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At least 19 recordsLinked to original sources
PubMed1976

[Coenzym properties of some Ade-1- and Ade-N6-substituted NAD derivatives (author's transl)].

By reaction of NAD with different oxiranes or with aziridine, derivatives of the coenzyme are obtained with substituents in position 1 or on the amino group in position 6 of the adenine ring. While the Ade-1-substituted derivatives show high Km values with different dehydrogenases and are reduced only very slowly by these enzymes, the coenzyme derivatives substituted at the amino group behave very similarly to NAD. Correlations were found between coenzyme efficiency of the compounds and the lipophilic character of their substituents. The results can be interpreted from the structure of the active site of the dehydrogenases investigated.

Coenzymes↗
PubMed1977

Purineless death: ribosomal RNA turnover in a purine-starved ade- mutant of Chinese hamster cells.

When V79 pur 1, a purine-requiring auxotroph of a Chinese hamster cell line, is deprived of adenine, nucleic acid and protein synthesis decline rapidly. However, on continuous starvation RNA and DNA synthesis recommences to reach approximately 30% of the normal level between 12 to 24 h starvation. This is accompanied by a rise in the intracellular nucleotide pool. Utilizing mengovirus, which gives a productive infection in V79 pur 1 cells even under conditions of starvation, we can show that rRNA is preferentially degraded and provides the nucleotides for RNA synthesis. Thus "purineless" death in mammalian cells is accompanied by turnover of stable RNA.

Adenine↗
PubMed2026

Nonclinical investigation of the potential of MHAA4549A, an anti-influenza A therapeutic antibody, to mediate antibody-dependent enhancement.

Antibody-dependent enhancement (ADE) of infection and disease is a theoretical safety risk for antiviral antibodies against seasonal viruses with antigenic drift, such as influenza. ADE of infection may occur if virus-specific antibodies at subtherapeutic, nonneutralizing concentrations facilitate virus uptake, thus potentially enhancing virus replication. In contrast, ADE of disease reflects exacerbation of viral disease severity through viral replication-dependent or -independent mechanisms. Because of the theoretical concern of ADE, nonclinical safety assessment of therapeutic anti-influenza antibodies includes a thorough evaluation of ADE potential. The current set of studies was conducted to investigate the potential of MHAA4549A-a broadly specific, neutralizing, therapeutic anti-influenza A antibody-to elicit ADE of infection and disease of influenza H3N2 A/Aichi/2/68 (X31) across a broad dose range. Assessment of ADE was based on totality of results from both in vitro and mouse influenza studies with integration across study endpoints. In vitro studies demonstrated that MHAA4549A can mediate increased X31 entry into human and murine monocytic cells, but increased uptake did not result in enhanced viral replication or release under physiologic conditions. In a mouse model of X31 infection, intravenous administration of MHAA4549A resulted in delayed body weight recovery, but no exacerbation in orthogonal endpoints including mortality, lung viral titers or genomes, lung weights, or severity of influenza pneumonia. Overall, the totality of nonclinical data did not demonstrate any clear indication of ADE of infection at nonneutralizing concentrations, suggesting a low risk for MHAA4549A to cause enhanced influenza A-mediated disease at subtherapeutic doses.

Animals↗
PubMed1976

[Intravital survival and deformability of weakly amidinated rat erythrocytes].

Rat erythrocytes previously labelled with 51Cr were treated with 0.1 mM and 0.5 mM dimethyladipic imidate (ADE) pH 9.5, respectively, or with borate buffer pH 9.5 for 15 minutes each. After reinjection into rats of amidinated or nonamidinated erythrocytes their elimination form the streaming blood was followed for 50 days (0.1 mM ADE) or 38 days (0.5 mM ADE). During the 1st day about 10% of amidinated erythrocytes were sequestered. There was no increased initial elimination rate of borate incubated red blood cells detectable. During the following period the elimination rate of erythrocytes amidinated with 0.5 mM ADE was slightly greater than in the case of erythrocytes treated with 0.1 mM ADE. The mean life span of 0.5 mM ADE-erythrocytes was shorter compared with the controls and with 0.1 mM ADE-erythrocytes. Red blood cells previously treated with 0.5 mM ADE are significantly less deformable. Presumably, the stiffness of amidinated erythrocytes causes their increased elimination rate.

Adipates↗
PubMed1977

Biochemical genetics of Chinese hamster cell mutants with deviant purine metabolism: characterization of Chinese hamster cell mutants defective in phosphoribosylpyrophosphate amidotransferase and phosphoribosylglycinamide synthetase and an examination of alternatives to the first step of purine biosynthesis.

