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Results for “Protein macromolecular action”

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At least 19 recordsLinked to original sources
PubMed2025

Proteomic hub proteins CDKN2B, TRAPPC2L, WFS1, and ARPP19 drive biochemical recurrence and metastatic progression in prostate cancer: Protein macromolecule action.

The biological characteristics and metastasis mechanism of prostate cancer are complex, involving the important role of many proteins in cell transcriptional regulation. This study focused on the role of the proteomic hub proteins CDKN2B, TRAPPC2L, WFS1 and ARPP19 in the biochemical recurrence and metastasis progression of prostate cancer. Cross-platform transcriptome integration and differential expression analysis were used to evaluate transcriptome characteristics in a prostate cancer cohort. Functional enrichment analysis was performed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation, and weighted gene co-expression network analysis (WGCNA) was used to investigate cancer progression subtypes. It was found that prostate cancer progression showed significant transcriptome heterogeneity, and low-expression genes dominated. We reveal the important role of epithelial-immune interactions and inflammatory signaling in transcriptional remodeling in prostate cancer. The co-expression network topology analysis showed that the immune-metabolic center module plays a central role in cancer progression. CDKN2B was identified as a key transcriptional determinant in prostate cancer typing, while TRAPPC2L and WFS1 acted as core transcriptional regulators, driving metastatic heterogeneity. ARPP19 and LOC650152 also show important transcriptional driving effects in advanced prostate cancer.

Humans↗
PubMed1998

Poly(ADP-ribose) polymerase, a potential target for drugs: Cellular regulatory role of the polymer and the polymerase protein mediated by catalytic and macromolecular colligative actions (Review).

The cellular coenzymatic role of NAD, being a pleiotropic cofactor for diverse cellular reactions, is extended to poly(ADP-ribose) and to the highly abundant nuclear protein, poly(ADP-ribose) polymerase, with special focus on the pharmacological action of ligands on the latter. The polymer is defined to possess a helical configuration. From direct analyses of the polymer under physiological conditions, it is concluded that the polymerase is dormant in normal tissues, but is activated under certain pathological conditions: malignancy, retroviral integrate containing cells, and in a variety of inflammatory states. The interaction of poly(ADP-ribose) polymerase ligands with the DNA component of the active poly (ADP-ribose) polymerase - DNA complex is shown. A major cellular function of the poly(ADP-ribose) polymerase protein is its binding capacity to a large number of nuclear proteins and DNA sites, an effect which is induced by drugs that inhibit the polymerase activity. The malignancy-reverting effect of poly(ADP-ribose) polymerase ligand drugs is illustrated in chemically and oncovirally transformed cancer cells. The poly(ADP-ribose) polymerase ligand-induced cessation of HIV replication is analyzed. Peroxynitrite-induced DNA damage-initiated pathological responses are shown to be inhibited by a specific poly(ADP-ribose) polymerase ligand. The irreversibly acting C-NO drugs oxidize asymmetric zinc fingers [poly(ADP-ribose) polymerase, HIV gag-precursor protein] and act as anti-cancer and anti-HIV agents, an effect that is regulated by cellular concentration of GSH.

Journal Article↗
PubMed1994

Photoaffinity labeling of chloroquine-binding proteins in Plasmodium falciparum.

A photoreactive analog of chloroquine, N-(4-(4-diethylamino-1-methylbutylamino)quinolin-6-yl)-4- azi do-2- hydroxybenzamide (referred to as ASA-Q), has been synthesized and shown to mimic the action of chloroquine in possessing substantial antimalarial activity against a chloroquine-sensitive strain of Plasmodium falciparum. As for chloroquine, ASA-Q is less effective at killing drug-resistant strains of malaria, and the resistance can be modulated using the reagent verapamil. ASA-Q has been radiolabeled with Na125I and used as a photoaffinity probe for labeling chloroquine-binding proteins in malaria-infected erythrocytes. Two proteins have been identified with apparent molecular masses of 42 and 33 kDa in both chloroquine-sensitive and chloroquine-resistant strains of malaria. Photoaffinity labeling of the two proteins by iodo-ASA-Q was competitively inhibited by an excess of unlabeled chloroquine. The structurally related antimalarials amodiaquine and quinine also inhibited labeling of the two proteins, while verapamil and doxycycline had no effect. We suggest that the two labeled proteins are the macromolecular targets of chloroquine action in malaria parasites.

