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PubMed2001

Carnitine palmitoyl transferase I and the control of beta-oxidation in heart mitochondria.

Mitochondrial beta-oxidation provides much of the fuel requirements of heart and skeletal muscle despite the malonyl-CoA concentration greatly exceeding the IC(50) of carnitine palmitoyl transferase for malonyl-CoA. To try to explore the relationship between inhibition of carnitine palmitoyl transferase I activity and beta-oxidation flux, we measured the flux control coefficient of carnitine palmitoyl transferase I over beta-oxidation carbon flux in suckling rat heart mitochondria. The flux control coefficient was found to be 0.08 +/- 0.05 and 50% of carnitine palmitoyl transferase I activity could be inhibited before beta-oxidation flux was affected. These observations may help to explain the presence of high rates of beta-oxidation despite the high concentration of malonyl-CoA in rat heart; we hypothesize that although not rate-limiting in vitro, carnitine palmitoyl transferase is rate-limiting in vivo because of the high malonyl-CoA concentration in heart and muscle.

Animals↗
PubMed1995

Fine structure of the peptidyl transferase centre on 23 S-like rRNAs deduced from chemical probing of antibiotic-ribosome complexes.

Ribosomal binding sites were investigated for the diverse group of antibiotics: anisomycin, anthelmycin, blasticidin S, bruceantin, carbomycin, chloramphenicol, griseoviridin, narciclasine, T2 toxin, tylosin and virginiamycin M1 all of which are considered to inhibit the peptidyl transferase reaction by different mechanisms. The drugs also exhibit differing degrees of specificity for bacterial, archaeal and eukaryotic ribosomes despite a high level of conservation of sequence and secondary structure at the peptidyl transferase centre of the 23 S-like rRNAs. The drug binding sites were characterized by incubating each antibiotic with ribosomes from a bacterium, an archaeon and a eukaryote and chemically probing the 23 S-like rRNA. The complexity of the changes in reactivity ranged from one or two nucleotides (anthelmycin, narciclasine) to eight or nine (virginiamycin M1) and it was inferred, at least for those drugs producing complex changes, that they induce, and stabilize, a particular functional conformer in the peptidyl transferase centre. The results were correlated with literature data on both ribosomal ligand binding and the putative inhibitory mechanisms of the drugs, and the following inferences are made concerning the fine structure of the peptidyl transferase centre. (1) An irregular secondary structural motif, which includes unpaired A2439 (Escherichia coli numbering), lies close to the catalytic centre; (2) nucleotides A2451 and C2452 contribute to a site for the binding of the side chains of aromatic amino acids; (3) the P-substrate site encompasses U2585, U2506 and, possibly, a site in domain IV (A1787), and (4) the sequence A2058 to A2062 and nucleotide U2609 contribute to, or modulate, the start of the peptide channel. No drug effects were found that could be directly attributed to an A-site and the possibility is raised that, if it exists, it consists mainly of ribosomal proteins. However, two drugs T2 toxin and virginiamycin M1 protected the only nucleotide in the peptidyl transferase loop region (C2394) associated with the E-site. Finally, it is proposed that the putative sub-sites are physically separated, that some drugs bind to more than one of them, and that they are conformationally interdependent.

Anti-Bacterial Agents↗
PubMed1983

Evaluation of serum gamma-glutamyl transferase as a screening method for excessive alcohol consumption during pregnancy.

Serum gamma-glutamyl transferase was analyzed in 669 pregnant women. They were interviewed with special emphasis on their consumption of alcohol during the first trimester. Thirteen percent admitted a consumption of greater than 30 gm of pure alcohol per day, and 3%, greater than 125 gm per day. One child with a complete fetal alcohol syndrome and one with a partial one were born to mothers with a high consumption of alcohol and elevated serum gamma-glutamyl transferase. The ninety-fifth percentile for serum gamma-glutamyl transferase in women classified as low consumers (less than 30 gm of alcohol per day) was 0.44 mukat/L. With this 95% specificity level used as a cutoff, the sensitivity of the serum gamma-glutamyl transferase test in identifying those who consumed more than 30 gm of alcohol per day was 25%. The conclusion was that screening based on analyses of serum gamma-glutamyl transferase is not to be recommended for routine use in prenatal care.

