Purine catabolism reactions

Two different immunodeficiency diseases are now known to result from defects in purine catabolic reactions. In adenosine deaminase deficiency, large concentrations of dATP inhibit ribonucleotide reductase. Consequently, DNA synthe- i= sis is depressed. For reasons that are not yet clear, this metabolic distortion is observed primarily in the T and B lymphocytes. ( / lymphocytes, or T cells, bear antibody-like molecules on their surfaces. They bind to and destroy foreign cells in a process referred to as cellular immunity. B lymphocytes, or B cells, produce antibodies that bind to foreign substances, thereby initiating their destruction by other immune system cells. The production of antibodies by B cells is referred to as the humoral immune response.) Children with adenosine deaminase deficiency usually die before the age of two because of massive infections. 

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... 

In most cells, more than 90% of the oxygen utilized is consumed in the respiratory chain that is coupled to the production of ATP. However, electron transport and oxygen utilization occur in a variety of other reactions, including those catalyzed by oxidases or oxygenases. Xanthine oxidase, an enzyme involved in purine catabolism (Chapter 27), catalyzes the oxidation of hypoxanthine to xanthine, and of xanthine to uric acid. In these reactions, reducing equivalents are transferred via FAD, and Fe and Mo " ", while the oxygen is converted to superoxide anion (O2) ... 

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).]... 

Xanthine is a product of purine catabolism. It is produced as a result of deamination of guanine (Figure 22.7) by guanine deaminase or by the reaction catalyzed by xanthine oxidase. These reactions are as follows ... 

The reaction is a part of the purine catabolic pathway (Figure 22.7)... 

FIGURE 23.23 The reactions of purine catabolism, (a) Purine nucleotides are converted to the free base and then to xanthine, (b) Catabolic reactions of xanthine. 

Xanthine oxidase and xanthine dehydrogenase represent different forms of the same gene product. Xanthine dehydrogenase and xanthine oxidase are interconvertable thus, these two enzyme forms and their reactions often are referred to as xanthine oxidoreduotase. Xanthine oxidase is the rate-limiting enzyme in purine catabolism of hypoxanthine to uric acid via xanthine. Both xanthine oxidase and xanthine dehydrogenase play important roles in the ... 

Purine degradation, purine catabolism a series of reactions in which purines are degraded by cleav-... 

Amphibian livers decompose allantoin to urea (278). This process requires two enzymes the first is allantoinase, which hydrolyzes allantoin to allantoic acid, and the second is allantoicase, which cleaves allantoic acid to glyoxylic acid and 2 moles of urea (279-281). Several species of teleost fishes convert allantoin only as far as allantoic acid, but most fishes, amphibia, and fresh water lamellibranchs possess allantoicase as well as allantoinase and degrade allantoin to glyoxylic acid and urea (282). Of interest is the further breakdown of urea to CO2 and NH3, which are the end products of purine catabolism by Crustacea and other lower forms (283). These reactions are shown in Fig. 16. 

Fumarate is hydrated to malate in a freely reversible reaction cat alyzed by fumarase (also called fumarate hydratase, see Figure 9.6). [Note- Fumarate is also produced by the urea cycle (see p. 251), in purine synthesis (see p. 293), and during catabolism of the amino acids, phenylalanine and tyrosine (see p. 261).]... 

As indicated in Fig. 25-18, free adenine released from catabolism of nucleic acids can be deaminated hydrolytically to hypoxanthine, and guanine can be deaminated to xanthine.328 The molybdenum-containing xanthine oxidase (Chapter 16) oxidizes hypoxanthine to xanthine and the latter on to uric acid. Some Clostridia convert purine or hypoxanthine to xanthine by the action of a selenium-containing purine hydroxylase.3283 Another reaction of xanthine occurring in some plants is conversion to the trimethylated derivative caffeine. 328b One of the physiological effects of caffeine in animals is inhibition of pyrimidine synthesis.329 However, the effect most sought by coffee drinkers may be an increase in blood pressure caused by occupancy of adenosine receptors by caffeine.330... 

All organisms synthesize, interconvert, and catabolize various purine and pyrimidine nucleotides. However, cells of different types, or even the same cells in different stages of development, differ greatly in their ability to carry out some of the reactions involved, with some cells favoring one set of reactions and others another. In the rest of the chapter we deal with the details of these reactions. 

Adenine phosphoribosyltransferase catalyzes the conversion of adenine to AMP in many tissues, by a reaction similar to that of hypoxanthine-guanine phosphoribosyltransferase, but is quite distinct from the latter. It plays a minor role in purine salvage since adenine is not a significant product of purine nucleotide catabolism (see below). The function of this enzyme seems to be to scavenge small amounts of adenine that are produced during intestinal digestion of nucleic acids or in the metabolism of 5 -deoxy-5 -methylthioadenosine, a product of polyamine synthesis. 

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... 

In addition to the obvious role in the catabolism of macromolecules, the TCA cycle provides numerous intermediates for anabolic reactions, such as the synthesis of porphyrins from succinyl-CoA, purines from a-ketoglutarate, pyrimidines from fumarate and oxaloacetate, and proteins from amino acids derived from oxaloacetate, fumarate, and a-ketoglutarate. 

The lung also possesses nonenzymatic antioxidants such as vitamin E, beta-carotene, vitamin C, and uric acid. Vitamin E is lipid-soluble and partitions into lipid membranes, where it is positioned optimally for maximal antioxidant effectiveness. Vitamin E converts superoxide anion, hydroxyl radical, and lipid peroxyl radicals to less reactive oxygen metabolites. Beta-carotene also accumulates in cell membranes and is a metabolic precursor to vitamin A. Furthermore, it can scavenge superoxide anion and react directly with peroxyl-free radicals, thereby serving as an additional lipid-soluble antioxidant. Vitamin C is widely available in both extracellular and intracellular spaces where it can participate in redox reactions. Vitamin C can directly scavenge superoxide and hydroxyl radical. Uric acid formed by the catabolism of purines also has antioxidant properties and primarily scavenges hydroxyl radical and peroxyl radicals from lipid peroxidation. 

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. 

Hypoxanthine is also a product of catabolism of purine nucleotides (Figure 22.7). Hypoxanthine can be converted to xanthine by the enzyme xanthine oxidase in the reaction that follows ... 

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. 

Xanthine oxidase (XO) catalyzes the hydroxylation of hypoxanthine to xanthine and xanthine to uric acid. It plays an important role in the catabolism of purines.As shown in Figure 7.11, this reaction is slightly more complicated than the pure oxo-transfer reaction catalyzed by the other two enzymes discussed in this review. The structure of the XO active site has also been more controversial than for the other two enzymes. However, using a combination of crystallographic, EXAFS and computational studies it has been shown that the oxidized state has the structure MoOS(OH)(MPT), with the 0x0 group in the axial position. " Extensive experimental and theoretical investigations have been performed on XO and related enzymes " and the latter are summarized in Table 7.3. 

---