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PubMed1983

Serum fucosyl transferase activity and serum fucose levels as diagnostic tools in malignancy.

Glycoproteins play a significant role in neoplastic transformations. Both the levels of fucose and the activity of fucosyl transferase, which mediates the assembly of the oligosaccharide moieties of the glycoprotein chains, have been found to be elevated in neoplastic conditions. Since these elevations are common features of a variety of neoplastic cells, these two have been designated as non-specific markers of malignancy. In the present study, the fucose level and fucosyl transferase activity were determined in the sera of cancer patients and an attempt was made to establish a relationship between the two. It was found that both the fucose levels and fucosyl transferase activities showed considerable elevation in the five cancer groups studied, establishing them as useful diagnostic parameters. However, it was also observed that the rate of increased fucosyl transferase activity was not fully reflected in the resulting serum fucose levels in a few cases.

Carcinoma↗
PubMed2006

Human terminal deoxynucleotidyl transferases as novel targets for anticancer chemotherapy.

Mammalian terminal deoxyribonucleotidyl transferase (TDT) catalyzes the non-template-directed polymerization of deoxyribonucleoside triphosphates and has a key role in V(D)J recombination during lymphocyte and repertoire development. Over 90% of leukemic cells in acute lymphocytic leukemia and approximately 30% of leukemic cells in the chronic myelogenous leukemia crisis show elevated TDT activity. This finding is connected to a poor prognosis and response to chemotherapy and reduced survival time. On the other hand, recent data indicated that TDT is not the only terminal deoxyribonucleotidyl transferase in mammalian cells. Its close relative, DNA polymerase (pol) pol lambda can synthesize DNA both in a template dependent (DNA polymerase) and template-independent (terminal deoxyribonucleotidyl transferase) fashion. Pol lambda might be involved in the nonhomologous end-joining (NHEJ) recombinational repair pathway of DNA double strand breaks (DSBs). Specific inhibitors of these enzymes hold the potential to be developed into a novel class of antitumoral agents. In this review, we will summarize the recent advances in the synthesis and characterization of the first classes of specific inhibitors of mammalian terminal transferases and their potential applications.

Animals↗
PubMed1982

Early variations of blood plasma gamma-glutamyl transferase in newborn calves--a test of colostrum intake.

Fourteen newborn calves had low gamma-glutamyl transferase catalytic activity concentration in blood plasma (10 to 31 U/liter). Colostrum intake induced a dramatic increase of plasma gamma-glutamyl transferase activity, which was maximal on the 1st or 2nd day (370 to 5000 U/liter) after birth; then plasma enzyme activity slowly decreased and was stable about 100 U/liter on the 20th day. In two calves given either boiled or synthetic milk, plasma gamma-glutamyl transferase activity was not higher than 25 U/liter. Gamma-glutamyl transferase activity of blood plasma in newborn calves is an easy and inexpensive test of colostrum intake.

Animals↗
PubMed1992

Endo-xyloglucan transferase, a novel class of glycosyltransferase that catalyzes transfer of a segment of xyloglucan molecule to another xyloglucan molecule.

