Xanthine formation from purines

Chronic gout is treated with allopurinol, a suicide inhibitor of xanthine oxidase the goal is to reduce the uric acid pool by inhibiting its formation from purines. The adverse effects of allopurinol are j considered. 

Purine bases are rather less reactive to HOCl than pyrimidines. Thus, in one study, treatment of guanine, adenine, or xanthine (60-62) with 1 or 2 equivalents of HOCl resulted only in high yields of starting material recovery. After prolonged exposure, variable yields of parabanic acid (63) were obtained (Hoyano et al., 1973). This compound has been demonstrated to be formed from both pyrimidines and purines in other high-energy oxidative processes (see, e. g., LeRoux et al. [1969]), but the details of its formation from purines by the HOCl process are not known. 

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.

Allopurinol is a uricosuric drug used in chronic gout that prevents formation of uric acid from purines by acting as a suicide substrate of xanthine oxidase. The drug is commonly used in patients undergoing treatment of cancer to slow down formation of uric acid derived from purines released by the cytotoxic action of drugs or radiation. The metabolism of 6-mercaptopurine (6-MP), a substrate for xanthine oxidase, is also inhibited by allopurinol, necessitating a major dose reduction to avoid its toxic effects. 

Formation from Elementary Precursors. Pigeon liver has been an indispensable tissue in the study of purine synthesis by in vitro techniques because it lacks the enzyme xanthine oxidase. Owing to the absence of xanthine oxidase, a substance accumulates during incubation of pigeon liver slices which may be converted into uric acid upon addition of the above-mentioned enzyme.This compound, correctly identified by Edson, Krebs, and Model as hypoxanthine,was believed to be an important intermediary in the synthesis of purines de novo. 

After discovering that extracts of Clostridium eylindrosporum and C. cridiurici which can derive their N, C, and energy from purine, e.g. xanthine, or 4-aminoimidazole, accumulated formate among other products, Rabinowitz and Pricer (1956) identified formimino ycine (FIG) as an intermediate, and then showed that formimino group transfer was involved. Details have since been adduced (VI, a-e) (Rabinowitz, 1958). 

An intermediate in the formation of uric acid from purines. It is excreted in the urine in large amounts in the inborn error of metabolism, xanthinuria, a condition in which xanthine stones can be found. It can be detected in urinary stones by its reaction with Ehrlich s diazo reagent to give a red colour. 

Dietary purines are not an important source of uric acid. Quantitatively important amounts of purine are formed from amino acids, formate, and carbon dioxide in the body. Those purine ribonucleotides not incorporated into nucleic acids and derived from nucleic acid degradation are converted to xanthine or hypoxanthine and oxidized to uric acid (Figure 36-7). Allopurinol inhibits this last step, resulting in a fall in the plasma urate level and a decrease in the size of the urate pool. The more soluble xanthine and hypoxanthine are increased. 

Amino-4-imidazole carboxamide ribotide, a precursor only two steps removed (formylation and cycli-zation) from inosinic acid, can be synthesized by the direct condensation of the imidazole with 5-phosphori-bosyl pyrophosphate. The enzyme catalyzing this reaction was purified from an acetone powder of beef liver. The same enzyme (AMP pyrophosphorylase) catalyzes the condensation of adenine, guanine, and hypoxan-thine. Nucleoside phosphorylase is an enzyme that catalyzes the formation of a ribose nucleoside from a purine base and ribose-1-phosphate. Guanine, adenine, xanthine, hypoxanthine, 2,6-diaminopurine, and aminoimidazole carboxamide are known to be converted to their respective nucleosides by such a mechanism. In the presence of a specific kinase and ATP, the nucleoside is then phosphorylated to the corresponding nucleotide. 

The first indication of an essential metabolic role for molybdenum was obtained in 1953, when it was discovered that xanthine oxidase, important in purine metabolism, was a metalloenzyme containing molybdenum. Subsequently the element was shown to be a component of two other enzymes, aldehyde oxidase and sulphite oxidase. The biological functions of molybdenum, apart from its reactions with copper (see p. 123), are concerned with the formation and activities of these three enzymes. In addition to being a component of xanthine oxidase, molybdenum participates in the reaction of the enzyme with cytochrome C and also facilitates the reduction of cytochrome C by aldehyde oxidase. 

Allopurinol therapy in hyperuricaemic man has been shown to be advantageous from two points of view. Firstly, it reduces urinary uric acid excretion and increases the excretion of the precursor purines xanthine and, to a lesser extent, hypoxanthine. In addition, total urinary purine excretion (the sum of these three) may be reduced by as much as 0 during allopurinol therapy (1). This latter effect has been attributed to the formation of nucleotides of either hypoxanthine (1) or allopurinol itself (2), which in turn exert a feed back inhibitary effect on the first enzyme of de novo purine synthesis. 

Uric Add Formation. In vertebrates purines are oxidized to uric acid. This reaction is catalyzed by xanthine oxidase (or dehydrogenase), which attacks both hypoxanthine and xanthine.Since adenine and guanine nucleotides can give rise to the hydroxylated purines either as the nucleotide, nucleoside, or free base, all of the naturally occurring purines of animals can be converted to uric acid. Adenine may also be oxidized to 2,8-dihydroxy-4-aminopurine, which is excreted in the urine. The formation of uric acid from any of its precursors is followed conveniently spectrophotometrically (Fig. 29). ... 

To end this chapter, we ll note that other kinds of complexes exist, whose formation may induce modifications of some physicochemical properties of the compounds giving them. Hence, their analysis may be perturbed. It is the case of ion pairs that we decided to include in the group of complexes and also of charge transfer derivatives. A good example is that of puric bases derived from 7H-purines xanthine, caffeine, theophylline, and theobromine. Some abnormal physical properties are exhibited by these derivatives. 

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