Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Enzymes involved in various protective and metabolic processes of carbonyl compounds were analysed utilising a micro-array method in a three-stage in vitro model for oral carcinogenesis involving cultured normal, immortalised and malignant human oral keratinocytes. A complete transcript profiling of identified carbonyl-metabolising enzymes belonging to the ADH, ALDH, SDR and AKR families is presented. Expression of 17 transcripts was detected in normal, 14 in immortalized and 19 in malignant keratinocytes of a total of 12,500 genes spotted on the micro-array chip. For the detected transcripts, about half were changed by cell transformation, and for the various enzyme families, differences in expression patterns were observed. The detected AKR transcripts displayed a conserved pattern of expression, indicating a requirement for the keratinocyte phenotype, while most of the detected SDRs displayed changed expression at the various stages of malignancy. The importance of multiple experiments in using a microarray technique for reliable results is underlined and, finally, the strength of the method in detecting co-expressed enzymes in metabolic pathways is exemplified by the detection of the formaldehyde-scavenging pathway enzymes and the polyol pathway enzymes.
Cell Mol Life Sci 2001 Oct
PMID:Micro-array chip analysis of carbonyl-metabolising enzymes in normal, immortalised and malignant human oral keratinocytes. 1170 98

Distribution of ADH, ALP, FBALD, GAPDH, G3PDH, G6PDH, GPI, LDH, MDH, PGM, and SOD was identified in retina, heart, muscle, liver, kidney, gills, brain, gut, lung and ovary of the African lungfish. Data are compared with patterns previously described in dipnoans and other vertebrates. The number of loci expressed for all enzymes was found to be similar to those of diploid Actinopterygii. Differences in the number of loci expressed in Amphibia were found for ALP, sG3PDH, GPI, LDH, MDH and SOD. Differences in tissue distribution were noted in ALP due to the absence of an intestinal-specific form typical of teleostean fish, amphibians, reptiles and birds, and in GPI and MDH, due to the tissue expression, as in primitive fish. There were also differences in LDH, where a third locus (LDH-C*) was expressed in the gills of Protopterus annectens and not in the retina or liver tissues, as in teleosts. LDH-A4 was most common in all the tissues. Major differences were noted in the tissue patterns of protein expression in the three dipnoans compared. As expected, the least divergence was found between the two species belonging to the same family (Lepidosirenidae). The highest index of divergence was observed between Neoceratodus forsteri and Lepidosiren paradoxa, belonging to the families Ceratontidae and Lepidosirenidae, respectively. The divergence is revealed by changes at the enzyme and morphological levels. These results suggest that P. annectens occupies an interesting systematic position, its biochemical characteristics distinguishing it from N. forsteri, L. paradoxa, the advanced fish and amphibians.
Comp Biochem Physiol B Biochem Mol Biol 2002 Jan
PMID:Multilocus isozyme systems in African lungfish, Protopterus annectens: distribution, differential expression and variation in dipnoans. 1174 62

The nucleotide sequences of the Adh and Adhr genes of Drosophila kuntzei were derived from combined overlapping sequences of clones isolated from a genomic library and from cloned PCR and inverse-PCR fragments. Only a proximal promoter was detected upstream of the Adh gene, indicating that D. kuntzei Adh is regulated by a one-promoter system. Further upstream of the Adh structural gene, an adult enhancer region (AAE) was found that contains most of the regulatory sequences described for AAEs of other Drosophila species. Analysis of the ADH protein showed an amino acid change from valine to threonine in the active site at position 189 which is also found in D. funebris but is otherwise unique among Drosophila. This difference alone may be responsible for the very low ADH activity found in this species and may cause a difference in substrate usage pattern. Codon bias in Adh and Adhr was comparable and found to be very low compared with other species. Phylogenetic analysis showed that D. kuntzei is closest related to D. funebris and D. immigrans. The time of divergence between D. kuntzei and D. funebris was estimated to be 14.2-20.2 Myr and that between D. kuntzei-D. funebris and D. immigrans to be 30.8-44.0 Myr. An analysis of the genetic variation in the Adh gene and upstream sequences of four European strains showed that this gene was highly variable. Overall nucleotide diversity (pi) was 0.0139, which is two times higher than that in D. melanogaster.
Mol Biol Evol 2002 Jul
PMID:Isolation and characterization of the genomic region from Drosophila kuntzei containing the Adh and Adhr genes. 1208 23