Xyloglucans are the major component of plant cell walls and bind tightly to the surface of individual cellulose microfibrils, thereby cross-linking them into a complex polysaccharide network of the cell wall. The cleavage and reconnection of xyloglucan cross-links are considered to play the leading role during chemical processes essential for wall expansion and, therefore, cell growth and differentiation. Although it is hypothesized that some transglycosylation is involved in these chemical processes, the enzyme responsible for the reaction was not identified. We have now purified a novel class of endo-type glycosyltransferase to apparent homogeneity from the extracellular space or the cell wall of the epicotyls of Vigna angularis, a bean plant. The enzyme is a glycoprotein with a molecular mass of about 33 kDa. The enzyme catalyzes both 1) endo-type splitting of a xyloglucan molecule and 2) linking of a newly generated reducing end of the xyloglucan to the nonreducing end of another xyloglucan molecule, thereby mediating the transfer of a large segment of the xyloglucan to another xyloglucan molecule. The transferase exhibits no glycosidase or glycanase activity. Substrate specificity of the enzyme was investigated using several polysaccharides with different glycosidic linkages as donor substrates and pyridylamino oligosaccharides as acceptor substrates, in which the reducing end of the carbohydrate was tagged with a fluorescent group. The enzyme required a basic xyloglucan structure, i.e. a beta-(1-->4)-glucosyl backbone with xylosyl side chains, for both acceptor and donor activity. Galactosyl or fucosyl side chains on the main chain were not required for the acceptor activity. The enzyme exhibited higher reaction rates when xyloglucans with higher M(r) were used as donor substrates. Xyloglucans smaller than 10 kDa were no longer the donor substrate. On the other hand, pyridylamino heptasaccharide acted as a good acceptor as did xyloglucan polymers. Based on these results we propose to designate this novel enzyme a xyloglucan: xyloglucano-transferase, to be abbreviated endo-xyloglucan transferase (EXT) or xyloglucan recombinase. This enzyme is the first enzyme identified that mediates the transfer of a high M(r) segment between polysaccharide molecules to generate chimeric polymers. We conclude that endo-xyloglucan transferase functions as a reconnecting enzyme for xyloglucans and is involved in the interweaving or reconstruction of cell wall matrix, which is responsible for chemical creepage that leads to morphological changes in the cell wall.

Carbohydrate Sequence↗
PubMed1976

Subcellular localization of acetoacetate coenzyme A transferase in rat hepatomas.

Succinyl coenzyme A:acetoacetate coenzyme transferase (EC 2.8.3.5), an initiator of ketone body usage and absent in normal liver, has been shown to be located in mitochondria from Morris hepatoma 7288ctc using differential and density gradient centrifugation. Furthermore, tumor mitochondrial subfractionation revealed that this transferase is associated with the matrix-soluble proteins. Comparison of the amounts of total transferase activity in several other hepatomas with the amounts found in the corresponding isolated mitochondria suggests that the results with the 7288ctc tumor pertain generally. The mitochondrial localization of coenzyme A transferase indicates the probable use of ketone bodies as energy sources for the hepatomas.

Acetyl Coenzyme A↗
PubMedDate not supplied

[Aging and atherosclerosis of human aorta. Comparative evolution of seven glycosyl-transferases and of lactate-dehydrogenase (author's transl)].

Seven glycosyl-transferases and the lactico-dehydrogenase from human aortas were assayed. These aortas were divided in five classes according to the age and in five steps according to the atherogenesis. These enzymic activities do not show any parallelism in their evolution; their variation with age and with atherogenesis is quite different. For example, the N-acetylgalactosaminyl-transferase activity increases with atherogenesis whereas it diminishes with age; on the other hand the lactate-dehydrogenase activity increases with age and decreases with atherogenesis; the sialyl-transferase activity is nearly constant during adulthood while it hardly declines with atherogenesis. These assays suggest: 1) an effect of energy metabolism on the glycosyl-transferase activities; 2) a qualitative and quantitative variation of the glycosaminoglycans biosynthesis; 3) a structural modification of the glucidic part of the glycoproteins which can induce the formation of antigenic sites.

Adolescent↗
PubMed1985

A new solid-phase immunoassay for terminal deoxynucleotidyl transferase: analysis of TdT antigen in cells, plasma, and serum.

A solid-phase immunoassay for terminal deoxynucleotidyl transferase has been developed using a primary antibody-coated polystyrene bead and secondary antibody conjugated with horseradish peroxidase. The immunoassay was compared with assays for enzyme activity and detection of antigen with immunofluorescence using cells from peripheral blood and bone marrow from patients with leukemia or lymphoma. In each instance, the solid-phase immunoassay correlated correctly with cellular samples judged to be positive by other tests. However, the level of detection of terminal transferase antigen in plasma or serum of patients with leukemia did not reflect accurately the level of terminal transferase in neoplastic cells. The solid-phase immunoassay was greater than 100-fold more sensitive than conventional assays for enzyme activity, rendering it potentially useful for quantitatively monitoring terminal transferase in patients with leukemia.

Antigens↗
PubMed1983

Glycosyl transferase activity in the brush border membrane of Hymenolepis diminuta.

