Xanthine oxidase action

Howes, B. D., Bray, R. C., Richards, R. L., Turner, N. A., Bennett, B., and Lowe, D. J., 1996, Evidence favoring molybdenum-carbon bond formation in xanthine oxidase action 0- and C-ENDOR and kinetic studies, Biochemistry 35 143291443. 

At the present time, the greatest importance of covalent hydration in biology seems to lie in the direction of understanding the action of enzymes. In this connection, the enzyme known as xanthine oxidase has been extensively investigated.This enzyme catalyzes the oxidation of aldehydes to acids, purines to hydroxypurines, and pteridines to hydroxypteridines. The only structural feature which these three substituents have in common is a secondary alcoholic group present in the covalently hydrated forms. Therefore it was logical to conceive of this group as the point of attack by the enzyme. 

Superoxide is formed (reaction 1) in the red blood cell by the auto-oxidation of hemoglobin to methemo-globin (approximately 3% of hemoglobin in human red blood cells has been calculated to auto-oxidize per day) in other tissues, it is formed by the action of enzymes such as cytochrome P450 reductase and xanthine oxidase. When stimulated by contact with bacteria, neutrophils exhibit a respiratory burst (see below) and produce superoxide in a reaction catalyzed by NADPH oxidase (reaction 2). Superoxide spontaneously dismu-tates to form H2O2 and O2 however, the rate of this same reaction is speeded up tremendously by the action of the enzyme superoxide dismutase (reaction 3). Hydrogen peroxide is subject to a number of fates. The enzyme catalase, present in many types of cells, converts... 

Hille R, H Sprecher (1987) On the mechanism of action of xanthine oxidase. J Biol Chem 262 10914-10917. 

The possibility that there might be long-range electron transfer between redox-active centers in enzymes was first suspected by biochemists working on the mechanism of action of metalloenzymes such as xanthine oxidase which contain more than one metal-based redox center. In these enzymes electron transfer frequently proceeds rapidly but early spectroscopic measurements, notably those by electron paramagnetic resonance, failed to provide any indication that these centers were close to one another. 

Allopurinol, in contrast to the uricosuric drugs, reduces serum urate levels through a competitive inhibition of uric acid synthesis rather than by impairing renal urate reabsorption. This action is accomplished by inhibiting xanthine oxidase, the enzyme involved in the metabolism of hypoxanthine and xanthine to uric acid. After enzyme inhibition, the urinary and blood concentrations of uric acid are greatly reduced and there is a simultaneous increase in the excretion of the more soluble uric acid precursors, xanthine and hypoxanthine. 

Mechanism of Action A xanthine oxidase inhibitor that decreases uric acid production by inhibiting xanthine oxidase, an enzyme. Therapeutic Effect Reduces uric acid concentrations in both serum and urine. 

Moini, H., Guo, Q., and Packer, L., Enzyme inhibition and protein-binding action of the procya-nidin-rich french maritime pine bark extract, pycnogenol effect on xanthine oxidase, J. Agric. 

Guerciohni R, Szumlanski C, Weinshilboum RM Human liver xanthine oxidase nature and extent of individual variation. Chn Pharmacol Ther 50 663-672, 1991 Guisti P, Ducic I, Puia G, et al Imidazenil a new partial positive allosteric modulator of gamma-amniobutyiic acid (GABA) action of GABAa receptors. J Pharmacol Exp Ther 266 1018-1028, 1993... 

Allopurinol is approximately 80% absorbed after oral administration and has a terminal serum half-life of 1-2 hours. Like uric acid, allopurinol is itself metabolized by xanthine oxidase, but the resulting compound, alloxanthine, retains the capacity to inhibit xanthine oxidase and has a long enough duration of action so that allopurinol is given only once a day. 

Formation of the hydroxyl radical. Because the killing of certain microbes was dependent on the ability of PMNs to undergo the respiratory burst, the actual microbicidal species was sought. It had been shown that a potent oxidant was formed during the catalytic action of xanthine oxidase on xanthine an enzymic reaction which, like the PMN, produces both 07 and H2O2. This potent oxidant was proposed to be the hydroxyl radical formed by the reaction between O7 and H2O2 (reaction 4). Because such an oxidant seemed a likely candidate to mediate the microbicidal activity of PMNs, the formation of OH was assessed in PMNs. 

Interception by various antioxidants of superoxide anions generated by the catalytic action of xanthine oxidase in converting xanthine to uric acid. 

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. 

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... 

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