Adenine, 8- , xanthine oxidase

Adenine phosphoribosyltransferase (APRT) deficiency is an inherited disorder of purine metabolism and is inherited in an autosomal recessive manner (K18, V7). This enzyme deficiency results in an inability to salvage the purine base adenine, which is oxidized via the 8-hydroxy intermediate by xanthine oxidase to 2,8-di-hydroxyadenine (2,8-DHA). This produces crystalluria and the possible formation of kidney stones due to the excretion of excessive amounts of this insoluble purine. Type I, with virtually undetectable enzyme activity, found predominantly in Caucasians, is found in homozygotes or compound heterozygotes for null alleles. Type II, with significant APRT activity, found only in Japan, is related to a missense mu-... 

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. 

Prosthetic groups Flavine Adenine Dinucleotide (FAD) Glycine oxidase, Fumaric hydrogenase, Xanthine oxidase... 

XOD is one of the most complex flavoproteins and is composed of two identical and catalytically independent subunits each subunit contains one molybdenium center, two iron sulfur centers, and flavine adenine dinucleotide. The enzyme activity is due to a complicated interaction of FAD, molybdenium, iron, and labile sulfur moieties at or near the active site [260], It can be used to detect xanthine and hypoxanthine by immobilizing xanthine oxidase on a glassy carbon paste electrode [261], The elements are based on the chronoamperometric monitoring of the current that occurs due to the oxidation of the hydrogen peroxide which liberates during the enzymatic reaction. The biosensor showed linear dependence in the concentration range between 5.0 X 10 7 and 4.0 X 10-5M for xanthine and 2.0 X 10 5 and 8.0 X 10 5M for hypoxanthine, respectively. The detection limit values were estimated as 1.0 X 10 7 M for xanthine and 5.3 X 10-6M for hypoxanthine, respectively. Li used DNA to embed xanthine oxidase and obtained the electrochemical response of FAD and molybdenum center of xanthine oxidase [262], Moreover, the enzyme keeps its native catalytic activity to hypoxanthine in the DNA film. So the biosensor for hypoxanthine can be based on... 

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. 

The amino groups are replaced with oxygen. Although here a biochemical reaction, the same can be achieved under acid-catalysed hydrolytic conditions, and resembles the nucleophilic substitution on pyrimidines (see Section 11.6.1). The first-formed hydroxy derivative would then tautomerize to the carbonyl structure. In the case of guanine, the product is xanthine, whereas adenine leads to hypoxanthine. The latter compound is also converted into xanthine by an oxidizing enzyme, xanthine oxidase. This enzyme also oxidizes xanthine at C-8, giving uric acid. 

The similarity in the pyrimidine ring of pteridines and pterins, especially to the purines adenine and guanosine, undoubtedly makes them good templates for inhibitor design as these examples show. Another enzyme for which inhibition by pteridines has been established is xanthine oxidase <1999BBA387>. In this case, the limitation on structure for inhibitors in the pteridine series was that there should be no substituent on C-7 and that the pteridines should be fully conjugated. The best inhibitors (ICso 0.1 xM) were 6-formylpterin and 6-hydroxylumazine. 

Xanthine oxidase, which requires Fe, Mo and flavin adenine dinucleotide (FAD) as co-factors, is capable of oxidizing lipids via the production of superoxide radicals. It represents about 20% of the MFGM protein and part is readily lost from the membrane, e.g. on cooling isoelectric focusing... 

The inhibition of enzyme systems dues nut necessarily cause unwarned effects. Consider the enzyme xanthine oxidase. It contains two atoms of molybdenum, four Fe2S2, and two FAD (flavin adenine dinucleotidei moieties, and it has a molecular weight of 275.000-300.000. There is no evidence that the two units (Mo/SFe Sj/FAD) are near each other or interact in any way. It is believed that the immediate environment of each molybdenum atom consists of one oxygen and three sulfur atoms (additional ligands may be present) 12... 

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... 