The isolated brush border membrane of Hymenolepis diminuta incorporates radiolabeled glucose when incubated in the presence of uridine diphospho(UDP)-D-(6-3H)glucose. The pH optimum for incorporation was 7.0 to 7.2 regardless of the buffer used. Transferase activity was maximal in 200 mM Tris buffer; 100 mM phosphate buffer inhibited significantly the incorporation of radiolabeled glucose, whereas 50 mM Tris-maleate and 100 mM PIPES resulted in moderate inhibition of activity. Incorporation of labeled glucose was not inhibited by low concentrations (0.01%) of Triton X-100, but activity was inhibited 50% by 0.25% Triton X-100. Addition of divalent cations to the brush border membrane preparation did not activate transferase activity, but addition of chelating agents (i.e., EDTA or EGTA) inhibited transferase activity nearly 90%. Incorporation of labeled glucose was inhibited by UDP, guanosine diphosphate (GDP), UDP- and GDP-activated monosaccharides, and monosaccharides, indicating that the transferase activity lacked substrate specificity.

Animals↗
PubMed1983

Increased activity of serum fucosyl transferase in diabetic patients.

Serum fucosyl- (but not sialyl-) transferase activity was significantly (p less than 0.001), increased in 57 patients with diabetes mellitus. A correlation also existed in diabetics between fucosyl- (but not sialyl-) transferase activity and glycosylated serum protein (r = 0.52, p less than 0.001). Sialyl (but not fucosyl) transferase activity on the other hand correlated with hemoglobin A1 (r = 0.28, p less than 0.05). The data suggest a relationship between fucosyl/sialyl- transferase activities and long-term glucose control. Changes in these enzyme activities may affect cell membrane glycoprotein turnover which may be of importance both for insulin receptor function and later development of diabetic microangiopathy.

Adolescent↗
PubMed1994

Identification of a tripartite basal promoter which regulates human terminal deoxynucleotidyl transferase gene expression.

In order to locate the promoter region of the human terminal deoxynucleotidyl transferase gene, serially truncated segments of the 5'-flanking region of the gene were cloned into a chloramphenicol acetyltransferase reporter vector. Transient transfection analyses of the terminal transferase-reporter gene constructs identified the basal promoter region within -34 to +40 base pairs relative to the transcription start site. Three promoter elements were defined in this region. The primary element is within 34 base pairs upstream of the transcription start site. The CAP site is 62 base pairs upstream of the translation start site. The secondary element involves sequences around the transcription start site. The third is located 25 base pairs downstream from the initiation site (+25 to +40). This tripartite basal promoter was not tissue specific; similar patterns of promoter activity were observed in terminal transferase expressing and non-expressing cells. Transfection analyses also indicated the presence of negative regulatory elements upstream of the basal promoter region, and these elements were preferentially active in cells expressing terminal transferase.

Base Sequence↗
PubMed1993

Molecular cloning and cDNA sequencing of endoxyloglucan transferase, a novel class of glycosyltransferase that mediates molecular grafting between matrix polysaccharides in plant cell walls.

Endoxyloglucan transferase is a novel class of glycosyltransferase recently purified from Vigna angularis (Nishitani, K,, and Tominaga, R. (1992) J. Biol. Chem. 267, 21058-21064). This enzyme is the first transferase identified that catalyzes molecular grafting between polysaccharide cross-links in the cell wall matrix and participates in reconstruction of the network structure in the cell wall. Based on the NH2-terminal amino acid sequence information of the purified transferase, we have here cloned and sequenced cDNAs derived from five different plant species, V. angularis, Triticum aestivum, Arabidopsis thaliana, Lycopersicon esculentum, and Glycine max. In the five plant species, the amino acid sequence of the mature proteins is conserved in the range of 71-90% throughout their length. The consensus sequence for N-linked glycosylation, and four cysteine residues are all conserved in the five species. Thus, the endoxyloglucan transferase protein is ubiquitous among higher plants. The highly conserved DNA sequence will serve as a promising tool for exploring the molecular process by which cell wall construction, and hence cell growth, is regulated.

Amino Acid Sequence↗
PubMed1999

Modulation of glutathione transferase P1-1 activity by retinoic acid in neuroblastoma cells.

