Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Exometabolites (EXOM) of an Indian strain of Leishmania donovani promastigotes isolated from a chemically defined medium by ultrafiltration consisted of proteins, glycoproteins, lipid and lipophosphopolysaccharide (LPPS). LPPS of Mr 40-28 kDa in SDS-PAGE could be labelled metabolically with [32P]-phosphate and recovered in the aqueous phase of hot-phenol-water extraction of EXOM (PE-Aq) along with a glycoprotein of Mr 150-130 kDa (GP150-130). These two molecules could be eluted from DE-52 column with 200 mM NaCl (D2). The 300 mM NaCl (D3) and 400 mM NaCl (D4) eluates from DE-52 column contained one unsaturated polar lipid component. The LPPS had Rf value of 0.65-0.75 in Thin Layer Chromatography (TLC) using saturated phenol water solvent system. EXOM revealed 15 bands in SDS-PAGE of which proteins of Mr 84, 66, 56, 50 and 29 kDa were prominent. When EXOM were fractionated through Con A-Sepharose column, the fraction eluted with alpha-methyl-D-mannoside (Con A-E) had seven bands as revealed by SDS-PAGE of which 25, 16, 13 and 12 kDa glycoproteins were prominent. The antigens present in EXOM can be classified as slower anodic migrating and faster anodic migrating antigens as revealed by immunoelectrophoresis (IEP). The slower anodic migrating antigens, LPPS and GP150-130 recovered in PE-Aq and D2 did not cross-react with kala-azar patients' sera but cross-reacted with homologous anti-promastigote sera. Two faster anodic migrating antigens which could be recovered in organic phase of hot phenol extraction of EXOM (PE-O) and eluted in D3 and D4 and Con A-E, cross-reacted with kala-azar patients' sera. The antigens of both the classes were sensitive to periodic acid oxidation.
Mol Cell Biochem 1991 Dec 11
PMID:Biochemical and immunological characterization of exometabolites from an Indian strain of Leishmania donovani promastigotes grown in a chemically defined medium. 177 62

The functional consequences of DNA condensation are investigated. The recognition of complementary strands is profoundly modified by this critical phenomenon. (1) Condensation of denatured DNA greatly accelerates the kinetics of DNA renaturation. We propose a unifying explanation for the effects of several accelerating solvents studied here including polymers, di- and multivalent cations, as well as effects seen with the phenol emulsions and single-stranded nucleic acid binding proteins. Optimal conditions for renaturation at or above the calculated three dimensional diffusion limit are theoretically consistent with a limited search space in the condensed phases. (2) In addition to these effects on association of two single strands, similar condensation acceleration effects can be seen in strand exchange experiments with double stranded DNA without proteins. These may model a mechanism of recombinational protein function.
J Mol Biol 1991 Dec 20
PMID:Complementary recognition in condensed DNA: accelerated DNA renaturation. 183 60

UDP-glucuronosyltransferases (UGT) play a major role in the elimination of nucleophilic metabolites of carcinogens, such as phenols and quinols of polycyclic aromatic hydrocarbons. In this way they prevent their further oxidation to electrophiles, which may react with DNA, RNA, and protein. They also inactivate carcinogenic, N-oxidized metabolites of aromatic amines. Furthermore, glucuronides may be stable transport forms of proximate carcinogens excreted via the biliary or urinary tract, thereby liberating the ultimate carcinogen at the target of carcinogenicity. Isozymes of the UGT enzyme superfamily that control the glucuronidation of metabolites of aromatic hydrocarbons and of N-oxidized aromatic amines have been identified in rats and humans. Phenol UGT appears to be coinduced with other drug-metabolizing enzymes via the Ah or dioxin receptor. This isozyme probably controls various proximate carcinogens and contributes to the persistently altered enzyme pattern, leading to the "toxin-resistance phenotype" at cancer prestages. Knowledge about UGTs in different species, their regulation, and their tissue distribution will improve the risk assessment of carcinogens.
Crit Rev Biochem Mol Biol 1991
PMID:Roles of UDP-glucuronosyltransferases in chemical carcinogenesis. 191 94