Oral administration of 42 to rats resulted in extensive reduction to trimethoprim106. The 1,4-di-N-oxide olaquindox (49), a substance used as a growth promotor in cattle breeding, pig husbandry and poultry farming, has been shown to be converted to a limited extent to the 4-mono-N-oxide in rats164, and compound 46 was readily reduced to N,N-diallylmelamine both in vivo and in vitro109. The anerobic reduction, in the presence of xanthine oxidase, of a series of purine N-oxides, such as adenine 1-N-oxide or guanine... 

Aldehyde Oxidase. This enzyme is usually found in similar locations to xanthine oxidase or dehydrogenase and has been isolated from insects, birds, and mammals (20, 21). Aldehyde oxidase seems to be a poor choice of name for this enzyme because, while it oxidizes aldehydes to carboxylic acids, it also accepts a variety of purines and pyrimidines as oxidizable substrates. For example, aldehyde oxidase catalyzes the conversion of 2-hydroxypyrimidine to uracil and of adenine to 8-hydroxy-adenine (25). It appears that xanthine oxidase and aldehyde oxidase are... 

Overproduction of superoxide ( Op has been implicated in the pathogenesis of various cardiovascular diseases. The main sources of human superoxide include the nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) enzyme complex, cyclooxygenase, mitochondrial oxidases, xanthine oxidase, and nitric... 

Metabolic pathways for the conversion of adenine. Adenine is normally salvaged by conversion to AMP by adenine phosphoribosyltransferase (APRT). In the absence of APRT, adenine is oxidized to the highly insoluble product 2,8-dihydroxyadenine by xanthine oxidase. 

Xanthine oxidase, which is capable of catalyzing the conversion of hypoxanthine and xanthine to uric acid, was first detected in 1882 by Horbaczewski (Hll), who noted that extracts of various tissues could catalyze the conversion of xanthine to uric acid. A similar enzyme was detected in milk (M15). These enzymes contain a flavin-adenine dinucleotide prosthetic group (C9). As a result of the essential nature of the flavin-adenine dinucleotide portion of the enzjmie, a striking parallelism was seen between the riboflavin content of the diet and the xanthine oxidase concentration in tissues of growing rats (DIO). The enzyme contains molybdenum. That the molybdenum is contained in a functionally important component has been demonstrated by several workers (G13, T5). Totter and his associates injected labeled molybdate into a cow, and then isolated the enzyme from the milk to show that the proportion between the molybdenum and flavin remained constant at a value of 0.5. Corran et al. (C9) postulated that the xanthine oxidase of milk is identical with the xanthine oxidase of liver, but the protein portions of the enzyme appear to differ. 

Xanthine oxidase is a rather nonspecific enzyme it not only catalyzes the oxidation of hypoxanthine and xanthine, but also the conversion of adenine to 2,8-dihydroxyadenine (B23, K9) as well as the oxidation of many unusual purines, such as 2-azaadenine (S14). It also acts on xanthopterin (K4), and catalyzes the oxidation of a variety of aldehydes and NADH. Several pterins, notably 2-amino-4-hydroxy-6-formyl- (K3), 2-amino-4-hydroxy-6-carboxy-, 2-amino-4-hydroxy-, and 6-hydroxymethyl- (P3) pterins, inhibit xanthine oxidase. A variety of purines are both substrate and inhibitor of the enzyme. Antabuse (tetraethylthiuram disulfide) has a considerable inhibitory effect on xanthine oxidase in rat... 

With the exception of reduced -nicotinamide adenine dinucleotide (NADH), substrates interact at the Mo centre and two electrons are transferred from the substrate to Mo(VI), reducing the metal to Mo(IV). The substrate residue reacts with an oxo ligand of Mo and a proton also reduces a terminal sulphide ligand of Mo. Hydrolysis of the Mo-substrate complex releases oxidized product, while the Mo(IV) is reoxidized by intramolecular transfer to other redox centres. The catalytic mechanism as described by Bray is depicted below [23], Aldehyde oxidase and xanthine oxidase can each take up to six... 

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