Adolescent↗
PubMed1980

Vitamin A and galactosyl transferase of tracheal epithelium.

We developed an assay for galactosyl transferase (uridine diphosphategalactose:glycoprotein galactosyltransferase, EC 2.4.1.22) in microsomes of rat tracheal epithelium and characterized the properties of this enzyme system. We found that vitamin A deficiency greatly depressed galactosyl transferase activity. Activity could be restored within 48 h by dosing the animal with retinyl acetate. Adding retinol to the microsomes from tracheal epithelium of vitamin A-deficient rats also restored galactosyl transferase activity to some extent. Full restoration was achieved by pre-incubating retinol with the microsomal preparation for 30 min. Optimal concentration of pre-incubated retinol was 10(-8) M. Pre-incubation with retinyl phosphate and retinoic acid stimulated galactosyl transferase activity in microsomes from tracheas of deficient rats; pre-incubation with dolichyl phosphate, anhydroretinol and the dimethylacetylcyclopentenyl analog of retinoic acid did not. We concluded that vitamin A is involved in the galactosyl transferase system of rat tracheal epithelium, possibly by being linked to galactose.

Animals↗
PubMed1981

Characterization of galactose-1-phosphate uridyl-transferase and galactokinase in human organs from the fetus and adult.

Some properties of galactose-1-phosphate uridyltransferase (EC 2.7.7.12) and galactokinase (EC 2.7.1.6) were investigated in human organs, i.e., in liver kidney, skeletal muscle, lung, spleen, heart and brain from fetuses as well as liver, kidney and skeletal muscle tissues from adults. (1) Galactose-1-phosphate uridyltransferase (transferase) is quite stable when stored below 4 degrees C, and can be frozen from a couple of months without noticeable loss of activity. Galactokinase is relatively stable as long as the cell structure is intact. In cell homogenates its activity decreases very fast, especially under freezing conditions. (2) The pH optimum of transferase in all human tissues is at pH values between 8.2 and 8.4 except in erythrocytes in which it is at a higher pH value. Maximal activity of galactokinase is observed at approximately 8.2 in all human tissues. (3) The Km values of transferase are similar in all human organs, and the values in fetal tissues are not significantly different from those in adult tissues. In the case of galactokinase also no distinct tissue variations are observed in Km values. However, galactokinase affinity for both substrates is considerably higher in adult organs than in fetal organs. (4) Transferase and galactokinase activity in human liver is resolved into two major components on DEAE-cellulose columns. It seems that transferase and galactokinase exist in human tissues as more than two isoenzyme constituents.

Adult↗
PubMed1987

Inactivation of yeast nucleotidyl transferase and its effect on the integrity of the aminoacid acceptor end of transfer RNA.

Yeast tRNA nucleotidyl transferase rapidly inactivates (half life c. 2 hr) upon nitrogen starvation of exponentially growing cells. The inactivation does not occur when glucose together with the nitrogen source is removed or when glucose is replaced by ethanol. The transferase activity reappears shortly after replenishment of the nitrogen source and this appearance of the enzymatic activity is blocked by cycloheximide, indicating the need for protein biosynthesis during the process. The nucleotidyl transferase activity is also very low in stationary phase yeast cells. A ten fold decrease in the transferase activity is not paralleled by loss of the integrity of the 3' end of the tRNA chains. It seems that there is a large excess of enzymatic activity over that needed to keep the tRNA chains complete. The observed lack of the 3' end of tRNAs from late stationary phase yeast cannot be accounted for by the observed drop in transferase activity in these cells.

Amino Acids↗
PubMed1983

Purification of human liver uridylyl transferase and comparison with the erythrocyte enzyme.

Uridylyl transferase (UDP glucose: alpha-D-galactose 1 phosphate uridylyl transferase, EC 2.7.7.12) has been purified 1350-fold from human liver to complete homogeneity. The purification procedure involved ammonium sulfate fractionation, batch treatment, chromatography on DEAE-cellulose, hexylagarose and hydroxylapatite. The specific activity of the homogeneous enzyme was 27 units/mg protein. The liver enzyme was compared to the red cell enzyme previously purified by us. The liver enzyme was similar to the red cell enzyme with respect to subunit molecular weight, kinetic studies and immunological properties. Differences in electrophoretic behaviour were found: the liver transferase has a more basic pI (between 5.5 and 5.8) than that of the erythrocyte enzyme (pI between 5.0 and 5.45). It is very likely that the liver uridylyl transferase and the red blood cell transferase are the same enzymes with post-translational modifications.