Progesterone enhances the synthesis of a 42 kDa protein secreted by rabbit endometrial stromal cells in primary culture. The duration of that response, the effects of estrogen and the inhibitory ability of antiprogestin steroid analogs, RU486, ZK98.299 and ZK98.734, were tested. Although there was a progressive decrease in the amount of the 42 kDa protein synthesized during a 6-day culture period, progesterone stimulated its rate of synthesis greater than 2-fold throughout that period. The addition of estrogen did not prevent the progressive decrease in the amount of the protein synthesized, nor did it enhance the progesterone effect when the culture medium contained phenol red. Estrogen alone did slightly induce 42 kDa protein synthesis by cells grown in phenol red-free medium, and the progesterone response was accentuated to the same degree. When present in a concentration that was 100-fold that of the progesterone, RU486, ZK98.299 and ZK98.734 each abolished stimulation. This antagonistic effect was overcome by addition of an equimolar concentration of progesterone. Deoxycorticosterone (DOC) also stimulated 42 kDa protein synthesis. The antiprogestins blocked this stimulatory effect, even when both steroids were in equimolar concentrations. There was no difference in the ability of ZK98.299 or ZK98.734 to block DOC stimulation, even though ZK98.734 exhibits no antiglucocorticoid activity [J. Steroid Biochem. 25 (1986) 835]. Therefore, it is likely that the DOC effect is mediated by the progesterone receptor system. These studies indicate that enhanced synthesis of the 42 kDa protein represents a progesterone receptor mediated event and that the cell culture system described can be used as a bioassay for determination of antiprogestin activity.
J Steroid Biochem Mol Biol 1991 Jul
PMID:Effects of progestin antagonists, glucocorticoids and estrogen on progesterone-induced protein secreted by rabbit endometrial stromal cells in culture. 206 62

An immunosorbent technique was developed to attenuate cross-reactivity of a polyclonal antiserum against a 4(2) (rho-carboxyphenylazo)-1,3,5[10]-estratrien-3,16 alpha,17 beta-triol-bovine serum albumin conjugate. The chromatographic separation of antiserum through stationary phases having either rho(carboxymethyl)phenylazo-phenol or rho(carboxymethyl)-phenylazo-2-naphthol side residues reduced the antiserum avidity, while increasing the apparent antiserum affinity and decreasing the residual cross-reactivities against heterologous ligands. The highly specific antiserum obtained allowed the development of a competitive binding assay over an extended analytical range, which opens up the possibility of direct measurement of estriol from the early pregnancy to delivery. The significance of the attenuation of antiserum cross-reactions after affinity chromatography is discussed with reference to epitope-paratope interaction in the case of small endogenous molecules like estrogens.
J Steroid Biochem Mol Biol 1991 Jul
PMID:Highly specific polyclonal antisera against estriol: cross-reactivity restriction following affinity chromatography. 206 67

A method is described for the isolation of DNA from spruce and fir, starting with 3 to 5 apices (5 mg material). Apices are prepared manually from dormant buds harvested in summer and autumn, which are homogenized in 30 microliters buffer containing 1% SDS. The DNA is extracted with phenol and precipitated with ethanol. Agarose gel electrophoresis and Southern hybridization show that its molecular length is ca. 30-40 kb and that it is readily digested with various restriction enzymes. The method is very fast, it does not need CsCl centrifugation and is therefore suited for the analysis of large numbers of individual trees. Moreover, the buds can be collected all over the year. The yield of the method is up to 30 micrograms of high molecular weight DNA, enough to do several digests and hybridizations.
Plant Mol Biol 1990 May
PMID:Genetic analysis of forest tree populations: isolation of DNA from spruce and fir apices. 210 67