Activities of the first three enzymes in the de novo purine biosynthetic pathway have been measured in cell-free extracts of the Chinese hamster ovary cell (CHO-K1) and two purine-requiring auxotrophs of this cell. Ade-A has been found to be defective in phosphoribosylpryophosphate (PRPP) amidotransferase while Ade-C has been found to be defective in glycinamide ribonucleotide (GAR) synthetase. Neither enzyme deficiency is due to the presence of an excess of diffusible inhibitor, and mixed extracts of Ade-A and Ade-C are capable of performing both enzymatic steps in a coupled assay. Assays of GAR formyltransferase show that it is present in Ade-A and Ade-C, indicating that these cell types are defective in only one enzyme each of the early purine biosynthetic enzymes. Using the Ade-A mutant, analysis of alternatives to PRPP plus glutamine as substrates for the first step in the purine biosynthetic pathway showed that a common genetic unit must direct the synthesis for both PRPP plus glutamine and PRPP plus ammonia activities. Although ribose-5-phosphate plus ammonia can be used in cell-free extracts to perform the first step in purine biosynthesis, it is shown that this activity is apparently not used by intact CHO-K1 cells.

Amidophosphoribosyltransferase↗
PubMed1978

Characterization of a guanine-sensitive mutant defective in adenylo-succinate synthetase activity.

A contingent auxotrophic mutant of CHO-Kl cell is described. This mutant grows in minimal medium. Its growth is inhibited by the exogenous addition of guanine at levels which do not affect the wild type parent. Adenine reverses the guanine effect. This mutant does not complement ade-H (defective in adenylosuccinate synthetase) and has been denoted as ade-HG because of its guanine sensitivity. Some partial revertants of ade-H are found to be also sensitive to guanine, suggesting a close relationship between the ade-H locus and the guanine sensitivity. Studies of 14C-hypoxanthine incorporation into nucleotides indicated that ade-HG has some adenylosuccinate synthetase activity whether it is pre-exposed to guanine or not. Early de novo purine synthesis in ade-HG, however, is greatly inhibited when pre-exposed to guanine. This inhibition of purine synthesis by guanine is reversible and its recovery is facilitated by adenine.

Adenine↗
PubMed1979

Preferential incorporation of an exogenous cytokinin, N6-benzyladenine, into 18S and 25S ribosomal RNA of tobacco cells in suspension culture.

Cytokinin-requiring tobacco cells were incubated for 10 h in the presence of a labeled cytokinin. N6-benzyl-[2-3H]Ade, and of [8-14C]Ado. After alkaline hydrolysis of total RNA and fractionation of the resulting nucleotides, 80 per cent of the 3H radioactivity of RNA were recovered as the N6-benzyl-Ado nucleotide, covalently inserted into polynucleotidic chains. The N6-benzyl-Ado nucleotide was not significantly labled by 14C: at most one part of this nucleotide per 10 000 may result from a transfer of the benzyl moiety to adenyl residues in preformed RNA. Thus, the covalent insertion of N6-benzyl-Ade into RNA involves the intact N6-substituted base. Total RNA was fractionated either by sucrose density gradient centrifugation or by polyacrylamide gel electrophoresis. All identified RNA species were shown to contain N6-benzyl-Ade. The insertion frequency, measured as the molecular proportion of N6-benzyl-Ade to the total base content, was 3 to 4 times larger in 25S and 18S rRNA than in 5S and 4S RNA. The amount of N6-benzyl-Ade inserted into cytoplasmic ribosomal RNA accounted for about 90 per cent of the amount incorporated into total RNA. Electrophoresis of denatured RNA in the presence of formamide provided additional evidence that N6-benzyl-Ade was indeed incorporated into RNA molecules.

Adenine↗
PubMed1977

Biochemical genetics of Chinese hamster cell mutants with deviant purine metabolism. VI. Enzymatic studies of two mutants unable to convert inosinic acid to adenylic acid.

Ade-H and ade-I are two auxotrophic mutants of Chinese hamster ovary (CHO-K1) cells which specifically require adenine as the purine source to grow. The enzymatic defects of these mutants were examined in cell-free extracts. It was found that ade-H did not have any detectable adenylosuccinate synthetase activity and ade-I was defective in the adenylosuccinate lyase enzyme. The relevance of adenine-requiring mutants to the study of the regulation of purine metabolism in mammalian cells is discussed.

