Guanine 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.

Purine catabolism to uric acid and salvage of the poime bases hypoxanthine (derived from adenosine) and guanine are shown in 1-18-5. 

For birds, insects, and reptiles, which have an egg stage during development, so that water availability is severely restricted, the synthesis of a highly soluble excretory product would have serious osmotic consequences therefore most of the ammonia is converted to the virtually insoluble uric acid (urate). This product can be safely retained in the egg or excreted as a slurry of fine crystals by the adult. In birds that nest colonially this can accumulate in massive amounts on islands off the coast of Peru cormorants have deposited so much that this guano (hence the name guanine) is collected for use as a fertiliser. Uric acid is less effective as an excretory product, since it has a lower nitrogen content than urea (33%) and is more expensive to synthesise (2.25 molecules ATP per atom of nitrogen). Mammals do produce uric acid but as a product of purine catabolism (see above). 

Anabolic and catabolic pathways are involved in the metabolism of thiopurines (Fig. 2) (90,91,92). The enzyme hypoxanthine guanine phosphoribosylferase, responsible for bio-activation of thiopurines, converts 6-MP into 6-thioinosine monophosphate. 

GMP catabolism also yields uric acid as end product. GMP is first hydrolyzed to guanosine, which is then cleaved to free guanine. Guanine undergoes hydrolytic removal of its amino group to yield xanthine, which is converted to uric acid by xanthine oxidase (Fig. 22-45). 

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... 

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. 

Inosine formed by either route is then phosphorolyzed to yield hypoxanthine. Although, as we have previously seen, much of the hypoxanthine and guanine produced in the mammalian body is converted to IMP and GMP by a phosphoribosyltransferase, about 10% is catabolized. Xanthine oxidase, an enzyme present in large amounts in liver and intestinal mucosa and in traces in other tissues, oxidizes hypoxanthine to xanthine, and xanthine to uric acid (see fig. 23.20). Xanthine oxidase contains FAD, molybdenum, iron, and acid-labile sulfur in the ratio 1 1 4 4, and in addition to forming hydrogen peroxide, it is also a strong producer of the superoxide anion 02, a very reactive species. The enzyme oxidizes a wide variety of purines, aldehydes, and pteridines. 

Dietary purines are largely catabolized in the gut, rather than used by the body for the synthesis of nucleic acids. The end-product of purine catabolism in humans is uric add. The diet accounts f[ir less than half of the uric add appearing in the bloodstream, Most of the plasma uric add, or urate, originates from catabolism of the purines synthesized by the body (endogenous purines). The major purines are adenine and guanine. They occur mainly as nucleotides, such as adenosine triphosphate (ATP) and guanosine triphosphate (GTP), and as parts of nucleic acids. For example, the adenine in (UvfA occurs as adenosine monophosphate, and the adenine in DNA occurs as deoxyadenosine monophosphate. 

The purine catabolic pathway appears in Figure 8,31, The end-product of purine cataboiism in primates, and in some other vertebrates, is uric acid, Purine catabolism differs in other species. Urate oxidase catalyzes the breakdown of uric acid to allantoin. Allantoin can be further broken down to produce urea and glyoxyJate, Allantoin is the purine excretory pixiduct in some mammals and reptiles. Urea is the purine excretory product in fish. Guanine is the purine excretory product in pigs and spiders. Uric acid is used for the packaging and excretion of waste N from amino acids in birds and some reptiles. 

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. 

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. 

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

Nucleic acids contain bases of two different types, pyrimidines and purines. The catabolism of the purines, adenine and guanine, produces uric acid. At physiological hydrogen ion concentration. uric acid is mostly ioni/ed and present in plasma as sodium urate (Fig. I). An elevated. serum urate concentration is known as hyperuricaemia. Uric acid and urate are relatively insoluble molecules which readily precipitate out of aqueous solutions such as urine or synovial fluid (Fig. 2). The consequence of this is the medical condition, gout. 

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 ... 

As is well known, the two purines, adenine and guanine, originating from nucleic acids or from high-energy phosphate compounds like ATP or GTP, are catabolized in man to uric acid. The intermediately formed hypoxanthine and xanthine are both oxidized to uric acid by the enzyme xanthine oxidase. This enzyme introduces an oxygen atom between the carbon and hydrogen atom in position Cg. Of the two tautomeric forms of uric acid, the amido (lactam) and the imido (lactim) forms, the latter has a more acid character. 

The purine phosphoribosyltransferases permit cells to use exogenous or dietary purines, and this function is undoubtedly important to some bacteria and to those animal cells (e.g., erythrocytes) which do not synthesize purines de novo. The importance of this role in other animal cells in vivo is far from clear, however, as hypoxanthine is present in serum only at very low concentrations (50), and adenine and guanine have not been detected in normal serum. Purine bases (especially hypoxanthine and guanine) can be produced intracellularly by the catabolism of messenger RNA and soluble purine nucleotides their reutilization via the phosphoribosyltransferases would prevent the loss of these compounds from the cells. 

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. 

The importance of blood and, in particular, of erythrocytes as a vehicle for transport of purines is well known >. Considerable quantities of purines enter and leave the nucleotide pools of red cells which take up adenine, guanine, hypoxanthine, and xanthine and convert them into nucleotides. No matter what purine is taken up by erythrocytes, hypoxanthine appears to be the main purine released in vivo. Human erythrocytes cannot synthesize purines de novo and are unable to convert hypoxanthine or guanine into adenine. Hypoxanthine release is mediated by prior conversion of the various purine nucleotides to IMP. In the present paper, some of the mechanisms which regulate the catabolic paths of this nucleotide are studied. 

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