High levels of inbreeding are expected to cause a strong reduction in levels of genetic variability, effective recombination rates and in adaptation compared with related outcrossing populations. We examined patterns of DNA polymorphism at five nuclear loci and one chloroplast locus within and between four populations of the outcrossing plant Arabidopsis lyrata, a close relative of the highly self-fertilizing model species A. thaliana. The observed patterns are compared with species-wide polymorphism at orthologous loci, as well as within- and between-population patterns at other studied loci in A. thaliana. In addition to evidence for much higher average within-population diversity, species-wide levels of silent polymorphism are generally higher in A. lyrata than in A. thaliana, unlike the results from a previous study of the ADH locus. However, polymorphism is also low in the North American A. lyrata subspecies lyrata compared with the European subspecies petraea, suggesting either a population bottleneck in North American populations or recent admixture involving diverged European populations. Differentiation between the two subspecies is strong, although there are few fixed differences, suggesting that their isolation is recent. Estimates of intralocus recombination rates and analysis of haplotype structure in European A. lyrata populations indicate lower recombination than predicted based on the variability together with physical recombination rates estimated from A. thaliana. This may be due to strong population subdivision, or to recent departures from demographic equilibrium such as a bottleneck or population admixture. Alternatively, there may be consistently lower recombination rates in the outcrossing species. In contrast, estimates of recombination rates from species-wide samples of A. thaliana are close to the values expected assuming a high rate of self-fertilization. Complex population histories in both A. thaliana and A. lyrata complicate theoretical predictions and empirical tests of the effects of inbreeding on polymorphism and molecular evolution.
Mol Ecol 2003 May
PMID:Subdivision and haplotype structure in natural populations of Arabidopsis lyrata. 1269 88

In the olive fruit fly Bactrocera oleae and the med fly Ceratitis capitata previous studies have shown the existence of two Adh genes in each species. This observation, in combination with the former finding that various Drosophila species of virilis and repleta group encode two isozymes of ADH which are the result of a gene duplication, challenged us to address a scenario dealing with the evolutionary history of the Adh gene duplication in Tephritidae. In our lab we proceeded to the cloning and sequence analysis of Adh genes from more tephritid species, a prerequisite for further study of this issue. Here we show that phylogenetic trees produced from either the nucleotide or the amino acid sequences of 14 tephritid Adh genes consisted of two main clusters, with Adh sequences of the same "type" grouping together (i.e., Adh1 sequences form a cluster and Adh2 sequences form a second one), as expected if there was one duplication event before speciation within the family Tephritidae. We used the amount of divergence between the two isozymic forms of Adh of the species carrying both Adh1 and Adh2 genes to obtain an estimate of the age of the duplication event. Interestingly, our data again support the hypothesis that the duplication of an ancestral Adh single gene in the family Tephritidae occurred before the emergence of the genera Bactrocera and Ceratitis, thus suggesting that Adh duplication was based on a prespeciation rather than a postspeciation event that might have involved two independent duplication events, one in each of the two genera.
J Mol Evol 2003 Aug
PMID:Exploring the evolutionary history of the alcohol dehydrogenase gene (Adh) duplication in species of the family tephritidae. 1456 61

Alcohol dehydrogenase is considered a very important enzyme in insect metabolism because it is involved (in its homodimeric form) in the catalysis of the reversible conversion of various alcohols in larval feeding sites to their corresponding aldehydes and ketones, thus contributing to detoxification and metabolic purposes. Using 14 amino acid ADH sequences recently determined in our laboratory, we constructed a three-dimensional (3D) model of olive fruit fly Bactrocera oleae ADH1 and ADH2, based on the known homologous Drosophila lebanonensis ADH structure, and the amino acid residues that have been proposed as being responsible for catalysis were located on it. Moreover, in a comparative study of the ADH sequences, the residues occupying characteristic positions in the ADH of species of the Bactrocera and Ceratitis genera (called genus-specific) as well as residues appearing only in ADH1 or ADH2 (called isozymic-specific) were defined and localized on the 3D model. All regions important for catalytic activity, such as those forming the substrate- and coenzyme-binding sites, are highly conserved in all tephritid species examined. Genus-specific amino acids are located on the outside of the protein, on loops and regions predicted to be antigenic. The higher percentage of genus-specific amino acid variation seems to be centered in the NAD adenine-binding site, located near the surface of the protein molecule. Nine of 12 isozymic-specific positions are lined along an "arc" on the surface of the protein, thus linking the two "monomer bases" of the dimer via the C-terminal interacting loops. Furthermore, the distribution of isozymic- and genus-specific amino acids on the monomer-monomer interface may have some evolutionary significance. Most amino acids predicted to be antigenic are positioned in peripheral regions of nonfunctional importance, but surprisingly, an additional antigenic region is contained within the (highly conserved in tephritids) C-terminal tail.
J Mol Evol 2004 May
PMID:Functional constraints of alcohol dehydrogenase (ADH) of tephritidae and relationships with other Dipteran species. 1517 Feb 53

The first intron of the gene encoding one of the alcohol dehydrogenase isoenzymes (ADH-1) in Ceratitis capitata is highly polymorphic in size. Five size variants of this intron were isolated from different strains and populations and characterized. Restriction map and sequence analysis showed that the intron size polymorphism is due to the presence or absence of (a) a copy of a defective mariner-like element, postdoc; (b) an approximately 550-bp 3' indel which exhibits no similarity to any known sequence; and (c) a central duplication of 704 bp consisting of part of the 3' end of the postdoc element, the region between postdoc and the 3' indel, and the first 20 bp of the 3' indel. The homologous Adh-1 intron was amplified from the congeneric species, Ceratitis rosa, in order to obtain an outgroup for comparative and phylogenetic analyses. The C. rosa introns were polymorphic in size, ranging from about 1100 to 2000 bp, the major difference between them being the presence or absence of a mariner-like element Crmar2, unrelated to the postdoc element. Phylogenetic analysis suggests that the shorter intron variants in C. capitata may represent the ancestral form of the intron, the longest variants apparently being the most recent.
J Mol Evol 2004 Jun
PMID:Molecular basis of the size polymorphism of the first intron of the Adh-1 gene of the mediterranean fruit fly, Ceratitis capitata. 1546 30