Adenine↗
PubMed1979

Biochemical genetics of Chinese hamster cell mutants with deviant purine metabolism: isolation and characterization of a mutant deficient in the activity of phosphoribosylaminoimidazole synthetase.

A new purine-requiring mutant of Chinese hamster ovary cells (CHO-Kl) is described. This mutant, Ade-G, grows on aminoimidazole carboxamide, hypoxanthine, or adenine. It complements all eight of our other previously described Ade- mutants. Biochemical analysis of de novo purine synthesis in whole cells suggests that Ade-G is capable of the first four reactions of de novo purine biosynthesis and that it synthesizes and accumulates phosphoribosylformylglycinamidine (FGAM). Direct enzyme assay in cell-free extracts confirms that Ade-G is defective in phosphoribosylaminoimidazole synthetase activity and does not convert FGAM to phosphoribosylaminoimidazole (AIR), the next intermediate in the de novo biosynthetic pathway.

Animals↗
PubMed1977

Donor strains of the soft-rot bacterium Erwinia chrysanthemi and conjugational transfer of the pectolytic capacity.

Donor strains of Erwinia chrysanthemi ICPB EC16, a member of the soft-rot (pectolytic) section of the enterobacterial genus Erwinia, were obtained by chromosomal integration of an F'lac(+) plasmid originating from Escherichia coli. These stable donor strains, selected from an unstable F'lac(+) heterogenote by repeated platings of single Lac(+) colonies on lactose minimal agar, do not segregate (as does the parent F'lac(+) heterogenote) into Lac(-) or F(-) clones, in either the presence or absence of acridine orange. One representative donor strain (from the 12 that have been selected) has been examined in more detail; it can transfer ade(+), gal(+), gtu(+) (utilization of galacturonate), his(+), lac(+), leu(+), lys(+), mcu(+) (multiple carbohydrate utilization), pat(+) (production of polygalacturonic acid trans-eliminase), thr(+), and trp(+) in a polarized manner to appropriate recipient strains of E. chrysanthemi; the frequencies of ade(+), leu(+), and thr(+) transfer were higher than those of the other markers tested to date. This donor strain transfers lac(+) genes during a 6-h mating on membranes; most of the Lac(+) recombinants are donors of chromosomal markers. The kinetics of entry as well as the frequencies of transfer of chromosomal markers indicate that thr(+) and leu(+) enter the recipient as proximal markers and that lac(+) enters as a distal marker. Analysis of the recombinants demonstrates close linkage between thr and leu, ade and thr, his and pat, and his and trp loci. The results suggest that the integration of F'lac(+) into the chromosome of E. chrysanthemi has occurred at a region adjacent to the leu-thr loci, and that the chromosome is transferred in the following sequence: origin----leu--thr--ade--lys--mcu--pat--his--trp--gal--gtu--lac--F. Plant-tissue maceration occurs in Pat(+) recombinants and not in Pat(-) recombinants, even though both form another pectolytic enzyme, hydrolytic polygalacturonase. This genetic evidence supports the idea that the E. chrysanthemi polygalacturonic acid trans-eliminase plays an essential role in bringing about plant-tissue maceration.

Chromosomes, Bacterial↗
PubMed1977

The identification, characterization, and mapping of a gene for flocculation in Saccharomyces sp.

Genetic studies of a flocculent haploid strain of Saccharomyces have revealed the flocculation to be dominant and controlled at a single gene locus. The flocculation character of both hybrids and haploids derived from such hybrids appears to be influenced by the repression or derepression status of the culture. Mapping studies of this flocculation gene have revealed that it is linked to ade 1 and therefore located on Chromosome I. Consequently, this is a different gene to the three flocculation genes studied by other laboratories because they have found such genes to be unlinked to ade 1. The flocculation gene being discussed in this paper has been designated FLO4. FLO4 has been located 32-33 cM from the Chromosome I centromere and 37 cM from ade 1 (i.e., FLO4 is on the opposite side of the centromere to ade 1).

Chromosome Mapping↗
PubMedDate not supplied

Joseph E. Smadel Memorial Lecture: neuroimmunologic diseases of animals and humans.