Chromatography, DEAE-Cellulose↗
PubMed1995

Inactivation of arginyl-tRNA protein transferase by a bifunctional arsenoxide: identification of residues proximal to the arsenoxide site.

Aminoacyl-tRNA protein transferases catalyze (posttranslational) aminoacylation of specific protein N-termini, using aminoacyl-tRNA as substrate. This modification targets the protein for ATP-dependent degradation; in eukaryotes, degradation occurs in the ubiquitin-mediated pathway. The eukaryotic transferase, which catalyzes Arg transfer to N-terminal Glu or Asp residues, is potently inhibited by phenylarsenoxides. The gene encoding Arg-tRNA protein transferase from the yeast Saccharomyces cerevisiae was subcloned and overexpressed in Escherichia coli to provide large amounts of homogeneous protein for a molecular analysis of this inhibition. The bifunctional reagent para-[(bromoacetyl)amino]-phenylarsenoxide is a potent and irreversible inactivator of the yeast transferase; the arsenoxide moiety of the reagent directs binding to the enzyme, while the alkyl halide moiety alkylates a residue(s) proximal to the arsenoxide site. One mole of 14C-labeled reagent was covalently incorporated during inactivation, with the side chain of Cys-315 representing the major site of alkylation. Mutation of Cys-315 to Ala yielded a fully active enzyme which was still subject to stoichiometric, irreversible inactivation by the bifunctional arsenoxide. With the C315A-enzyme, the major fraction of the 14C-labeled bifunctional reagent was associated with the side chain(s) of one or more of a stretch of Glu residues (Glu 339-341). These results show that phenylarsenoxides inhibit Arg-tRNA protein transferase by binding to a site that is either itself essential, or regulates an essential site. Inhibition appears to occur through a steric blockade mechanism.

Acyltransferases↗
PubMed1989

ADP-ribosylation of ADPR-transferase and topoisomerase I in intact mouse epidermal cells JB6.

Poly(ADP-ribosylation) [poly(ADPR)] is a posttranslational modification of chromosomal proteins that affects the structural and functional properties of chromatin. We have studied poly(ADPR) of ADPR-transferase and topoisomerase I in intact mouse epidermal cells JB6 (clone 41) by a combination of affinity chromatography on phenylboronate and immunoblotting with monoclonal antibodies against poly(ADPR) chains and polyclonal antibodies against ADPR-transferase and topoisomerase I, respectively. Constitutive, steady-state poly(ADPR) substitution of ADPR-transferase was estimated at 4% and that of topoisomerase I at 0.1%. Active oxygen produced extracellularly by xanthine-xanthine oxidase and the methylating agent N-methyl-N'-nitro-N-nitrosoguanidine transiently increased the level of poly(ADPR) substitution of these enzymes by a factor of 6-10. While the poly(ADPR) substitution of ADPR-transferase remained elevated after 60 min of incubation, the poly(ADPR) substitution of topoisomerase I had returned to control values within this time. Benzamide (100 microM) partially prevented the stimulation of poly(ADPR) synthesis by these agents. We speculate that self-inactivation of ADPR-transferase by poly(ADPR) represents a feedback mechanism that has the function to avoid excessive poly(ADPR) synthesis and concomitant NAD and ATP depletion. Inactivation of topoisomerase I in the neighborhood of DNA breakage may temporarily shut down DNA replication and allow DNA repair to occur.

Animals↗
PubMed1985

Glycosyl transferases in chondroitin sulphate biosynthesis. Effect of acceptor structure on activity.

