Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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A 1 ns trajectory from a molecular dynamics study of 1.4 ns total length was used for a detailed analysis of the residence times of water molecules located near 227 selected bovine pancreatic trypsin inhibitor (BPTI) atoms. The simulation was performed using the GROMOS force field, with apolar hydrogen atoms treated as united atoms, and the SPC/E water model. The system consisted of 568 BPTI atoms and 2371 water molecules. The theoretical results are in good agreement with experimental data available from nuclear magnetic resonance spectroscopy. The residence times of individual water molecules coming near a given BPTI atom, as obtained from the simulation, vary greatly and range between 10 and 500 ps. The effective residence time, calculated using a correlation function technique from the presence of all individual water molecules visiting the hydration shell of a given BPTI atom, never exceeds 200 ps. The average residence time near backbone and side-chain atoms is approximately 39 ps and 24 ps, respectively. The shortest residence times, on average, are found near charged atoms (19 ps), whereas near non-polar and polar side-chain atoms the residence times are 25 ps and 36 ps, respectively. There is no apparent correlation between the residence times of the hydration water molecules of solvent-accessible residues and their location in different regular or non-regular secondary structures.
J Mol Biol 1993 Jun 20
PMID:Hydration of proteins. A comparison of experimental residence times of water molecules solvating the bovine pancreatic trypsin inhibitor with theoretical model calculations. 768 28

A microsomal cytochrome P450 from the house fly (Musca domestica), termed P450lpr, is involved in P450 monooxygenase-mediated pyrethroid resistance and is expressed at 8-fold higher levels in the insecticide resistant LPR strain compared to a susceptible strain. An internal cDNA sequence was amplified by polymerase chain reaction (PCR) using degenerate primers based on known P450lpr polypeptide sequences, and the remainder of the sequence was amplified by single side-specific PCR. A 1.8 kb cDNA sequence was obtained from 3 overlapping PCR products, with an open reading frame encoding a P450 protein of 516 residues (M(r) 59,182). This gene has been designated CYP6D1 within the P450 gene superfamily. CYP6D1 exhibits most similarity (28.2-29.8% positional identity) to butterfly CYP6B1, house fly CYP6A1 and Drosophila CYP6A2, and also exhibits comparable similarity (24.7% identity) to rat CYP3A1. The deduced protein sequence contains a hydrophobic N-terminal region and conserved sequences thought to be involved in heme-binding and electron donor-protein interactions. Comparison of CYP6D1 with its four most similar proteins (CYP6B1, CYP6A1, CYP6A2 and CYP3A1) reveals the presence of extensive stretches of residues in an alignment row in 2 possible substrate-binding regions. Three introns of 74, 66 and 64 bp, having 5'-GT and AG-3' ends, split the CYP6D1 coding region in genomic DNA. Results indicate that CYP6D1 is likely the P450lpr gene.
Insect Biochem Mol Biol 1995 Feb
PMID:cDNA and deduced protein sequence of CYP6D1: the putative gene for a cytochrome P450 responsible for pyrethroid resistance in house fly. 771 55

Oxidative desulfuration of diethyldithiocarbamate methyl ester (DDTC-Me), a thione xenobiotic and a metabolite of disulfiram, was studied. Using a rat liver microsomal incubation system, DDTC-Me was oxidized at the thionosulfur group, forming DDTC-Me sulfine. Only minimal desulfuration of DDTC-Me to S-methyl-N,N-diethylthiolcarbamate (DETC-Me) occurred. Desulfuration of DDTC-Me increased 4-fold when the microsomal incubation was supplemented with reduced glutathione (GSH) and increased 8-fold when both GSH and glutathione-S-transferase (EC 2.5.1.18) were added. Similar results were obtained using a simplified system containing DDTC-Me sulfine, GSH, and glutathione-S-transferase. This suggested that DDTC-Me sulfine is a stable intermediate formed before DDTC-Me is desulfurated to DETC-Me. This unprecedented desulfuration process can be explained as follows. GSH attacks the oxithiirane isomer of DDTC-Me sulfine, resulting in ring opening followed by loss of glutathione hydrodisulfide, which is reduced by GSH to oxidized glutathione and H2S. GSH can also reduce DDTC-Me sulfine to DDTC-Me. This mechanism is supported by in vitro studies. An approximately 1:1 stoichiometry was observed for the formation of H2S and DETC-Me. A 1:1 stoichiometry was also observed for the consumption of DDTC-Me sulfine, formation of DETC-Me plus DDTC-Me, and formation of oxidized glutathione. Glutathione hydrodisulfide was trapped by derivatization in situ using 4-vinylpyridine. Oxidative desulfuration of a series of dithiocarbamate esters also followed a similar mechanism.
Mol Pharmacol 1994 Dec
PMID:Glutathione- and glutathione-S-transferase-dependent oxidative desulfuration of the thione xenobiotic diethyldithiocarbamate methyl ester. 780 45