Affinity Labels↗
PubMed1982

Purine analogs revisited: interference in protein formation.

We have examined in L1210 cells in vitro the effects of three guanine analogs (8-azaguanine, 3-deazaguanine, and 6-thioguanine) on protein biosynthesis and have compared this action with respect to effects on macromolecular synthesis and mechanisms of tumor growth inhibition and cell viability. The major site of action of azaG was the inhibition of protein synthesis. TG seemed to inhibit RNA synthesis more than DNA and protein synthesis. In contrast, DG inhibited both protein and DNA synthesis but not RNA synthesis. Whereas the LD50 and ID50 for macromolecular synthesis for DG and also for azaG were quite similar, for TG the LD50 was one-tenth that of the ID50 for macromolecular synthesis. Since azaG, DG, and TG had different effects on protein and RNA synthesis, the effects of the analogs on the process of translation were examined. DG and azaG, but not TG, altered the polyribosome sedimentation profile, increasing the numbers of monosomes and smaller polysomes and decreasing the number of larger polysomes. This shift in the polysome profile was reversed by low concentrations of cycloheximide, suggesting that DG and azaG inhibited the initiation of translation. This was examined directly by the incorporation of 35S-met-tRNA into the initiation complexes. DG and azaG inhibited the formation of the 43S and 80S initiation complexes and this inhibition correlated closely with the inhibition of total protein synthesis. It is likely that the inhibition of tumor growth by azaG is due to the inhibition of initiation of translation, perhaps through actions on mRNA. The mechanism of growth inhibition for DG is not yet known but may similarly involve actions at this level.

Animals↗
PubMed1990

Mechanism of action of a new macromolecular antitumor antibiotic, C-1027.

C-1027 is a new antitumor protein antibiotic containing a non-protein chromophore. The active moiety and the mechanism of action of this antibiotic were studied. C-1027 and its chromophore inhibited the growth of KB carcinoma and L1210 leukemia cells, even at extremely low concentrations. C-1027 inhibited DNA synthesis of L1210 cells and cleaved cellular DNA in a drug concentration-dependent manner. C-1027 and chromophore caused directly DNA single strand breaks in the purified DNA without any supplement of reducing agents. These results suggest that C-1027 chromophore may inhibit cell growth by causing DNA breakage with subsequent inhibition of DNA synthesis.

Aminoglycosides↗
PubMed2002

Extended interactions with prothrombinase enforce affinity and specificity for its macromolecular substrate.

The specific action of serine proteinases on protein substrates is a hallmark of blood coagulation and numerous other physiological processes. Enzymic recognition of substrate sequences preceding the scissile bond is considered to contribute dominantly to specificity and function. We have investigated the contribution of active site docking by unique substrate residues preceding the scissile bond to the function of prothrombinase. Mutagenesis of the authentic P(1)-P(3) sequence in prethrombin 2/fragment 1.2 yielded substrate variants that could be converted to thrombin by prothrombinase. Proteolytic activation was also observed with a substrate variant containing the P(1)-P(3) sequence found in a coagulation zymogen not known to be activated by prothrombinase. Lower rates of activation of the variants derived from a decrease in maximum catalytic rate but not in substrate affinity. Replacement of the P(1) residue with Gln yielded an uncleavable derivative that retained the affinity of the wild type substrate for prothrombinase but did not engage the active site of the enzyme. Thus, active site docking of the substrate contributes to catalytic efficiency, but it is does not determine substrate affinity nor does it fully explain the specificity of prothrombinase. Therefore, extended interactions between prothrombinase and substrate regions removed from the cleavage site drive substrate affinity and enforce the substrate specificity of this enzyme complex.

Culture Media, Conditioned↗
PubMed1985

Leishmania donovani: amastigote inhibition and mode of action of berberine.

