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The Drosophila saltans group of the subgenus Sophophora consists of five species subgroups whose phylogenetic relationships are poorly known. We have analyzed 2085 coding nucleotides from the xanthine dehydrogenase (Xdh) gene in six species, at least one from each subgroup. We follow a model-based maximum likelihood framework. We first model the substitution process using a tree topology that is approximately accurate. Then we evaluate several candidate tree topologies using a working model of nucleotide substitution. We found that a minimally realistic description of the substitution process along the Xdh region should allow two transition and four transversion rate parameters and different fixed rates for codon positions, which are distributed statistically according to different gamma distributions. The phylogeny obtained using this description differs in significant respects from a phylogeny based on anatomical criteria. We have also analyzed data from five additional (three nuclear and two mitochondrial) gene regions. In our analysis, these relatively short DNA sequences, either separately or jointly, fail to discriminate statistically among alternative phylogenies. When the data for these five gene regions are combined with the Xdh sequences, the strong phylogenetic signal emerging from Xdh becomes somewhat diluted rather than reinforced. The phylogeny of the species and biogeographical considerations suggest that the D. saltans group originated in the tropics of the New World, similarly as the closely related D. willistoni group.
Mol Phylogenet Evol 1999 Oct
PMID:Molecular evolution and phylogeny of the Drosophila saltans species group inferred from the Xdh gene. 1050 44

The idea that the pattern of point mutation in Drosophila has remained constant during the evolution of the genus has recently been challenged. A study of the nucleotide composition focused on the Drosophila saltans group has evidenced unsuspected nucleotide composition differences among lineages. Compositional differences are associated with an accelerated rate of amino acid replacement in functionally less constrained regions. Here we reassess this issue from a different perspective. Adopting a maximum-likelihood estimation approach, we focus on the different predictions that mutation and selection make about the nonsynonymous-to-synonymous rate ratio. We investigate two gene regions, alcohol dehydrogenase (Adh) and xanthine dehydrogenase (Xdh), using a balanced data set that comprises representatives from the melangaster, obscura, saltans, and willistoni groups. We also consider representatives of the Hawaiian picture-winged group. These Hawaiian species are known to have experienced repeated bottlenecks and are included as a reference for comparison. Our results confirm patterns previously detected. The branch ancestral to the fast-evolving willistoni/saltans lineage, where most of the change in GC content has occurred, exhibits an excess of synonymous substitutions. The shift in mutation bias has affected the extent of the rate variation among sites in Xdh.
J Mol Evol 2000 Jan
PMID:Fluctuating mutation bias and the evolution of base composition in Drosophila. 1065 54

In this study, the hypouricemic efficacy of a novel xanthine oxidase/xanthine dehydrogenase inhibitor, TEI-6720, was compared with that of allopurinol in a hyperuricemic rat model established by feeding the animals oxonate, a uricase inhibitor. In addition, using normal rats, the changes in xanthine concentration in plasma and the concentrations and absolute quantities of uric acid, allantoin and xanthine in urine were analyzed during a 28-day period of repeated administration of TEI-6720 to determine the changes occurring during this period and the conditions required for the formation of xanthine crystals and calculi in comparison with allopurinol. TEI-6720 and allopurinol caused a significant dose-dependent decrease in plasma uric acid levels in the hyperuricemic rat model and the ED50 of TEI-6720 was lower than that of allopurinol, indicating that in terms of hypouricemic efficacy TEI-6720 is more potent than allopurinol. TEI-6720 also showed more potent activity than allopurinol in decreasing urinary uric acid and allantoin levels in normal rats. In addition, TEI-6720 and allopurinol showed similar dose-response curves for the decrease in uric acid or allantoin concentration, and the associated increase in xanthine concentration, indicating that TEI-6720 and allopurinol have similar pharmacological characteristics although the dosage required differs. The efficacy of TEI-6720 in increasing plasma and urinary xanthine levels in normal rats was approximately 10- to 30-fold greater than that of allopurinol. However, with respect to renal xanthine calculus formation, there was only about a 3-fold difference in dosage comparing TEI-6720 and allopurinol. This difference suggests that there may be another factor independent of xanthine, and dependent on the drug itself, involved in renal calculus formation caused by allopurinol. The daily excretion of purine metabolites per body weight was about 20-fold higher in rats than in humans. From these results, it is concluded that TEI-6720 has potent hypouricemic activity and that, compared to allopurinol, administration of TEI-6720 is not likely to result in a higher incidence of calculus formation.
Res Commun Mol Pathol Pharmacol 1999
PMID:A comparative study on the hypouricemic activity and potency in renal xanthine calculus formation of two xanthine oxidase/xanthine dehydrogenase inhibitors: TEI-6720 and allopurinol in rats. 1074 81