Female rat liver cytosol contained at least three sulfotransferases (STs) that were separable on a DEAE-Sephadex A-50 column and transformed the carcinogen 5-hydroxymethylchrysene (5-HCR) to the potent mutagen 5-HCR sulfate. The STs also catalyzed sulfation of dehydroepiandrosterone (DHA), a typical substrate for hydroxysteroid STs. Of these three isozymes, the one (STa) with the highest 5-HCR-sulfating activity was isolated and purified (100-fold) as a homogeneous protein, in 15% yield, by successive column chromatography on agarose modified with 3'-phosphoadenosine 5'-phosphate as an affinity ligand and on Sephadex G-100. Purified STa was classified as a hydroxysteroid ST because the 5-HCR- and DHA-sulfating activities were inseparable from each other throughout the purification steps. Sulfation of 5-HCR by purified STa was competitively inhibited by DHA. STa also catalyzed sulfation of other potent carcinogens, 7-hydroxymethylbenz[a]anthracene, 7-hydroxymethyl-12-methylbenz[a]anthracene, and 7,12-dihydroxymethylbenz[a], anthrocene, to produce sulfate esters with high reactivity and mutagenicity. However, STa had no activity with 4-nitrophenol, a typical substrate for phenol STs, or with N-hydroxy-2-acetylaminofluorene. STa had a pl value of 6.4 and existed on a gel filtration column as a homooligomer of a subunit protein with Mr 30,500, determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The N-terminal amino acid sequence of STa was as follows: Pro-Asp-Tyr-Thr-Trp-Phe-Glu-Gly-Ile-Pro-Phe-Pro-Ala-Phe-Gly-Ile- Pro-Lys-Glu-Thr-. Immunoblot analysis of female and male rat liver cytosol, carried out by using rabbit antiserum raised against the purified enzyme STa and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, indicated that the female liver contained a much higher level of the enzyme than did the male liver. The marked sex difference in STa level was in good accordance with the previous demonstration that cytosol from the liver of female rats catalyzed sulfation of 5-HCR to a greater extent than did cytosol from the liver of male rats.
Mol Pharmacol 1990 Jun
PMID:Rat liver cytosolic hydroxysteroid sulfotransferase (sulfotransferase a) catalyzing the formation of reactive sulfate esters from carcinogenic polycyclic hydroxymethylarenes. 211 4

Chlorinated phenols, which are used primarily as wood preservatives and fungicides, are present in most air, water, and soil samples in industrialized areas as well as in the urine of most people. We have examined the ability of phenol and the 19 isomers of chlorophenol to induce DNA damage using the Microscreen prophage-induction assay in Escherichia coli. Seven of the isomers (2,3,4,-tri, 2,4,5-tri, 3,4,5-tri, 2,3,4,5-tetra, 2,3,6-tri, 2,4,6-tri, and pentachlorophenol) induced prophage lambda in the presence of S9, with the first three being approximately 10 times more potent than the last three. The more potent isomers have either one or no chlorine atom ortho to the OH group; whereas the less potent isomers have two chlorine atoms ortho to the OH group. Although none of the 20 compounds is mutagenic in Salmonella, the prophage-induction results agree with findings by others that most of these seven isomers are clastogenic, are associated with cancer and chromosomal aberrations in humans (pentachlorophenol), and are carcinogenic in rodents (2,4,6-tri and pentachlorophenol). A likely basis for the genotoxicity of the seven isomers involves the metabolism of the parent isomer to a chlorohydroquinone, which can form a chlorobenzosemiquinone in the presence of oxygen. These two metabolites can produce free radicals that can cause DNA strand breaks, resulting in prophage induction in E. coli or, possibly, the chromosomal aberrations/cancer associated with human exposure to chlorophenols.
Environ Mol Mutagen 1990
PMID:Induction of prophage lambda by chlorophenols. 213 84