Berberine, an alkaloid from Berberis aristata Linnaeus, may be a useful drug for the treatment of visceral leishmaniasis. In both the 8-day and long-term models of Leishmania donovani infection in hamsters, it markedly diminished the parasitic load and proved to be less toxic than pentamidine. It rapidly improved the hematological picture of infected animals. Like pentamidine, it inhibited in vitro multiplication of amastigotes in macrophage culture and their transformation to promastigotes in cell free culture. Manometric studies showed that both drugs had inhibitory action on both the endogenous and the glucose-stimulated respiration of amastigotes. They inhibited incorporation of [14C]adenine, [14C]uracil, and [3H]thymidine into nucleic acids, and of [14C]leucine into the protein of amastigotes, indicating an inhibitory action on macromolecular biosynthesis. They also decreased deoxyglucose uptake. Using spectrophotometric, spectrofluorimetric, and circular dichroism techniques, berberine was found to interact in vitro with nuclear DNA from L. donovani promastigotes.

Animals↗
PubMed1990

A80915, a new antibiotic complex produced by Streptomyces aculeolatus. Discovery, taxonomy, fermentation, isolation, characterization, and antibacterial evaluation.

New semi-naphthaquinone antibiotics A80915A, B, C, and D were isolated from the fermented broth of Streptomyces aculeolatus A80915 (NRRL 18422). Factors A and C, present in both the broth filtrate and mycelial methanol extract, and factors B and D, found predominantly in the broth filtrate, were recovered by extraction with ethyl acetate. Purification of the individual factors was accomplished by preparative reverse phase high performance liquid chromatograph on C18 bonded silica supports. Factors A through D show antimicrobial activity against Gram-positive aerobic and anaerobic organisms in vitro. Mechanism of action studies demonstrated nearly complete inhibition of macromolecular biosynthesis (protein, RNA, DNA, and cell wall) by A80915 factors A through D. A less highly cyclized semi-naphthaquinone, A80915 factor G, was isolated from the broth of the strain fermented in an alternate medium.

Animals↗
PubMed1996

Dosage-dependent modification of position-effect variegation in Drosophila.

Many loci in Drosophila exhibit dosage effects on single phenotypes. In the case of modifiers of position-effect variegation, increases and decreases in dosage can have opposite effects on variegating phenotypes. This is seemingly paradoxical: if each locus encodes a limiting gene product sensitive to dosage decreases, then increasing the dosage of any one should have no effect, because the others should remain limiting. An earlier model put forward to resolve this paradox suggested that dosage-dependent modifiers encode protein subunits of a macromolecular complex that is sensitive to mass action equilibrium conditions. Because chemical equilibria are dynamic, however, such hypothetical complexes will be unstable to an extent that is inconsistent with the known properties of molecules that make up chromatin. An alternative model accounts for the dosage effects in terms of interactions between structural proteins that bind at multiple linked sites. These might include indirect interactions occurring between regulatory proteins and genes for structural proteins or their protein products. The large number of direct and inverse regulatory genes which are known to exist in Drosophila could account for the apparent genetic complexity that is seen for modifiers of position-effect variegation and for other systems of phenotypic modification.

Animals↗
PubMed1993

The role of synovial fluid filtration by cartilage in lubrication of synovial joints--I. Mixture model of synovial fluid.

A mathematical model of lubrication of human synovial joints under squeeze-film conditions is presented in this several-part paper. Squeeze-film action leads to a concentration of hyaluronic-acid-protein macromolecular complex in the synovial fluid between the approaching cartilage surfaces as a result of the diffusion of water and low molecular weight substances through the cartilage surfaces or along the gap. Increasing viscosity of synovial fluid delays the approach of these surfaces and the formation of stable gels then protects cartilage, if sliding motion ensues, before fluid film lubrication is restored. In Part I of the present paper synovial fluid is considered as a mixture of two incompressible fluids. The material parameters of this mixture of fluids are found using previously published experimental results. Squeeze-film analysis is carried out for the axially symmetric synovial film.

Cartilage, Articular↗
PubMed1999

Gold-tagged RNA-A probe for macromolecular assemblies.

