards cancer cells. For zebularine, it has been shown that much less activation towards triphosphate metabolites that can be incorporated into DNA occurs in normal muscle tissue as compared to cancer tissue [80]. 

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. 

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

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.

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 ... 

The phosphoribosyltiansferases The nucleoside kinases Nucleoside phosphokinases Nucleotide reductases Methylases and demethylases Other anabolic enzymes Catabolism... 

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... 

ATP is the primary high-energy phosphate compound produced by catabolism, in the processes of glycolysis, oxidative phosphorylation, and, in photosynthetic cells, photophosphorylation. Several enzymes then cany phosphoryl groups from ATP to the other nucleotides. Nucleoside diphosphate kinase, found in all cells, catalyzes the reaction... 

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.

Nucleotides - [AMINO AC IDS - L-MONOSODIUM GLUTAMATE (MSG)] (Vol 2) -as antibiotics [ANTIBIOTICS - NUCLEOSIDES AND NUCLEOTIDES] (Vol 3) -catabolism of [MINERALNUTRIENTS] (Vol 16) -electrodes for [BIOPOLYMERS - ANALYTICAL TECHNIQUES] (Vol 4) -phosphorus nmr [MAGNETIC SPIN RESONANCE] (Vol 15) -as radioactive tracers [RADIOACTIVETRACERS] (Vol 20)... 

Very little can be said about the physiological function of the enzyme except that it is obviously involved in normal cellular catabolism of nucleosidemonophosphates. Its surface localization in microorganisms must have metabolic relevance its presence in membrane structures in mammalian tissues also points to specialized functions. Perhaps, even the nucleoside product has physiological functions yet to be discovered. 

Conversion of Nucleoside Monophosphates to Triphosphates Goes through Diphosphates Inhibitors of Nucleotide Synthesis Catabolism of Nucleotides... 

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... 

The free nucleotides, nucleosides, and bases which are present in physiological fluids result from the catabolism of nucleic acids, enzyme-catalyzed degradation of bodily tissues, anabolic pathways such as the de novo or salvage pathways, or dietary intake. 

The vital role of PNP in the proliferation of T-cells is evident from the fact that people with an inherited deficit in this activity have 30- to 100-fold lower numbers of T-lympho-cytes than normal (197). The accumulation of dGTP and the resulting inhibition of ribonucleotide reductase in PNP-deficient T-cells causes the suppression of T-cell proliferation. B-lymphocytes are unaffected. Hence, small molecule inhibitors of PNP could be used to treat T-cell lymphomas and other T-cell-me-diated diseases such as psoriasis. Adjunct therapy with PNP inhibitors could also block the catabolism of therapeutically useful nucleoside analogs. 

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).]... 

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. 

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