Dermorphin structural analogues were utilized to determine the nature of opioid receptor subsite specificity, affinity, and selectivity in rat brain membranes. The data suggest that these parameters are influenced by the amino acid composition and sequence and the known solution conformation of dermorphin, in addition to the conformation of the membrane receptor. Two hydrophobic components of dermorphin are required for optimal binding. One component encompasses the stacked phenol groups in Tyr1 and Tyr5; the second involves the phenyl group of Phe3. Evidence to support this proposal includes the following results: (a) removal of aromaticity, as occurs in [des-Tyr5]- and [Gly5]dermorphin, drastically reduced binding to both mu and delta sites; (b) inversion of the Phe3-Gly4 sequence in dermorphin to the Gly3-Phe4 in enkephalin enhanced binding to delta receptor sites, yet the peptide remained mu-selective; (c) substitution of Pro4 for Gly4 disrupted the solution conformation of dermorphin and decreased affinities at both receptor subsites, substantiating the requirement for the Phe3-Gly4-Tyr5 sequence in dermorphin to interact with mu sites; and (d) modification of the serine residue, as occurs in [Ser(Bzl7)] dermorphin and [Ser-NHNHZ7]dermorphin, enhanced interaction with delta opioid receptors; the apparent delta affinity increased over 50-fold with [Ser(Bzl7)]dermorphin, although it retained a weak mu-selectivity. However, both [Ser(Bzl7)]- and [Ser-NHNHZ7]dermorphin exhibited high affinity for mu receptor sites. Furthermore, the D-configuration about the alpha-carbon of residue 2 and the alpha-amine function and hydroxyl group on Tyr1 are essential for receptor binding. We conclude that mu-opioid receptors contain distinct regions that accomodate the stacked phenol groups of Tyr1 and Tyr5 residues and the phenyl group of Phe3.
Mol Pharmacol 1990 Jun
PMID:Dermorphin interaction with rat brain opioid receptors: involvement of hydrophobic sites in the binding domain. 216 14

Structure-activity relationship studies have suggested that the phenolic hydroxyl group is essential for the pharmacological activity of the cannabinoids. However, it remains to be established whether it is the hydrogen of the phenolic hydroxyl that is important (possibly because this hydrogen can participate in a hydrogen bonding interaction) or whether it is the oxygen of the phenolic hydroxyl that is important (possibly because one of the lone pairs of electrons in this oxygen can serve as a hydrogen bond acceptor). Two new etherified cannabinoids were prepared in which the phenolic hydroxyl oxygen is incorporated into a fourth ring. These new compounds were designed to test the importance both of the phenolic hydroxyl oxygen and of the orientation of its lone pairs of electrons for cannabinoid pharmacological activity. O,2-Propano-delta 8-tetrahydrocannabinol (0,2-Propano-delta 8-THC) was designed to mimic delta 9-THC in its phenol conformation I (C2-C1-O-H = 7 degrees). O,10-Methano-delta 9-tetrahydro-cannabinol (0,10-Methano-delta 9-THC) was designed to mimic delta 9-THC in its phenol conformation II (C2-C1-O-H = 167 degrees). Molecular mechanics calculations revealed that 1) there are two accessible minimum energy conformers for O,2-propano-delta 8-THC, which differ principally in the conformation of the new fourth ring, and 2) there are three accessible minimum energy conformers for O,10-methano-delta 9-THC, the first two of which differ mainly in the conformation of the new fourth ring, whereas the third possesses an alternate pyran ring conformation. Wave functions and molecular electrostatic potential (MEP) maps were calculated for each accessible conformer of O,2-propano-delta 8-THC and of O,10-methano-delta 9-THC. The resultant MEP maps compared well with the corresponding MEP maps generated for delta 9-THC in each of its two minimum energy conformations (two phenolic hydroxyl positions). These results imply that 1) O,2-propano-delta 8-THC should be capable of being recognized at a site that would recognize delta 9-THC in its phenol conformation 1 and 2) O,10-methano-delta 9-THC should be capable of being recognized at a site that would recognize delta 9-THC in its phenol conformation II. Pharmacological evaluation of the analogs revealed that O,10-methano-delta 9-THC was inactive in all mouse tests, as well as the rat drug discrimination model. O,2-Propano-delta 8-THC was similar to delta 8-THC in that it depressed rectal temperature and produced antinociception and ring immobility in mice.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Pharmacol 1990 Dec
PMID:Investigation of the role of the phenolic hydroxyl in cannabinoid activity. 217 6


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