The buzzatii complex of the mulleri subgroup (Drosophila repleta group) consists of three clusters of species whose evolutionary relationships are poorly known. We analyzed 2,085 coding nucleotides from the xanthine dehydrogenase (XDH:) gene in the 10 available species of the complex and Drosophila mulleri and Drosophila hydei. We adopted a statistical model-fitting approach within the maximum-likelihood (ML) framework of phylogenetic inference. We first modeled the process of nucleotide substitution using a tree topology which was reasonably accurate. Then we used the most satisfactory description so attained to reconstruct the evolutionary relationships in the buzzatii complex. We found that a minimally realistic description of the substitution process of XDH: should allow six substitution types and different substitution rates for codon positions. Using this description we obtained a strongly supported, fully resolved tree which is congruent with the already-known (yet few) relationships. We also analyzed published data from three mitochondrial cytochrome oxidases (CO I, II, and III). In our analyses, these relatively short DNA sequences failed to discriminate statistically among alternative phylogenies. When the data of these three gene regions are combined with the XDH: sequences, the phylogenetic signal emerging from XDH: becomes reinforced. All four of the gene regions evolve faster in the buzzatii and martensis clusters than in the stalkeri cluster, paralleling the amount of chromosomal evolution.
Mol Biol Evol 2000 Jul
PMID:Molecular evolution and phylogeny of the buzzatii complex (Drosophila repleta group): a maximum-likelihood approach. 1088 24

This symposium was organized to present some aspects of current research pertaining to lung redox function. Focuses of the symposium were on roles of pulmonary endothelial NADPH oxidase, xanthine oxidase (XO)/xanthine dehydrogenase (XDH), heme oxygenase (HO), transplasma membrane electron transport (TPMET), and the zinc binding protein metallothionein (MT) in the propagation and/or protection of the lung or other organs from oxidative injury. The presentations were chosen to reflect the roles of both intracellular (metallothionein, XO/XDH, and HO) and plasma membrane (NADPH oxidase, XO/XDH, and unidentified TPMET) redox proteins in these processes. Although the lung endothelium was the predominant cell type under consideration, at least some of the proposed mechanisms operate in or affect other cell types and organs as well.
Am J Physiol Lung Cell Mol Physiol 2000 Sep
PMID:Lung redox homeostasis: emerging concepts. 1095 13

Rooting is frequently the most precarious step in any phylogenetic analysis. Outgroups can become useless for rooting if they are too distantly related to the ingroup. Specifically, little attention has been paid to scenarios where outgroups have evolved different nucleotide frequencies from the ingroup. We investigate one empirical example that arose seeking to determine the phylogenetic relationship between the saltans and the willistoni groups of Drosophila (subgenus Sophophora). We have analyzed 2085 coding nucleotides from the xanthine dehydrogenase (Xdh) gene in 14 species, 6 from the saltans group and 8 from the willistoni group. We adopt a two-step strategy: (1) we investigate the phylogeny without outgroups, rooting the network by the midpoint method; (2) we reinvestigate the rooting of this phylogeny using predefined outgroups in both a parsimony- and a model-based maximum-likelihood framework. A satisfactory description of the substitution process along the Xdh region calls for six substitution types and substitution rate variation among codon positions. When the ingroup sequences are considered alone, the phylogeny obtained using this description corroborates the known relationships derived from anatomical criteria. Inclusion of the outgroups makes the root unstable, apparently because of differences between ingroups and outgroups in the substitution processes; these differences are better accounted for by a simplified model of evolution than by more complex, realistic descriptions of the substitution process.
Mol Phylogenet Evol 2000 Sep
PMID:Tree rooting with outgroups when they differ in their nucleotide composition from the ingroup: the Drosophila saltans and willistoni groups, a case study. 1099 88

The molecular basis for heart failure is unknown, but oxidative stress is associated with the pathogenesis of the disease. We tested the hypothesis that the activity of xanthine oxidoreductase (XOR), a free-radical generating enzyme, increases in hypertrophied and failing heart. We studied XOR in two rat models: (1) The monocrotaline-induced right ventricular hypertrophy and failure model; (2) coronary artery ligation induced heart failure, with left ventricular failure and compensatory right ventricular hypertrophy at different stages at 3 and 8 weeks post-infarction, respectively. XOR activity was measured at 30 degrees C and the reaction products were analysed by HPLC. In both models XOR activity in hypertrophic and control ventricles was similar. In the monocrotaline model, the hearts showed enhanced XOR activity in the failing right ventricle (65+/-5 mU/g w/w), as compared to that in the unaffected left ventricle (47+/-3 mU/g P<0.05, n=6-7). In the coronary ligation model, XOR activities did not differ at 3 and 8 weeks. In the infarcted left ventricle, XOR activity increased from 29.4+/-1.4 mU/g (n=6) in sham-operated rats, to 48+/-3 and 80+/-6 mU/g (n=8 P<0.05 v sham) in the viable and infarcted parts of failing rat hearts, respectively. With affinity-purified polyclonal antibody, XOR was localized in CD68+ inflammatory cells of which the number increased more in the failing than in sham-operated hearts. Our results show that the expression of functional XOR is elevated in failing but not in hypertrophic ventricles, suggesting its potential role in the transition from cardiac hypertrophy into failure.
J Mol Cell Cardiol 2000 Nov
PMID:Enhanced expression and activity of xanthine oxidoreductase in the failing heart. 1104 Jan 11

