Purine nucleotides degradation

Kuracka, L. Kalnovicova, T. Liska, B. Turcani, P. HPLC method for measurement of purine nucleotide degradation products in cerebrospinal fluid. Clin. Chem. 1996, 42 (5), 756-760. 

I. H. Fox, Metabolic basis for disorders of purine nucleotide degradation Metabolism. 30 616 (1981). 

These data confirm that at this rate of ethanol administration, uric acid excretion did not decrease. The increased excretion of uric acid precursors suggests, in fact, that there is increased flux through the pathways of purine nucleotide degradation to uric acid. Excretion of labeled degradation products derived from the adenine nucleotide pool is significantly accelerated and suggests accelerated ATP or adenine nucleotide degradation. 

Adenosine is an intermediate of the pathway of purine nucleotide degradation. Many biological properties of adenosine have been identified It is toxic to mammalian and bacterial cells, and its... 

Since biosynthesis of IMP consumes glycine, glutamine, tetrahydrofolate derivatives, aspartate, and ATP, it is advantageous to regulate purine biosynthesis. The major determinant of the rate of de novo purine nucleotide biosynthesis is the concentration of PRPP, whose pool size depends on its rates of synthesis, utilization, and degradation. The rate of PRPP synthesis depends on the availabihty of ribose 5-phosphate and on the activity of PRPP synthase, an enzyme sensitive to feedback inhibition by AMP, ADP, GMP, and GDP. 

Pyrimidine 5 -nucleotidase (P5N) is a unique enzyme that was recognized from studies of families with relatively common hemolytic disorders. The enzyme catalyzes the hydrolytic dephosphorylation of pyrimidine 5 -nucleotides but not purine nucleotides. The role of this enzyme is to eliminate RNA and DNA degradation products from the cytosol during erythroid maturation by conversion of nucleotide monophosphates to diffusible nucleosides. P5N is inhibited by lead, and its activity is considered to be a good indicator of lead exposure (PI). 

Nucleic acid degradation in humans and many other animals leads to production of uric acid, which is then excreted. The process initially involves purine nucleotides, adenosine and guanosine, which are combinations of adenine or guanine with ribose (see Section 14.1). The purine bases are subsequently modified as shown. 

Purine (left). The purine nucleotide guano-sine monophosphate (CMP, 1) is degraded in two steps—first to the guanosine and then to guanine (Gua). Guanine is converted by deamination into another purine base, xanthine. 

A. Purine nucleotides are degraded or disassembled to uric acid (Figure 10-6). 

Purine nucleotides are degraded by a pathway in which they lose their phosphate through the action of 5 -nucleotidase (Fig. 22-45). Adenylate yields adenosine, which is deaminated to inosine by adenosine deaminase, and inosine is hydrolyzed to hypoxanthine (its purine base) and D-ribose. Hypoxanthine is oxidized successively to xanthine and then uric acid by xanthine oxidase, a flavoenzyme with an atom of molybdenum and four iron-sulfur centers in its prosthetic group. Molecular oxygen is the electron acceptor in this complex reaction. 

FIGURE 22-45 Catabolism of purine nucleotides. Note that primates as uric acid from purine degradation. Similarly, fish excrete much more... 

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. 

Free purine and pyrimidine bases are constantly released in cells during the metabolic degradation of nucleotides. Free purines are in large part salvaged and reused to make nucleotides, in a pathway much simpler than the de novo synthesis of purine nucleotides described earlier. One of the primary salvage pathways consists of a single reaction catalyzed by adenosine phosphoribosyltransferase, in which free adenine reacts with PRPP to yield the corresponding adenine nucleotide ... 

Degradation of dietary nucleic acids occurs in the small intestine, where a family of pancreatic enzymes hydrolyzes the nucleotides to nucleosides and free bases. Inside cells, purine nucleotides are sequentially degraded by specific enzymes, with uric acid as the end product of this pathway. [Note Mammals other than primates oxidize uric acid further to allantoin, which, in some animals other than mammals, may be further degraded to urea or ammonia.]... 

The degradation of purine nucleotides to uric acid, illustrating some of the genetic diseases associated with this pathway. [Note The numbers in brackets refer to the corresponding numbered citations in the text.]... 

Muscular work is accompanied by the production of ammonia, the immediate source of which is adenosine 5 -phosphate (AMP).301 302 This fact led to the recognition of another substrate cycle (Chapter 11) that functions by virtue of the presence of a biosynthetic pathway and of a degradative enzyme in the same cells (cycle A, Fig. 25-17). This purine nucleotide cycle operates in the brain303 304 as well as in muscle. The key enzyme 5-AMP aminohydrolase (AMP deaminase step a, Fig. 25-17) also occurs in erythrocytes and many other tissues.304 305 Persons having normal erythrocyte levels but an absence of this enzyme in muscles suffer from muscular weakness and cramping after exercise.306... 

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. 

A serious genetic disorder is associated with the salvage pathways, the Lesch-Nyhan syndrome. It is believed that it is caused by a failure to control the de novo purine biosynthetic pathway. In the Lesch-Nyhan syndrome, the enzyme HGPRTase is severely depressed. Because the de novo pathway is controlled largely via feedback effects of purine nucleotides, the pathway is derepressed and excessive quantities of purine nucleotides and their degradation product, uric acid, are accumulated. This results is neurologic effects, self-mutilation, and mental retardation. 

The determination of the purine-nucleotide metabolites xanthine, hypox-an thine, and inosine by biosensors is of special interest for the estimation of meat or fish freshness. After the death of a fish, adenosine triphosphate (ATP) in the fish tissue is quickly degraded to inosine monophosphate (IMP). Further enzymatic decomposition of IMP leads to the accumulation of hypoxan thine (Hx), which is used as an indicator of fish freshness. To quantify these compounds with biosensors, it is possible to perform amperometric measurements of the generated hydrogen peroxide or the consumed oxygen according to the following enzymatic reactions ... 

Purines are degraded to urate in human beings. Gout, a disease that affects joints and leads to arthritis, is associated with the excessive accumulation of urate. The Lesch-Nyhan syndrome, a genetic disease characterized by self-mutilation, mental deficiency, and gout, is caused by the absence of hypoxanthine-guanine phosphoribosyltransferase. This enzyme is essential for the synthesis of purine nucleotides by the salvage pathway. 

Other useful pH values are pH 1.9 where fractionation depends mostly on the number of Up residues pH 3.5 where the four main ribonucleotides may be separated and higher pH values where differences between Ap and Cp can be exploited, although Rushizky et al. (1965) did not have much success at pH 4.0-4.4 with penta-to heptanucleotides. Degradation of purine nucleotides may occur at pH 1.9, although this is not observed on DEAE-paper electrophoresis and deamination of cytosine to uridine may occur at very high pH values. 

Fig. 1 Degradation of purine nucleotides and formation of purine derivatives.

In the degradation of the purine nucleotides, phosphate and ribose are removed first then the nitrogenous base is oxidized. 

Reutilization of purine bases after conversion to their respective nucleotides constitutes salvage pathways. These pathways are particularly important in extrahepatic tissues. Purines arise from several sources intermediary metabolism of nucleotides, degradation of polynucleotides, and dietary intake. Quantitatively, the first two sources are the more important. Salvage occurs mainly by the phosphoribosyltransferase reaction ... 

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.

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