Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.17.1.4 (xanthine dehydrogenase)
1,236 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurospora crassa can utilize various purine bases such as xanthine or uric acid and their catabolic products as a nitrogen source. Four classes of mutants which affect the purine degradative pathway were isolated and studied. Mutants of the aln-1 class specifically lack allantoinase, while alc-1 mutants lack allantoicase. Mutants designated as xdh-1 cannot utilize hypoxanthine as a nitrogen source and are presumed to be deficient in xanthine dehydrogenase activity. A regulatory mutant, amr, was found to have only very low, uninduced levels of uricase, allantoinase, and allantoicase. None of these genes are closely linked to each other. The three initial enzymes involved in the catabolism of uric acid are controlled in a complex manner by both induction and repression. Several lines of evidence indicate that the true inducer of uricase and allantoicase is uric acid. The use of the newly isolated mutant strains made it possible to demonstrate that neither allantoin nor allantoic acid could act as inducers. Furthermore, hypoxanthine itself was shown to be ineffective as an inducer although it can be metabolized to form an inducer. A non-metabolizable analogue of uric acid, 8-azaxanthine, is a gratuitous inducer of these enzymes. Uricase and allantoicase were found to be synthesized coordinately, but they were not coordinately regulated with allantoinase. Both uricase and allantoicase are stable enzymes and do not undergo turnover; nor are they subject to feedback inhibition by ammonia. Allantoinase, however, is quite labile both in vivo and in vitro. This enzyme was found to turnover in vivo in the presence of cycloheximide with a half-life of approximately 20 minutes. The amr (for ammonia regulation) mutant cannot utilize a wide range of compounds, including purines, nitrate, and many amino acids as a nitrogen source and also displays a multiple enzyme loss. The amr gene appears to play a major role in the control of nitrogen metabolism. It is postulated that the amr locus encodes a regulatory protein which is required to activate transcription of the structural genes for a group of related enzymes involved in nitrogen metabolism.
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PMID:Genetic and metabolic control of the purine catabolic enzymes of Neurospora crasse. 12 63

Xanthine dehydrogenase (EC 1.2.1.37) is the first enzyme in the degradative pathway by which fungi convert purines to ammonia. In vivo, the activity is induced 6-fold by growth in uric acid. Hypoxanthine, xanthine, adenine, or guanine also induce enzyme activity but to a lesser degree. Immunoelectrophoresis using monospecific antibodies prepared against Neurospora crassa xanthine dehydrogenase shows that the induced increase in enzyme activity results from increased numbers of xanthine dehydrogenase molecules, presumably arising from de novo enzyme synthesis. Xanthine dehydrogenase has been purified to homogeneity by conventional methods followed by immunoabsorption to monospecific antibodies coupled to Sepharose 6B. Electrophoresis of purified xanthine dehydrogenase reveals a single protein band which also exhibits enzyme activity. The average specific activity of purified enzyme is 140 nmol of isoxanthopterine produced/min/mg. Xanthine dehydrogenase activity is substrate-inhibited by xanthine (0.14 mM), hypoxanthine (0.3 mM), and pterine (10 micron), is only slightly affected by metal binding agents such as KCN (6 mM), but is strongly inhibited by sulfhydryl reagents such as p-hydroxymercuribenzoate (2 micron). The molecular weight of xanthine dehydrogenase is 357,000 as calculated from a sedimentation coefficient of 11.8 S and a Stokes radius of 6.37 nm. Sodium dodecyl sulfate-gel electrophoresis of the enzyme reveals a single protein band having a molecular weight of 155,000. So the xanthine dehydrogenase protein appears to be a dimer. In contrast to xanthine dehydrogenases from animal sources which typically possess as prosthetic groups 2 FAD molecules, 2 molybdenum atoms, 8 atoms of iron, and 8 acid-labile sulfides, the Neurospora enzyme contains 2 FAD molecules, 1 molybdenum atom, 12 atoms of iron, and 14 eq of labile sulfide/molecule. The absorption spectrum of the enzyme shows maxima between 400 and 500 nm typical of a non-heme iron-containing flavoprotein.
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PMID:Regulation, purification, and properties of xanthine dehydrogenase in Neurospora crassa. 14 74