Rhizobium tropici strain CIAT899 displays a high intrinsic thermal tolerance, and had been used in this work to study the molecular basis of bacterial responses to high temperature. We generated a collection of R. tropici CIAT899 mutants affected in thermal tolerance using TnS-luxAB mutagenesis and described the characterization of a mutant strain, CIAT899-10T, that fails to grow under conditions of high temperature. Strain CIAT899-10T carries a single transposon insertion in a gene showing a high degree of similarity with the guaB gene of Escherichia coli and other organisms, encoding the enzyme inosine monophosphate dehydrogenase. The guaB strain CIAT899-10T does not require guanine for growth due to an alternative pathway via xanthine dehydrogenase and, phenotypically, in addition to the thermal sensitivity, the mutant is also defective in symbiosis with beans, forming nodules that lack rhizobial content. Guanine and its precursors restore wild-type tolerance to grow at high temperature. Our data show that, in R. tropici, the production of guanine via inosine monophosphate dehydrogenase is essential for growth at extreme temperatures and for effective nodulation.
Mol Plant Microbe Interact 2000 Nov
PMID:A guaB mutant strain of Rhizobium tropici CIAT899 pleiotropically defective in thermal tolerance and symbiosis. 1105 89

In contrast to its parent strain, transposon Tn5-Mob insertion mutant HB6 of the facultative chemoautotroph Ralstonia eutropha was unable to grow organoautotrophically on formate and exhibited no activity of Mo-dependent, membrane-bound formate dehydrogenase (M-FDH) when cultivated mixotrophically on fructose plus formate. The activity of another molybdoenzyme, the soluble, NAD+-linked formate dehydrogenase which is the key enzyme of formate utilization in R. eutropha, was greatly diminished in the mutant. HB6 also lacked the W-dependent M-FDH activities that were newly discovered in organoautotrophically, lithoautotrophically, or mixotrophically grown wildtype cells. However, an additional W-dependent M-FDH activity, observed in heterotrophically grown stationary-phase cells, was present in the mutant although at a considerably reduced level. Sequence analyses of the complementing chromosomal wildtype and the corresponding mutant DNA fragment revealed the transposon insertion to be located in moeA, a gene involved in the biosynthesis of the molybdopterin cofactor (MoCo). Nevertheless, mutant HB6 was able to grow on xanthine as carbon and energy source and with nitrate as nitrogen source. The utilization of these substrates requires the function of the MoCo-containing enzymes xanthine dehydrogenase and assimilatory nitrate reductase, respectively, that were still active in the mutant. A moeA deletion mutant exhibited the same phenotype as that of HB6. The moeA gene belongs to an unusual mol operon consisting of four genes (moeA, moaD, moaE, and moaF) and being constitutively expressed at low level. Unlike MoeA, the large subunit of molybdopterin synthase encoded by moaE is essential for molybdopterin biosynthesis as was evident by the phenotype of a moaE deletion mutant. MoaF is a novel gene product which showed no similarity to proteins with known function but was indispensable for reconstituting organoautotrophic growth in HB6. The findings suggest that MoeA of R. eutropha is differentially involved in the biosynthesis or incorporation of pterin cofactors of/into the various molybdo- and tungstoenzymes.
J Mol Microbiol Biotechnol 2001 Oct
PMID:Involvement of an unusual mol operon in molybdopterin cofactor biosynthesis in Ralstonia eutropha. 1154 79

We investigated the evolution of xanthine dehydrogenase (Xdh) in 34 species from the three multicellular kingdoms, including one plant, two fungi, and three animal phyla, two classes of vertebrates, four orders of mammals, and two orders of insects. We adopted a model-based maximum-likelihood framework of inference. After accounting for among-site rate variation and heterogeneous nucleotide composition of the sequences using the discrete gamma distribution, and using nonhomogeneous nonstationary representations of the substitution process, the rate of amino acid replacement is 30.4 x 10(-10)/site/year when Drosophila species are compared but only approximately 18 x 10(-10)/site/year when comparisons are made between mammal orders, between insect orders, or between different animal phyla and approximately 11 x 10(-10)/site/year when comparisons are made between birds and mammals, between fungi, or between the three multicellular kingdoms. To account for these observations, the rate of amino acid replacement must have been eight or more times higher in some lineages and at some times than in others. Spastic evolution of Xdh appears to be related to the particularities of the genomes in which the locus is embedded.
J Mol Evol
PMID:Xanthine dehydrogenase (XDH): episodic evolution of a "neutral" protein. 1167 9


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