Ribonucleic acids (RNAs) play a key role in many fundamental life processes. These polymers are often found complexed with proteins in extremely large particles whose molecular mass may reach several millions of daltons (e.g., ribosomes, spliceosomes, and viruses). Structural studies of such RNA-protein complexes should help elucidate their mode of action. For the structural analyses of many macromolecular assemblies, electron microscopy (EM) has served an instrumental role. However, localization by EM of RNA within biological complexes is not yet a straightforward undertaking. Here we describe a methodology for the covalent tagging of RNA molecules with gold clusters, thereby enabling their direct visualization by microscopical methods. Our strategy involves transcription in vitro of RNAs that carry free thiol groups, using ribonucleoside triphosphate analogs containing a substituent with a terminal thiol group on their heterocyclic ring. This synthesis is followed by coupling of gold clusters to the thiolated transcript through a maleimido group. Visualization of such gold-tagged RNAs by transmission electron microscopy showed spots of gold clusters, with a diameter of 1-2 nm, arranged at nearly regular distances on an imaginary curve that presumably corresponds to the RNA chain. This assignment was corroborated by atomic force microscopy that exhibited images of RNA chains in which knob-like structures, whose height corresponds to the diameter of the gold clusters, were clearly seen. This study demonstrates the potential use of nucleic acids that are covalently labeled with gold clusters for the structural characterization of protein-RNA complexes.

Globins↗
PubMed1998

Effective diameter and structural organization of reconstituted calcium channels from the Characeae algae Nitellopsis.

Using hydrophilic non-electrolytes, we determined the effective diameter of calcium channels from the Characeae alga Nitellopsis, reconstituted in a planar lipid membrane. It is suggested that a "single" reconstituted channel is a cluster consisting of several protochannels, in which the channel-forming molecules are stabilized by calcium ions. It is shown that the channels assembled in a cluster with the common conductivity of 350 pS (in 0.1 M KCl) have a funnel-like structure. The diameter of the smaller section is 0.96 +/- 0.20 nm, the diameter of the wider vestibule is 1.78 +/- 0.30 nm. Similarity of the structural organization of the channels investigated to the channels formed by annexin proteins is discussed.

Action Potentials↗
PubMed1992

Effect of dietary protein level on aflatoxin B1 actions in the liver of weanling rats.

The hepatocarcinogenic responses of rats to aflatoxin B1 (AFB1) are believed to depend on microsomal activation of the toxin, followed by macromolecular binding. Dietary protein insufficiency is reported to reduce the level of microsomal metabolism, and therefore would be expected to reduce the AFB1-induced carcinogenicity. Indeed, diminished hepatocarcinogenicity in low-protein diet fed weanling rats that had received AFB1 has been reported. In the present study, carcinogenicity and other toxic effects of AFB1 (0.5 p.p.m.) fed to weanling male Fischer F344 rats on a low-protein diet (5%) or normal-protein (20%) diet for up to 8 weeks were examined. In our study, in contrast with the previous report, all animals that had survived some initial toxicity were found to have developed hepatic tumors or hyperplastic gamma-glutamyltransferase-positive foci a year later. The low-protein diet also produced sub-acute toxicity after AFB1 exposure in the weanling rats, leading to severe histological changes, and the death of about half the animals after 3-4 weeks of exposure. Animals fed an AFB1-containing normal-protein diet also exhibited AFB1-induced hepatocarcinogenicity, but not the sub-acute toxicity. The levels of hepatic enzymes involved in AFB1 metabolism were examined in animals fed the low- or normal-protein diets in the absence of AFB1. The low-protein diet, fed to 3 week weanlings for the subsequent 5 weeks, decreased hepatic cytochrome P450 levels, as well as the in vitro capacity of microsomal fractions to form AFB1-8,9-dihydrodiol, an index of AFB1-8,9-epoxide formation. Rats on a normal-protein diet did not show these changes. This discrepancy between the observed increase in sub-acute toxicity and decrease in microsomal activities in the low-protein fed animals implies that the toxic effects observed in these rats were not directly related to metabolic activation of the toxin. In contrast to the diminished microsomal in vitro AFB1 activation, however, in vivo AFB1-DNA adduct formation ability in rats receiving the low-protein diet in the absence of AFB1 was found to become elevated more rapidly during the 5 week experimental feeding period, compared with animals receiving the normal-protein diet. This was accompanied by a more rapid fall in the levels of AFB1-glutathione S-transferase isozyme activity in the low-protein fed animals. The results of this study on weanling rats support the importance of AFB1-GSH in protecting against the carcinogenic responses to AFB1, and probably also the sub-acute toxicity of the latter.(ABSTRACT TRUNCATED AT 400 WORDS)

Aflatoxin B1↗
PubMed1975

Studies of the metabolism of asialotransferrins: the metabolic heterogeneity of human asialotransferrin.