E.p.r- (electron-paramagnetic-resonance) spectroscopy was used to compare chemical environment and reactivity of molybdenum, flavin and iron-sulphur centres in the enzyme xanthine dehydrogenase from Veillonella alcalescens (Micrococcus lactilyticus) with those of the corresponding centres in milk xanthine oxidase. The dehydrogenase is frequently contaminated with small but variable amounts of a species resistant to oxidation and giving a new molybdenum (V) e.p.r. signal, "Resting I". There is also a "desulpho" form of the enzyme giving a Slow Mo(V) signal, indistinguishable from that of the milk enzyme. Molybdenum of the active enzyme behaves in a manner analogous to that of the milk enzyme, giving a Rapid Mo(V) signal on partial reduction with substrates or dithionite. Detailed comparison shows that molybdenum in each enzyme must have the same ligand atoms arranged in the same manner. As with the milk enzyme, complex-formation between reduced dehydrogenase and purine substrate molecules, presumably interacting at the normal substrate-binding site, modifies the Rapid signal, confirming that such substrates interact near molybdenum. The dehydrogenase-flavin semiquinone signal is identical with that of the oxidase but, in contrast, there is only one iron-sulphur signal. The latter gives an e.p.r. spectrum similar to that of aldehyde oxidase.
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PMID:Studies by electron-paramagnetic-resonance spectroscopy on the mechanism of action of xanthine dehydrogenase from Veillonella alcalescens. 17 32

Studies by e.p.r. (electron-paramagnetic-resonance) spectroscopy and by stopped-flow spectrophotometry on turkey liver xanthine dehydrogenase revealed strong similarities to as well as important differences from the Veillonella alcalescens xanthine dehydrogenase and milk xanthine oxidase. The turkey enzyme is contaminated by up to three non-functional forms, giving molybdenum e.p.r. signals designated Resting I, Resting II and Slow. Slow and to a lesser extent Resting I signals are like those from the Veillonella enzyme, whereas Resting II is very like a resting signal described by K. V. Rajagopolan, P. Handler, G. Palmer & H. Beinert (1968) (J. Biol. Chem. 243, 3784-3796) for aldehyde oxidase. Another non-functional form that gives the Inhibited signal is produced on treatment of the enzyme with formaldehyde. Stopped-flow measurements at 450 nm show that, as for the milk enzyme, reduction by xanthine is rate-limiting in enzyme turnover. The active enzyme gives rise to Very Rapid and Rapid molybdenum(V) e.p.r. signals, as well as to an FADH signal. That these signals are almost indistinguishable from those of the milk enzyme, confirms the similarities between the active sites. There are two types of iron-sulphur centres that give signals like those in the milk enzyme, though with slightly different parameters. Quantitative reduction titration of the functional enzyme with xanthine revealed two important differences between the turkey and the milk enzymes. First, the turkey enzyme FADH/FADH2 system has a redox potential sufficiently low that xanthine is incapable of reducing the flavin completely. This finding presumably explains the very low oxidase activity. Secondly, whereas the Fe/S II chromophore in the milk enzyme has a relatively high redox potential, for the turkey enzyme the value of this potential is lower and similar to that of its Fe/S I chromophore.
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PMID:Studies by electron-paramagnetic-resonance spectroscopy and stopped-flow spectrophotometry on the mechanism of action of turkey liver xanthine dehydrogenase. 17 33

A new non-functional modified form of milk xanthine oxidase is described. This contains molybdenum in a quinquivalent state, which is resistant to both oxidation and reduction. The new species is derived from the native enzyme in a two-step process. The first step is the conversion into the desulpho form, via loss of the 'persulphide' sulphur, and the second involves reaction with ethylene glycol or other reagents. The species gives a characteristic Mo(V) electron-paramagnetic-resonance signal, without proton splittings, designated Resting II. This is virtually identical with signals reported previously from resting turkey liver xanthine dehydrogenase and rabbit liver aldehyde oxidase. The possibility is discussed that species Resting II, prepared with ethylene glycol, contains a -COCH2OH residue bound to a nitrogen ligand of molybdenum.
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PMID:A new non-functional form of milk xanthine oxidase containing stable quinquivalent molybdenum. 18 Sep 83