Drosophila alcohol dehydrogenase (DADH) is an NAD+-dependent enzyme that catalyzes the oxidation of alcohols to aldehydes/ketones and that is also able to further oxidize aldehydes to their corresponding carboxylic acids. The structure of the ternary enzyme-NADH-acetate complex of the slow alleloform of Drosophila melanogaster ADH (DmADH-S) was solved at 1.6 A resolution by X-ray crystallography. The coenzyme stereochemistry of the aldehyde dismutation reaction showed that the obtained enzyme-NADH-acetate complex reflects a productive ternary complex although no enzymatic reaction occurs. The stereochemistry of the acetate binding in the bifurcated substrate-binding site, along with previous stereochemical studies of aldehyde reduction and alcohol oxidation shows that the methyl group of the aldehyde in the reduction reaction binds to the R1 and in the oxidation reaction to the R2 sub-site. NMR studies along with previous kinetic studies show that the formed acetaldehyde intermediate in the oxidation of ethanol to acetate leaves the substrate site prior to the reduced coenzyme, and then binds to the newly formed enzyme-NAD+ complex. Here, we compare the three-dimensional structure of D.melanogaster ADH-S and a previous theoretically built model, evaluate the differences with the crystal structures of five Drosophila lebanonensis ADHs in numerous complexed forms that explain the substrate specificity as well as subtle kinetic differences between these two enzymes based on their crystal structures. We also re-examine the electrostatic influence of charged residues on the surface of the protein on the catalytic efficiency of the enzyme.
J Mol Biol 2005 Jan 21
PMID:Drosophila alcohol dehydrogenase: acetate-enzyme interactions and novel insights into the effects of electrostatics on catalysis. 1558

High frequencies of the fast allele of alcohol dehydrogenase-2 (Adh-2F) are found in populations of Drosophila mojavensis that inhabit the Baja California peninsula (race BII) whereas the slow allele (Adh-2S) predominates at most other localities within the species' geographic range. Race BII flies utilize necrotic tissue of pitaya agria cactus (Stenocereus gummosus) which contains high levels of 2-propanol, whereas flies from most other localities utilize different cactus hosts in which 2-propanol levels are low. To test if 2-propanol acts as a selective force on Adh-2 genotype, or whether some other yet undetermined genetic factor is responsible, mature males of D. mojavensis lines derived from the Grand Canyon (race A) and Santa Catalina Island (race C), each with individuals homozygous for Adh-2F and Adh-2S, were exposed to 2-propanol for 24 h and ADH-2 specific activity was then determined on each genotype. Flies from five other localities homozygous for either the fast or slow allele also were examined. Results for all reported races of D. mojavensis were obtained. 2-propanol exposure inhibited ADH-2 specific activity in both genotypes from all localities, but inhibition was significantly less in two populations of race BII flies homozygous for Adh-2F. When F/F and S/S genotypes in flies from the same locality were compared, both genotypes showed high 2-propanol inhibition that was not statistically different, indicating that the F/F genotype alone does not provide a benefit against the inhibitory effects of 2-propanol. ADH-1 activity in female ovaries was inhibited less by 2-propanol than ADH-2. These results do not support the hypothesis that 2-propanol acts as a selective factor favoring the Adh-2F allele.
J Exp Zool B Mol Dev Evol 2005 Mar 15
PMID:Inhibition of alcohol dehydrogenase after 2-propanol exposure in different geographic races of Drosophila mojavensis: lack of evidence for selection at the Adh-2 locus. 1572 39

The ability to modify plant traits is of great commercial potential in agricultural biotechnology. To this end we have engineered plant-based zinc finger protein transcription factors (ZFP TFs) that minimize the use of non-plant DNA sequences. This novel architecture supports the use of tandem arrays of zinc-finger DNA recognition domains such that the ZFP TF binds a contiguous DNA target site - thus emulating the design of ZFP TFs described previously for mammalian gene regulation. We show that this plant-based ZFP TF architecture supports high affinity DNA binding while allowing the specificity of the DNA-protein interaction to be determined by the amino acid sequences of the recognition helices. This plant-based backbone thus supports the use of previously characterized DNA recognition helices originally identified in a mammalian ZFP context without using mammalian DNA sequences. Moreover, we show that plant-based ZFP TFs employing this new architecture can up-regulate endogenous ADH activity by > 20-fold in transgenic Arabidopsis. Thus plant-based ZFP TFs are shown to be potent regulators of gene expression in vivo.
Plant Mol Biol 2005 Feb
PMID:Gene regulation in planta by plant-derived engineered zinc finger protein transcription factors. 1583 Jan 30


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