The xyl genes in Lactobacillus pentosus are induced by xylose and repressed by glucose, ribose, and arabinose. Northern blot analysis showed that regulation is mediated at the transcriptional level. Under inducing conditions, two xylA transcripts were detected, a major transcript of 1.5 kb and a minor transcript of 3 kb. The 3 kb transcript also comprises sequences from xylB, suggesting that xylA and xylB are transcribed together. A 1.2 kb xylR transcript was found under inducing and non-inducing conditions. In the presence of xylose, a second xylR transcript (> 7 kb) was detected, which includes sequences from two upstream genes, xylQ and xylP. The transcription start sites for xylA and xylR were mapped by primer extension and S1 nuclease experiments at 42 and 83 nucleotides, respectively upstream of the translation start sites. Induction by xylose of the chloramphenicol acetyltransferase (CAT) gene under control of the xylA promoter, on a multicopy plasmid, was 60 to 80-fold, but only 3 to 10-fold in the presence of glucose and xylose. Expression of CAT under control of the xylR promoter was constitutive at a level tenfold less than that observed under control of the xylA promoter. Sequence analysis suggests the presence of two operator-like elements, one overlapping with the promoter -35 region of xylA and controlling the expression of xylA by binding factors involved in catabolite repression, and a second operator downstream of the promoter -10 region of xylA, which may bind the product of xylR, the repressor.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Gen Genet 1994 Oct 17
PMID:Promoter analysis and transcriptional regulation of Lactobacillus pentosus genes involved in xylose catabolism. 784 54

A 1:1 complex formed by the mutant Antennapedia(C39S) homeodomain and a 14 base-pair DNA duplex (molecular weight approximately 18,000) was prepared in which the protein was uniformly 13C-labeled. Using two-dimensional nuclear Overhauser enhancement (NOE) spectroscopy with 13C(omega 1, omega 2)-double-half-filter and three-dimensional 13C-correlated NOE spectroscopy, nearly complete sequence-specific resonance assignments were obtained for both the protein and the DNA in the complex. On this basis conformational constraints needed for a three-dimensional structure determination were collected. Using 855 intramolecular distance constraints as input, the structure of the DNA-bound Antp(C39S) homeodomain was calculated with the program DIANA, followed by restrained energy minimization with the program OPAL. A group of 20 conformers characterizes a well-defined structure for residues 8 to 56, with an average of 0.5 A of the pairwise root-mean-square deviations calculated for the backbone atoms of the individual conformers relative to the mean coordinates. The quality of the resulting structure is comparable to the one for the free protein, and the global fold of the free Antp(C39S) homeodomain was found to be conserved in the DNA complex. The structure of the DNA-bound protein was the starting point for the subsequent structure determination of the complete Antp(C39S) homeodomain-DNA complex in solution.
J Mol Biol 1993 Dec 20
PMID:Nuclear magnetic resonance spectroscopy of a DNA complex with the uniformly 13C-labeled Antennapedia homeodomain and structure determination of the DNA-bound homeodomain. 790 97