The kinetics of reduction of turkey liver xanthine dehydrogenase by substrates were investigated by stopped-flow spectrophotometry. The results may be explained in terms of the known redox potentials of the various centres in the enzyme [Barber, Bray, Cammack & Coughlan (1977) Biochem. J. 163, 279-289]. They are, morover, consistent with the scheme [Olson, Ballou, Palmer & Massey (1974) J. Biol. Chem. 249, 4363-4382] in which reduction occurs in three consecutive steps, one molecule of substrate reacting with the active site at each step. First-order rate constants believed to correspond respectively to the combined first and second steps and to the third step in the reduction by excess of xanthine and of NADH were determined. The rates of reaction with these substrates in the combined first and second steps are independent of the degree of enzyme functionality.
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PMID:Stopped-flow spectrophotometric studies on the reaction of turkey liver xanthine dehydrogenase with reducing substrates. 20 67

Inactivation of chicken liver xanthine dehydrogenase by arsenite is reflected in the molybdenum electron paramagnetic resonance signal at g = 1.97. The arsenite spectrum shows additional splittings and considerable broadening yet remains comparable to the native in total intensity. Further subtle alterations of the molybdenum signal of arsenite-treated enzyme are seen in the presence of purine-type substrates or inhibitors.
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PMID:The interaction of arsenite with the molybdenum center of chicken liver xanthine dehydrogenase. 21 Aug 44

The release and metabolism of adenosine was examined using rat fat cells in which the nucleotide pool has been labeled by incubation with radioactive adenine. The accumulation of adenosine in the medium was near maximal at the start of the incubation and increased only slightly thereafter. Adenosine was rapidly deaminated to inosine and subsequently oxidized to uric acid. In the presence of allopurinol, and inhibitor of xanthine dehydrogenase, hypoxanthine accumulated in the medium as the end-product of adenosine catabolism. Adenosine accumulated in the medium only if fat cells were incubated in the presence of erythro-9-(2-hydroxy-3-nonyl)adenine, an inhibitor of adenosine deaminase. Even in the presence of this inhibitor there was no acceleration of adenosine release by norepinephrine in the presence of theophylline. However, there was an increase in labeled intracellular AMP accumulation by norepinephrine plus theophylline. The increase in labeled AMP correlated with the final free fatty acid to albumin ratio suggesting that the rise in AMP was related to an accumulation of intracellular free fatty acids. The addition of sodium oleate to the medium mimicked the effect of norepinephrine plus theophylline on the accumulation of labeled AMP. These results indicate that AMP rather than adenosine accumulates in isolated fat cells during incubation with lipolytic agents.
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PMID:Effect of lipolytic agents on adenosine and AMP formation by fat cells. 22 45

Chicken liver xanthine dehydrogenase, like other xanthine-oxidizing enzymes, is a dimer of Mr = 150,000 subunits. Each subunit contains one molybdenum, one FAD, and two distinct Fe2S2 centers. Treatment with a number of proteases shows that the native enzyme subunit is cleaved at three distinct sites. However, the cleavage products can be separated only under denaturing conditions. Prolonged treatment with subtilisin at pH 10.1 has permitted the isolation of an Mr = 65,000 catalytically active fragment that is devoid of FAD but which contains the molybdenum and both types of iron-sulfur center. A model of the domain structure of the native enzyme is proposed.
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PMID:Isolation of the domain containing the molybdenum, iron-sulfur I, and iron-sulfur II centers of chicken liver xanthine dehydrogenase. 22 49

Maroon-like homozygotes are completely deficient for xanthine dehydrogenase (XDH) and aldehyde oxidase (AO), however, ma-l is not a structural locus for either enzyme. Quantitative immunoelectrophoresis of ma-l and wild type extracts suggests that the ma-l function must be post-translational. To determine whether the ma-l function involves some direct physical changes in XDH and/or AO the enzymes were characterized with respect to temperature sensitivity and behavior in gel sieving electrophoresis. Since the XDH and AO from complementary ma-l heterozygotes is more thermolabile and different in shape from wild type XDH and AO, we conclude that ma-l is involved in a post-translational modification of these enzymes.
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PMID:Gene expression in Drosophila: post-translational modification of aldehyde oxidase and xanthine dehydrogenase. 28 73


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