The D-glucuronosyl (GlcA)- and N-acetyl-D-galactosaminyl (GalNAc)-transferases involved in chondroitin sulphate biosynthesis were studied in a microsomal preparation from chick-embryo chondrocytes. Transfer of GlcA and GalNAc from their UDP derivatives to 3H-labelled oligosaccharides prepared from chondroitin sulphate and hyaluronic acid was assayed by h.p.l.c. of the reaction mixture. Conditions required for maximal activities of the two enzymes were remarkably similar. Activities were stimulated 3.5-6-fold by neutral detergents. Both enzymes were completely inhibited by EDTA and maximally stimulated by MnCl2 or CoCl2. MgCl2 neither stimulated nor inhibited. The GlcA transferase showed a sharp pH optimum between pH5 and 6, whereas the GalNAc transferase gave a broad optimum from pH 5 to 8. At pH 7 under optimal conditions, the GalNAc transferase gave a velocity that was twice that of the GlcA transferase. Oligosaccharides prepared from chondroitin 4-sulphate and hyaluronic acid were almost inactive as acceptors for both enzymes, whereas oligosaccharides from chondroitin 6-sulphate and chondroitin gave similar rates that were 70-80-fold higher than those observed with the endogenous acceptors. Oligosaccharide acceptors with degrees of polymerization of 6 or higher gave similar Km and Vmax. values, but the smaller oligosaccharides were less effective acceptors. These results are discussed in terms of the implications for regulation of the overall rates of the chain-elongation fractions in chondroitin sulphate synthesis in vivo.

Animals↗
PubMed1978

Terminal transferase as a predictor of initial responsiveness to vincristine and prednisone in blastic chronic myelogenous leukemia: a co-operative study.

We undertook a prospective trial to evaluate terminal deoxynucleotidyl transferase activity as a predictor of responsiveness to vincristine and prednisone in 22 Philadelphia-chromosome-positive patients with blastic chronic myelogenous leukemia. Thirteen patients were transferase positive, and nine negative. None of the nine negative patients responded, whereas eight of the 13 positive (P = 0.004) responded with complete clearing of peripheral blood blast cells and a return of normal marrow cellularity with less than 5 per cent blast cells. Among transferase-positive patients under 50 years of age the response rate was 78 per cent. Blast-cell morphology (i.e., lymphoblastic versus myeloblastic) had no significant correlation with either responsiveness or terminal transferase activity. The results of this study suggest that responsiveness to vincristine and prednisone in blastic chronic myelogenous leukemia is confined to patients whose leukemic cells are transferase positive.

Adolescent↗
PubMed1974

Terminal deoxyribonucleotidyl transferase in human leukemia.

Terminal deoxyribonucleotidyl transferase (EC 2.7.7.31; nucleoside triphosphate:DNA nucleotidylexotransferase) is usually found only in thymus, but has been reported in leukemic cells from children with acute lymphoblastic leukemia. In an unusual adult patient with acute myelomonocytic leukemia, terminal transferase was found at a level of 16 units per 10(8) bone marrow cells and 14 units per 10(8) circulating leukocytes (1 unit = 1 nmol of nucleotide per hr). This activity is comparable to that found in normal thymus. Assays of transferase in marrow and peripheral leukocytes from patients with typical acute and chronic myelogenous leukemias gave average values of 0.5 and 0.3 unit per 10(8) cells, respectively. Transferase activity is also found in normal bone marrow at about 0.07 unit per 10(8) cells. Terminal deoxyribonucleotidyl transferase in all samples of human marrow and peripheral blood had reaction characteristics, sedimentation, and chromatographic properties similar to the homogeneous enzyme from calf thymus.

Aged↗
PubMed1977

Demonstration of terminal deoxynucleotidyl transferase in thymocytes by immunofluorescence.

The cellular and subcellular distribution of terminal deoxynucleotidyl transferase (DNA nucleotidylexotransferase; nucleosidetriphosphate:DNA deoxynucleotidylexotransferase, EC 2.7.7.31) in thymocytes and peripheral lymphocytes from rat, mouse, and calf was studied by immunofluorescence using rabbit antiserum to homogeneous transferase from calf. Terminal transferase was readily detected in approximately 75% of cortical thymocytes, but not in medullary thymocytes or lymph node lymphocytes. The enzyme appeared to be present predominantly in the cytoplasm of positive thymocytes in ethanol-fixed cell smears and frozen sections. The reactivity of anti-terminal-transferase for thymocytes could be neutralized with purified calf enzyme. Results of experiments in which thymocytes were separated on 7-step discontinuous Ficoll density gradients suggested that cortical thymocytes are heterogeneous with respect to terminal deoxynucleotidyl transferase content.

