Xanthine, purine degradation

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)... 

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. 

In addition to analyzing compounds, enzyme sensor has been used to determine the freshness of meats. Xanthine oxidase has been used to determine the levels of xanthine and hypoxanthine that are accumulated from purine degradation during muscle aging so as to monitor fish freshness for a long time. Traditional methods including the automated colorimetric method (54) were time consuming. Jahn et al (55) developed a dipstick test by... 

Allopurinol is a drug given to gout sufferers. It inhibits an enzyme of the purine degradation pathway called xanthine oxidase by acting in the capacity of a substrate. However, its product, oxidized allopurinol, is not able to leave the active site of the enzyme, thus blocking it. Is there a name for this type of substrate What inhibition kinetics would you observe with a Lineweaver-Burk plot, and why ... 

A very important enzyme is xanthine oxidase, which catalyzes two reactions in the purine degradation process. It contains a number of subunits, and Fe, Mo, and FAD are its prosthetic groups. It acts, in this case, as an oxidase using 02 as an electron sink. In other reactions, however, this enzyme can act as a dehydrogenase using NAD+ as an oxidizing agent. A xanthine oxidase... 

See p. 350 in Biochemistry (2nd ed.) for role of xanthine oxidase in purine degradation. 

Xanthine oxidase The enzyme that catalyzes the final steps in purine degradation to produce urate. This enzyme is inhibited by compounds such as aUopurinol in treatment regimens designed to decrease sodium urate concentrations in the blood. 

Experiments with liver slices and cultured cell lines have corroborated this pathway of purine degradation. In human liver slices 16 xanthine derivatives were produced from caffeine by action of P-450 system. Demethylation at N-3 was the most prominent process [18, 19]. Comparison of cell lines from humans, hamsters, mice, and rats show some interspecies differences but all of them demethylated and oxidized caffeine [20]. Human liver cells give 1,3,7-trimethylurate as the major metabolite of caffeine, but also made were the intermediate products theobromine, theophylline, and paraxanthine [21]. Human liver microsomes convert theophylline to 1-methylxanthine, 3-methylxanthine, and 1,3-dimethyluric acid [22, 23]. Human kidney microsomes produced each of the three possible demethylated products as well as 1,3,7-... 

See also Urea Cycle Reactions, Urea, Antioxidants (from Chapter 15), Excessive Uric Acid in Purine Degradation (from Chapter 22), Purine Degradation (from Chapter 22), Pathways in Nucleotide Metabolism (from Chapter 22), HGPRT, Hypoxanthine, Xanthine Oxidase... 

Hyperuricemia in Lotta Topa ne s case arose as a consequence of over-j production of uric acid. Treatment with allopurinol not only inhibits xan-thine oxidase, lowering the formation of uric acid with an increase in the excretion of hypoxanthine and xanthine, but also decreases the overall synthesis of purine nucleotides. Hypoxanthine and xanthine produced by purine degradation are salvaged (i.e., converted to nucleotides) by a process that requires the consumption of PRPP. PRPP is a substrate for the glutamine phosphoribosyl amidotransferase reaction that initiates purine biosynthesis. Because the normal cellular levels of PRPP and glutamine are below the of the enzyme, changes in the level of either substrate can accelerate or reduce the rate of the reaction. Therefore, decreased levels of PRPP cause decreased synthesis of purine nucleotides. 

Xanthine oxidase (EC 1.2.3.2). Failure to convert xanthine to uric acid (see Purine degradation). Xanthine therefore replaces uric acid as end product of purine metabolism. Urinary xanthine greatly increased. Urinary uric acid abnormally low. Xanthine calculi tend to form in renal tract. 

Malabsorption of molybdenum. Activities of xanthine oxidase, sulfite oxidase and aldehyde oxidase are therefore deficient (see Molybdoenzymes). Urinary xanthine and uric acid high and low, respectively (see Purine degradation). Mental retardation, seizures, cerebral atrophy, lens dislocation. 

U.a. is generated from xanthine by the enzyme xanthine oxidase (see Purine degradation). The amino nitrogen from the degradation of amino adds can also be transferred to U.a. The enzyme uricase converts U. a. to allantoin (uricolysis see Purine degradation). 

Xanthine, Xan 2,6-dihydroxypurine, a purine and the starting point for Purine degradation (see). 152.1, m.p. >400°C (d.). Xan was discovered in 1817 in renal stones. It occiu in the free form, accompanied by other purines. Some derivatives are physiologically important, in particular xanthosine phosphates and Methylated xanthines (see). 

Xanthina oxidase, xanthine dehydrogenase, Schardtnger enzyme an enzyme of aerobic purine degradation, which catalyses the oxidation of hypoxan-thine to xanthine, and xanthine to uric acid Hypox-anthine + HjO + 62 -> Xanthine -h H2O2 Xanthine + H2O -H O2 -> Uric acid + H2O2. It is a dimeric enzyme, M, 275,000, pH-optimum 4.7, pi 5.35, containing 2 FAD, 2 Mo and 8 Fe (data for the enzyme from milk). The substrate specificity is low it catalyses the oxidation of other purines (e. g. adenine), aU-phatic and aromatic aldehydes, pyrimidines, pteri-dines and other heterocyclic compounds. 

Compared with purine alkaloids, an extensive number of studies have investigated cytokinins, and many reviews have been published. Readers interested in this topic are directed to a number of recent, excellent reviews [27,62, 73]. The studies on paralytic shellfish toxin metabolism in the cyanobacteria suggested that saxi-toxin and derivatives are converted into xanthine, urea, and further to CO2 and NH4 or recycled via primary metabolism through the purine degradation pathway [74]. Details on the current status of saxitoxin 16 and tetrodotoxin 17 can be found in recent reviews [28, 46, 47, 50, 75]. 

When xanthine oxidase was depleted in the liver by dietary means, the homogenate was unable to oxidize any of the above substrates. However, addition of purified milk xanthine oxidase to the homogenate restored the normal pattern of oxidation, thus demonstrating the importance of xanthine oxidase in purine degradation. 

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 (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. 

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. 

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