The ability of retinoic acid to modulate glutathione S-transferase P1-1 (GSTP1-1) activity has important implications both for cancer prevention and for anticancer therapy. We investigated GSTP1-1 expression and activity in the human neuroblastoma cell line SK-N-BE(2) (genotype A*/B*) under basal conditions and during 48-h incubation with 0.1 microM all-trans-retinoic acid. The steady-state levels of glutathione transferase P1-1 mRNA and protein during 48-h incubation with all-trans-retinoic acid did not increase substantially, but we detected a significant reduction of GSTP1-1 specific activity. This reduction in enzymatic activity could not be ascribed to a differential action of retinoic acid on the gene variants A* and B*; indeed, the two GSTP1-1 isoforms have different affinities toward 1-chloro-2,4-dinitrobenzene (CDNB), while we found a substantial invariance of the K(m) (CDNB) in the cytosol during retinoid treatment. A modulatory effect of retinoic acid on other enzymes involved in glutathione transferase P1-1 metabolism, such as the retinoic acid-induced tissue trans-glutaminase, might be hypothesized, as well as a direct inactivation of GSTP1-1 by the oxidative stress that characterizes the early phases of apoptosis.

Antineoplastic Agents↗
PubMed1995

A fluorescence assay for geranylgeranyl transferase type I.

A new fluorescence assay for measuring the activity of geranylgeranyl transferase (type I) is described. It does not require the use of either radiolabeled geranylgeranyl diphosphate or the purified recombinant Ras protein substrate with the carboxy terminal sequence of CVLL. Dansyl GCVLL and unlabeled geranylgeranyl diphosphate are used as substrates. The Km for Dansyl GCVLL and for geranylgeranyl diphosphate is 5 microM and 800 nM, respectively. At equimolar concentrations, enzymatic activity is higher when Dansyl GCVLL is used as a substrate compared to Dansyl GCVII. Dansyl GCVLS, a substrate for farnesyl transferase, is inactive in this assay. CVFL is a competitive inhibitor of geranylgeranyl transferase and exhibits a Ki of 200 nM.

Alkyl and Aryl Transferases↗
PubMed1995

Farnesyl-derived inhibitors of ras farnesyl transferase.

The synthesis and evaluation of farnesyl-derived inhibitors of ras farnesyl transferase are presented. Evaluation of inhibitors of farnesyl transferase and comparison with the previously described inhibitor was accomplished using purified enzyme and Amersham's Farnesyl:Transferase enzyme assay kit. These results show an order of magnitude increase in inhibitory activity for beta-ketophosphonic acid over beta-hydroxyphosphonic acid. Incorporation of fluorines in alpha-position, led to an increase in inhibitory activity over the nonfluorinated analogues.

Alkyl and Aryl Transferases↗
PubMedDate not supplied

Actinoplanic acids A and B as novel inhibitors of farnesyl-protein transferase.

Actinoplanic acids A and B are macrocyclic polycarboxylic acids that are potent reversible inhibitors of farnesyl-protein transferase. Actinoplanic acids A and B were isolated from Actinoplanes sp. MA 7066 while actinoplanic acid B was isolated from both MA 7066 and Streptomyces sp. MA 7099. Actinoplanic acids A and B are competitive with respect to farnesyl diphosphate and are selective inhibitors of farnesyl-protein transferase because they do not inhibit geranylgeranyl-protein transferase type 1 or squalene synthase. MA 7066 is believed to be a novel species of actinomycetes while MA 7099 is believed to be a novel strain of Streptomyces violaceusniger on the basis of morphological, biochemical and chemotaxonomic characteristics as well as its production of actinoplanic acids.

Actinomycetales↗
PubMed2000

Concurrent expressions of metallothionein, glutathione S-transferase-pi, and P-glycoprotein in colorectal cancers.