The mechanism by which etoposide, a topoisomerase II inhibitor, killed replicating mouse L929 fibroblasts was investigated. Etoposide at 10 microM killed 70% of the cells within 4 days, a result that was accompanied by DNA fragmentation. A characteristic "ladder" pattern of DNA fragmentation was confirmed by agarose gel electrophoresis. Simultaneous exposure of the cells to 10 microM etoposide plus 1 microM cycloheximide reduced both the extent of cell killing and the fragmentation of DNA. Delayed addition of cycloheximide protected cells only if cycloheximide was added 1-6 hr after exposure to etoposide. When added 6-24 hr after treatment with etoposide, cycloheximide lost the ability to protect cells. Cell growth was completely inhibited by either etoposide or cycloheximide. Furthermore, DNA synthesis was inhibited by either etoposide or cycloheximide within 6 hr. Protein synthesis, however, was not inhibited by etoposide. Thus, the ability of cycloheximide to protect cells correlated with inhibition of protein synthesis, rather than inhibition of DNA synthesis. A 1-hr exposure to 2.5 mM N-methyl-N-nitrosourea similarly inhibited DNA synthesis within 6 hr. without affecting protein synthesis. However, no loss of viability accompanied N-methyl-N-nitrosourea treatment. Thus, an imbalance between protein synthesis and DNA synthesis cannot explain the cell killing by etoposide. H-7, a protein kinase C inhibitor, prevented the cell killing and DNA fragmentation, whereas aurintricarboxylic acid, an endonuclease inhibitor, reduced the extent of DNA fragmentation but did not have an effect on cell killing. The data document that the killing of replicating mouse fibroblasts by etoposide represents an example of programmed cell death (apoptosis) that depends on protein synthesis. Although protein synthesis is required during the first 24 hr of exposure to etoposide, cell death is delayed until several days later.
Mol Pharmacol 1994 Nov
PMID:Programmed cell death (apoptosis) of mouse fibroblasts is induced by the topoisomerase II inhibitor etoposide. 796 76

The Adh (alcohol dehydrogenase, EC 1.1.1.1.) gene from Arabidopsis thaliana (L.) Heynh. can be induced by dehydration and cold, as well as by hypoxia. A 1-kb promoter fragment (CADH: -964 to +53) is sufficient to confer the stress induction and tissue-specific developmental expression characteristics of the Adh gene to a beta-glucuronidase reporter gene. Deletion mapping of the 5' end and site-specific mutagenesis identified four regions of the promoter essential for expression under the three stress conditions. Some sequence elements are important for response to all three stress treatments, whereas others are stress specific. The most critical region essential for expression of the Arabidopsis Adh promoter under all three environmental stresses (region IV: -172 to -141) contains sequences homologous to the GT motif (-160 to -152) and the GC motif (-147 to -144) of the maize Adh1 anaerobic responsive element. Region III (-235 to -172) contains two regions shown by R.J. Ferl and B.H. Laughner ([1989] Plant Mol Biol 12: 357-366) to bind regulatory proteins; mutation of the G-box-1 region (5'-CCACGTGG-3', -216 to -209) does not affect expression under uninduced or hypoxic conditions, but significantly reduces induction by cold stress and, to a lesser extent, by dehydration stress. Mutation of the other G-box-like sequence (G-box-2: 5'-CCAAGTGG-3', -193 to -182) does not change hypoxic response and affects cold and dehydration stress only slightly. G-box-2 mutations also promote high levels of expression under uninduced conditions. Deletion of region I (-964 to -510) results in increased expression under uninduced and all stress conditions, suggesting that this region contains a repressor binding site. Region II (-510 to -384) contains a positive regulatory element and is necessary for high expression levels under all treatments.
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PMID:Differential interactions of promoter elements in stress responses of the Arabidopsis Adh gene. 797 89