Animals↗
PubMed1996

A new approach to mapping co-localization of multiple glycosyl transferases in functional Golgi preparations.

We have developed a new method to co-localize multiple glycosyl transferases in different Golgi compartments. The approach relies on the proven ability of intact, sealed rat liver Golgi preparations to concentrate exogenous labeled sugar nucleotides into the lumen where they glycosylate either endogenous or artificial acceptors. The premise is that if two glycosyl transferases are co-localized within the same compartment, they will compete for the limited amount of transported donor. If the donor is consumed in glycosylating a permeable artificial glycoside within a Golgi compartment, it will be unavailable to glycosylate endogenous products within that same compartment. The greater the degree of transferase co-localization, the greater the potential decrease in glycosylation of endogenous acceptors. We provide an example consistent with these predictions. Adding 1 microM UDP[3H]Gal to Golgi preparations followed by a chase with a cocktail of unlabeled sugar nucleotides labels mostly endogenous N-linked oligosaccharides containing both beta 1,3- and beta 1,4[3H]Gal residues with and without sialic acid. Addition of increasing amounts of 4-methylumbelliferyl-beta-xyloside (Xyl beta MU) produces [3H]Gal1 beta, 4Xyl beta MU and leads to a reciprocal decrease in labeling of a restricted set of the endogenous acceptors. This decrease is preferential for [3H]Gal beta 1-->3GlcNAc beta 1-->R and, to a lesser extent, [3H]Gal beta 1-->4GlcNAc beta 1-->R structures in neutral and mono-sialylated oligosaccharides; synthesis of these structures in di- and tri-sialylated oligosaccharides was unaffected. These preferential decreases are not seen in detergent permeabilized, sugar nucleotide transport-independent Golgi incubations, and are not due to inhibition by the Gal beta 1,4Xyl beta MU product. These results argue that there is significant overlap in the functional co-localization of sialyl and galactosyltransferases in rat liver Golgi preparations and that GAG chain core specific Galactosyltransferase I is co-localized with subsets of N-glycan Gal beta 1,3 and Gal beta 1,4 transferases. This approach can be used with other glycosides and sugar nucleotides to map and co-localize other glycosyl transferases. The functional compartments defined by this approach may or may not correspond entirely with morphologically defined Golgi domains.

Animals↗
PubMed2007

The lectin domains of polypeptide GalNAc-transferases exhibit carbohydrate-binding specificity for GalNAc: lectin binding to GalNAc-glycopeptide substrates is required for high density GalNAc-O-glycosylation.

Initiation of mucin-type O-glycosylation is controlled by a large family of UDP GalNAc:polypeptide N-acetylgalactosaminyltransferases (GalNAc-transferases). Most GalNAc-transferases contain a ricin-like lectin domain in the C-terminal end, which may confer GalNAc-glycopeptide substrate specificity to the enzyme. We have previously shown that the lectin domain of GalNAc-T4 modulates its substrate specificity to enable unique GalNAc-glycopeptide specificities and that this effect is selectively inhibitable by GalNAc; however, direct evidence of carbohydrate binding of GalNAc-transferase lectins has not been previously presented. Here, we report the direct carbohydrate binding of two GalNAc-transferase lectin domains, GalNAc-T4 and GalNAc-T2, representing isoforms reported to have distinct glycopeptide activity (GalNAc-T4) and isoforms without apparent distinct GalNAc-glycopeptide specificity (GalNAc-T2). Both lectins exhibited specificity for binding of free GalNAc. Kinetic and time-course analysis of GalNAc-T2 demonstrated that the lectin domain did not affect transfer to initial glycosylation sites, but selectively modulated velocity of transfer to subsequent sites and affected the number of acceptor sites utilized. The results suggest that GalNAc-transferase lectins serve to modulate the kinetic properties of the enzymes in the late stages of the initiation process of O-glycosylation to accomplish dense or complete O-glycan occupancy.