Catabolism of human transferrin and human asialotransferrin was simultaneously studied in guinea pigs by means of total body radioactivity measurements. Total body activity representing transferrin decreased at a constant rate with an average half-life of 88 h. Decrease of the total body activity representing asialotransferrin exhibited at least two rates; the half-life of the fast initial component averaged at 25 h, whereas the half-life of the slower component averaged at 55 h. Transition occurred between the 50th and 80th hours of the experiments. The complex character of the elimination curves could not be explained by differences in the iron content of asialotransferrin, by the presence of transferrin variants or of denatured protein in the injected material, by residual sialic acid in the preparations, by accumulation of radioactive terminal catabolic products in the body, by an association of asialotransferrin with any other macromolecular plasma constituent, by changing conditions for mass action, or by a continuing return of labeled protein from the extravascular space. Injection of bovine asialotransferrin into guinea pigs did not result in complex total body curves. Analyses of guinea pig tissues demonstrated that human asialotransferrin had marked affinity for the liver and none for the kidney, lung, or spleen. These observations are consistent with the hypothesis that the glycopeptides in human transferrin are heterogeneous in that removal of the sialyl residues exposes structures with different affinities for the hepatic asialoglycoprotein receptor. The precise chemical basis for the metabolic heterogeneity is unknown.

Animals↗
PubMed1996

Photoaffinity labeling of mefloquine-binding proteins in human serum, uninfected erythrocytes and Plasmodium falciparum-infected erythrocytes.

A photoreactive quinolinemethanol analog, N-[4-[1-hydroxy-2-(dibutylamino)ethyl]quinolin-8yl]-4- azido-2-salicylamide (ASA-MQ) has been synthesized which closely mimics the action of mefloquine. ASA-MQ possesses potent antimalarial activity against a mefloquine-sensitive strain of Plasmodium falciparum and shows decreased activity against a mefloquine-resistant parasite strain. Radioiodinated ASA-MQ has been used in photoaffinity labeling studies to identify mefloquine-interacting proteins in serum, uninfected erythrocytes and Plasmodium falciparum-infected erythrocytes. We have shown that mefloquine interacts specifically with apo-A1, the major protein of serum high density lipoproteins. In addition, mefloquine was shown to interact specifically with the erythrocyte membrane protein, band 7.2b (stomatin). A further two high affinity mefloquine-binding proteins with apparent molecular masses of 22 and 36 kDa were identified in three different strains of Plasmodium falciparum. We suggest that these two mefloquine-binding parasite proteins may be involved in the uptake of mefloquine or may represent macromolecular targets of mefloquine action in malaria parasites.

Affinity Labels↗
PubMed1972

Mode of action of primaquine: preferential inhibition of protein biosynthesis in Bacillus megaterium.

The growth of a strain of Bacillus megaterium was prevented by a minimal inhibitory concentration of primaquine of 52 mug/ml or 2 x 10(-4)m. When exponentially growing cultures received the drug at 6 x 10(-4)m, the rate of growth was drastically reduced and no further growth occurred after 15 min of exposure. At this concentration, primaquine was bactericidal, causing a 50% reduction in the viable population after one doubling time of 45 min. Supplying primaquine to cultures 30 min after adding radioactive-labeled phenylalanine, thymidine, uracil, or diaminopimelic acid produced an immediate and complete inhibition of protein biosynthesis but no inhibition of deoxyribonucleic acid biosynthesis for at least 15 min, and caused the formation of ribonucleic acid and cell wall polymer to proceed linearly at rates similar to those established prior to the addition of drug. This pattern of inhibition of macromolecular biosyntheses suggests that the major in vivo action of primaquine in B. megaterium is to block protein synthesis.

Amino Acids↗