Reserpine treatment was used to examine whether short- and long-term neural stimulation regulates rat adrenal medullary dopamine beta-hydroxylase (DBH, EC 1.14.17.1) through transcriptional activation and to examine the extent of coordinate control of DBH and phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28). A single dose of reserpine (10 mg/kg i.p.) elevates DBH mRNA 1.5-fold by 6 h post-injection. Chronic treatment (10 mg/kg i.p., 4 alternate day injections) continues the rise in DBH mRNA, with a peak of 3.4-fold control values after 2 doses of reserpine and a plateau at this level thereafter. Even though DBH mRNA is elevated 6 h after a single injection of reserpine, DBH activity does not change in parallel. A 1.3-fold rise in activity occurs at 24 h post-injection. In contrast, chronic reserpine treatment concomitantly increases DBH activity and mRNA. As observed for DBH mRNA, enzyme activity peaks and plateaus after 2 injections on alternate days. However, the rise in enzymatic activity is less than the rise in mRNA (2.4-fold versus 3.4-fold). Ribosomal loading experiments demonstrate that the DBH mRNA pool is fully utilized for protein synthesis with an apparent decrease in the number of ribosomes loaded per molecule of mRNA. Western analysis and thermal denaturation studies indicate that an altered form of DBH may be expressed. With a single dose of reserpine, the enzyme shows a decline in specific activity while repeated treatment leads to an enzyme with higher specific activity. In both cases, the protein appears to be more stable. Reserpine treatment also markedly elevates adrenal glucocorticoids. A 1.5-fold increment in glucocorticoid receptor mRNA accompanies the corticosteroid rise, with the receptor mRNA peaking at 6 h and remaining at this level thereafter. The up-regulation of glucocorticoid receptor mRNA expression, together with the presence of a putative glucocorticoid response element in the 5' flanking region of the DBH gene, suggests that neural and hormonal regulatory mechanisms may work in concert to control DBH gene transcription. Finally, by comparison to PNMT, activation of DBH appears to require sustained stimulation of the neural axis, since acute changes in mRNA lead to only minor changes in enzyme expression. Similar to PNMT, continuous neural stimulation increases both DBH mRNA and enzymatic activity. However, the discordance in the magnitude of these indices suggests that other regulatory controls may be important in setting the ultimate limits on DBH expression, glucocorticoids perhaps being one such influence.
Brain Res Mol Brain Res 1994 Aug
PMID:Neural control of dopamine beta-hydroxylase in vivo: acute and chronic effects. 798 52

One-cell mouse embryos that block at the 2-cell stage can progress to the morula stage in CZB medium, but fail to cavitate and then swell and lyse. A 1-min exposure to 27 mM glucose at the 4-cell stage (approximately 42 hr) will support a high frequency of development to the blastocyst stage (75%) in the same medium. A glucose exposure is beneficial anytime between 30 and 54 hr of culture (67-73% blastocysts). Of a group of additional sugars and glucose analogues tested for their ability to replace glucose, only galactose was equivalent in promoting embryo development to the blastocyst stage (64% blastocysts).
Mol Reprod Dev 1994 Apr
PMID:One-minute exposure of 4-cell mouse embryos to glucose overcomes morula block in CZB medium. 801 25

We have investigated patterns of evolution in the nonrecombining portion of the Y chromosome in mice by comparing levels of polymorphism within Mus domesticus with levels of divergence between M. domesticus and M. spretus. A 1,277-bp fragment of noncoding sequence flanking the sex determining locus (Sry) was PCR amplified, and 1,063 bases were sequenced and compared among 20 M. domesticus and 1 M. spretus. Two polymorphic base substitutions and two polymorphic insertion/deletion sites were identified within M. domesticus; nucleotide diversity was estimated to be 0.1%. Divergence between M. domesticus and M. spretus for this region (1.9%) was slightly lower than the average divergence of single-copy nuclear DNA for these species. Comparison of levels of polymorphism and divergence at Sry with levels of polymorphism and divergence in the mitochondrial DNA control region provided no evidence of a departure from the expectations of neutral molecular evolution. These findings are consistent with the presumed lack of function for much of the Y chromosome.
Mol Biol Evol 1994 May
PMID:Polymorphism and divergence at the 5' flanking region of the sex-determining locus, Sry, in mice. 801 46


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