Acetylgalactosamine↗
PubMed1997

Inhibitors of prenyl transferases.

Because farnesylation of Ras is required for its cancer-causing activity, several classes of farnesyl transferase inhibitors have recently been developed as potential anticancer drugs. During the last 12 months, important advances have been made in this field. In this review, we focus on three topics: targets of farnesyl transferase inhibitors other than Ras, alternative prenylation of K-Ras by the closely related prenyl transferase, geranyl geranyl transferase I, and the effects of geranyl geranyl transferase I inhibitors on cell cycle, apoptosis, and human tumor growth.

Animals↗
PubMed2006

An association study between catechol-O-methyl transferase gene polymorphism and methamphetamine psychotic disorder.

OBJECTIVE: A series of methamphetamine psychosis reveals two kinds of clinical courses of methamphetamine psychosis: transient type and prolonged type. Furthermore, paranoid psychosis sometimes recurs without methamphetamine reuse, referred to as spontaneous relapse. Dysfunction of central dopaminergic neurotransmission has been implicated in the pathogenesis of these psychiatric states. Catechol-O-methyl transferase appears to play a unique role in regulating synaptic dopaminergic activity. This study aimed to investigate whether a functional polymorphism of the catechol-O-methyl transferase gene would be involved in the development of these psychiatric states. BASIC METHODS: We examined the functional polymorphism of val 158 met (catechol-O-methyl transferase) in 143 patients with methamphetamine psychosis and 200 healthy controls in Japan. The patients were divided into subgroups by several characteristic clinical features. MAIN RESULTS: We found a significant difference in the catechol-O-methyl transferase allele frequency between patients with spontaneous relapse and the controls (P=0.018, odds ratio=1.67). Odds ratio implied that the patients with spontaneous relapse had a nearly 1.7-fold higher rate of the low activity alleles (met) than the controls. CONCLUSIONS: Our results indicate that the met allele frequency of the catechol-O-methyl transferase is associated with patients who experienced methamphetamine psychosis and spontaneous relapse, suggesting that patients with a met allele appear to be at increased risk of an adverse response to methamphetamine.

Adult↗
PubMed2004

Production of coumaroylserotonin and feruloylserotonin in transgenic rice expressing pepper hydroxycinnamoyl-coenzyme A:serotonin N-(hydroxycinnamoyl)transferase.

Transgenic rice (Oryza sativa) plants were engineered to express a N-(hydroxycinnamoyl)transferase from pepper (Capsicum annuum), which has been shown to have hydroxycinnamoyl-CoA:tyramine N-(hydroxycinnamoyl)transferase activity, a key enzyme in the synthesis of hydroxycinnamic acid amides, under the control of constitutive maize (Zea mays) ubiquitin promoter. The transgenic rice plants require foliar application of amines to support synthesis of hydroxycinnamic acid amides, suggestive of limiting amine substrates in rice shoots. In addition, when T2 homozygous transgenic rice plants were grown in the presence of amines or phenolic acids, two novel compounds were exclusively identified in the leaves of the transgenic plants. These compounds eluted earlier than p-coumaroyltyramine and feruloyltyramine during HPLC chromatography and were identified as p-coumaroylserotonin and feruloylserotonin by liquid chromatography/mass spectrometry and other methods. To test whether the unpredicted production of serotonin derivatives is associated with the pepper N-(hydroxycinnamoyl)transferase, the substrate specificity of the pepper enzyme was analyzed again. Purified recombinant pepper N-(hydroxycinnamoyl)transferase exhibited a serotonin N-hydroxycinnamoyltransferase (SHT) activity, synthesized p-coumaroylserotonin and feruloylserotonin in vitro, and demonstrated a low K(m) for serotonin. SHT activity was inhibited by 10 to 50 mm tyramine. In addition, SHT activity was predominantly found in the root tissues of wild-type rice in parallel with the synthesis of serotonin derivatives, suggesting that serotonin derivatives are synthesized in the root of rice. This is the first report of SHT activity and the first demonstration, to our knowledge, that serotonin derivatives can be overproduced in vivo in transgenic rice plants that express serotonin N-(hydroxycinnamoyl)transferase.

Acyltransferases↗