Xanthine, degradation

One of the steps in the metabolic degradation of guanine is hydrolysis lo give xanthine. Propose a mechanism. 

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.

The initial electrochemical and biological oxidation with xanthine oxidase are essentially identical. However, electrochemically 2,8-dioxyadenine the final product in the presence of xanthine oxidase is much more readily oxidizable than adenine 59) so that considerable further oxidation occurs. To the authors knowledge, 2,8-dioxyadenine is not a major metabolite of adenine in man or other higher organisms. Accordingly, it is likely that other enzymes accomplish further degradation of 2,8-dioxyadenine. The relationship between the products so formed and the mechanism of the reaction to the related electrochemical processes has yet to be studied. 

It is usually accepted that the augmentation of the XO activity in ischemic tissues undergoing reperfusion is a consequence of the formation of hypoxanthine from degradation of ATP in the presence of dioxygen. It has been confirmed by Xia and Zweier [55] who studied the mechanism of stimulation of the XO-catalyzed superoxide production in postischemic tissues. It was found that an increase in superoxide production in isolated rat hearts after reperfusion was triggered by the enhancement of hypoxanthine and xanthine levels due to the degradation of ATP during ischemia. 

Gout is one of the most ancient diseases its clinical characteristics have been known for at least 2000 years. It is now very effectively treated with drugs that decrease production of uric acid by inhibition of the enzyme xanthine oxidase in purine degradation (Figure 10.9) (allopurinol), and a drug that increases the excretion of uric acid (probenecid)... 

Azaguanine and thioguanine are catabolized by guanase, and both the purinethiones are degraded by xanthine oxidase. Methylation and demethylation is an important factor in the activity of the thiopurihes and certain adenine or adenosine analogues also. 

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. 

In the most important degradative pathway for adenosine monophosphate (AMP), it is the nucleotide that deaminated, and inosine monophosphate (IMP) arises. In the same way as in GMP, the purine base hypoxanthine is released from IMP. A single enzyme, xanthine oxidase [3], then both converts hypoxanthine into xanthine and xanthine into uric acid. An 0X0 group is introduced into the substrate in each of these reaction steps. The oxo group is derived from molecular oxygen another reaction product is hydrogen peroxide (H2O2), which is toxic and has to be removed by peroxidases. 

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. 

In man, BH4 is degraded either nonenzymatically by side-chain cleavage to pterin or is enzymatically metabolized in the gastrointestinal tract to become a lumazine [2]. Pterin and dihydropterin are converted by xanthine dehydrogenase to isoxanthopterin and xanthopterin, respectively [3,4]. It is assumed, however, that most of the ingested BH4 is used as a cofactor (mainly for PAH in the liver) and is catabolized to nonfluorescing compounds it may even be degraded to C02 and ammonia. 

Hyaluronate of bovine synovial fluid was extensively degraded within 30 min in the presence of the xanthine oxidase system, as indicated by the decrease of the relative viscosity. This degradation of hyaluronate was inhibited by (Cu,Zn)-SOD and by catalase The formation of OH radicals was attributed to an iron-catalysed... 

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. 

Hypoxanthine is oxidized by xanthine oxidase to xanthine, which is further oxidized by xanthine oxidase to uric acid, the final product of human purine degradation. Uric acid is excreted in the urine. 

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