PURPOSE: Because the status of the inherent drug-resistance of colorectal cancers remains obscure, human colorectal cancers with no neoadjuvant therapy were retrospectively investigated regarding the expression of three drug-resistant proteins: metallothionein, glutathione S-transferase-pi, and P-glycoprotein. METHODS: Paraffin-embedded tissues of 130 colorectal cancers (Dukes A, 20; B, 49; C, 41; D, 20) obtained by surgical resections from 1982 to 1989 were used. The three proteins were immunostained by the streptavidin-biotin complex method. The immunostaining was judged to be positive if more than 5 percent of cells showed positive staining by use of cell analysis system. The data were compared with clinicopathologic features (Dukes A-D) and patients' prognosis (Dukes AC). RESULTS: Metallothionein, glutathione S-transferase-pi, and P-glycoprotein were positively expressed in 91 (70 percent), 30 (23 percent), and 98 (75 percent), respectively. A total of 120 (86 percent) expressed at least one drug-resistant protein. No intergroup differences were observed between positive and negative expressions of the proteins and their clinicopathologic features except tumor location. Rectal cancers positively expressed P-glycoprotein and three proteins more frequently. Twenty-six (20 percent), 65 (50 percent), and 21 (16 percent) cancers positively expressed one, two, and three proteins, respectively. The disease-free survival rates of patients with Dukes A through C cancer with positive staining for one, two, and three proteins were 100, 94, and 83 percent (at 1 year); 100, 72, and 51 percent (at 3 years); and 94, 66, and 38 percent (at 5 years), respectively (Kaplan-Meier with log-rank test; P = 0.016). In the multivariate Cox analysis, age, Dukes stage, tumor size, and glutathione S-transferase-pi were independent prognostic factors. CONCLUSIONS: The patients with concurrent expression of drug-resistant proteins in their cancers had worse prognoses. Examining drug-resistant proteins in colorectal cancers may be useful in selecting adjuvant chemotherapy and in predicting prognosis more accurately.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1980

Effect of phosphoenolpyruvate analogs on the activity of enoylpyruvate transferase and the effect of UDP-N-acetylglucosamine on the reactivity of the active site SH group.

Effect of several phosphoenolpyruvate analogs on the activity of enoylpyruvate (phosphoenolpyruvate: UDP-2-acetamido-2-deoxy-D-glucose 2-enoyl-1-carboxyethyltransferase, EC 2.5.1.7) transferase was examined. The results suggest that the phosphoenolpyruvate binding site of the transferase is very similar to that of pyruvate kinase (ATP: pyruvate 2-O-phosphotransferase, EC 2.7.1.40). Evidence is presented to show that the binding of UDP-GlcNAc to the transferase enhances the reactivity of the active site SH group.

Alkyl and Aryl Transferases↗
PubMed1996

Structure of UDP-N-acetylglucosamine enolpyruvyl transferase, an enzyme essential for the synthesis of bacterial peptidoglycan, complexed with substrate UDP-N-acetylglucosamine and the drug fosfomycin.

BACKGROUND: UDP-N-acetylglucosamine enolpyruvyl transferase (MurA), catalyses the first committed step of bacterial cell wall biosynthesis and is a target for the antibiotic fosfomycin. The only other known enolpyruvyl transferase is 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase, an enzyme involved in the shikimic acid pathway and the target for the herbicide glyphosate. Inhibitors of enolpyruvyl transferases are of biotechnological interest as MurA and EPSP synthase are found exclusively in plants and microbes. RESULTS: The crystal structure of Escherichia coli MurA complexed with UDP-N-acetylglucosamine (UDP-GlcNAc) and fosfomycin has been determined at 1.8 A resolution. The structure consists of two domains with the active site located between them. The domains have a very similar secondary structure, and the overall protein architecture is similar to that of EPSP synthase. The fosfomycin molecule is covalently bound to the cysteine residue Cys115, whereas UDP-GlcNAc makes several hydrogen-bonding interactions with residues from both domains. CONCLUSIONS: The present structure reveals the mode of binding of the natural substrate UDP-GlcNAc and of the drug fosfomycin, and provides information on the residues involved in catalysis. These results should aid the design of inhibitors which would interfere with enzyme-catalyzed reactions in the early stage of the bacterial cell wall biosynthesis. Furthermore, the crystal structure of MurA provides a model for predicting active-site residues in EPSP synthase that may be involved in catalysis and substrate binding.

3-Phosphoshikimate 1-Carboxyvinyltransferase↗