New precepts gained from the crescendo of neuroimmunobiologic research of recent decades have increased our understanding of experimental allergic encephalomyelitis (EAE), virus-associated acute disseminated encephalomyelitis (ADE), and multiple sclerosis (MS). EAE of animals and humans provides evidence of the existence in mammalian lymphoid tissues of potential clones of cells with autoreactivity for myelin basic protein (MBP) and other antigenic constituents of the central nervous system (CNS). In a new hamster model, EAE has been strikingly potentiated by persistent infection of the CNS with defective measles virus, a finding that also has implications for virus-associated ADE. Endogenous MBP or MBP degradation fragments, reactive with MBP antibodies of various affinities, have been detected by a recently devised radioimmunoassay in serum, plasma, and other body fluids of normal rats, rats with EAE, and patients with virus-associated ADE or MS. Circulating MBP or MBP fragments may be of great importance in inhibiting neuroautoimmune reactivity and play a role in repair of immunologic CNS injury should it inadvertently occur. Finally, the impressive degree of concordance of immunologic events in EAE, virus-associated ADE, and MS provides additional support for the central importance of host neuroimmunologic responses in the pathogenesis of these neutologic diseases.

Animals↗
PubMed1977

Extrachromosomal inheritance in Schizosaccharomyces pombe. IV. Isolation and genetic characterization of mutants resistant to chloramphenicol and erythromycin using the mutator properties of mutant anar-8.

Spontaneous chloramphenicol (capr)- and erythromycin (eryr)-resistant mutants were isolated from strain ade7-50 h- and the antimycin-resistant mutant anar-8 ade 7-50 h- of Schizosaccharomyces pombe (Sch. p.). By mitotic segregation analysis all 154 capr- and 120 eryr-mutants derived from ade 7-50 h- proved to be recessive chromosomal, whereas all 108 capr- and 200 eryr-mutants originating from anar-8 were extrachromosomally inherited. The rate of spontaneous capr- and eryr-mutants was about hundredfold in anar-8 compared to ade 7-50 h-. Growth of capr- and eryr-mutants was not inhibited by chloramphenicol or erythromycin, respectively, in glucose-medium and only slightly in glycerol-medium at concentrations which completely inhibited anar-8. By mitotic segregation-, tetrad-, and mitotic haploidization-analysis the extrachromosomal inheritance of mutants derived from anar-8 was established. Segregational patterns of capr- and eryr-determinants during mitosis, meiosis, and mitotic haploidization of diploids are discussed.

Ascomycota↗
PubMed1975

Mutants of Serratia marcescens lacking cyclic nucleotide phosphodiesterase activity and requiring cyclic 3',5'-AMP for the utilization of various carbohydrates.

Adenine requiring mutants of Serratia marcescens SM-6-F'lac+ have been found to grow well in minimal-glucose medium solely supplemented with cAMP. From one of these ade strains double mutants (called ade cpd) were isolated which could no longer utilize cAMP but which still grew on 5'AMP. Dialyzed cell extracts (soluble fraction) of the double mutants, assayed for cAMP phosphodiesterase, were unable to hydrolyze cAMP whereas cell extracts of the parental strains yielded 5'AMP at a rate of 1.6-2.0 mumoles min-1 mg-1 protein. The loss of the phosphodiesterase activity in S. marcescens cpd W 1181 did not cause an accumulation of large amounts of cAMP as was found for the diesterase-negative mutant AB257pc-1 of Escherichia coli. The induced synthesis of beta-galactosidase in mutant cpd W 1181 showed about the same sensitivity to transient and permanent catabolite (glucose) repression as the corresponding cpd+ strain. Starting from S. marcescens cpd W 1182 three independent double mutants (called cpd cya) were isolated which required exogenous cAMP for utilizing various carbohydrates as carbon source, for motility and for the formation of extracellular lipase and the red pigment prodigiosine. The intracellular concentration of cAMP in these mutants, grown in nutrient broth, was 40-60% of that of the parental strain which is about 4 x 10(-4) M. However, the adenylate cyclase in cell extracts of the mutants W 1237 and W 1270 was like that of the corresponding cya+ strain (about 2 x 10(-2) mumoles min-1 mg-1 protein).

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1976

Biochemical genetics of Chinese hamster cell mutants with deviant purine metabolism: isolation, selection, and characterization of a mutant lacking hypoxanthine-guanine phosphoribosyltransferase activity by nutritional means.

Mutants of the Chinese hamster ovary cell derived from CHO-K1 have been selected for lack of hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8) (HGPRT) without the use of a drug-resistance protocol. The procedure depends on the use of a parental strain carrying a mutation making it unable to synthetize purines and thus dependent upon exogenously added purines for growth. The standard "BUdR-visible-light" procedure is then used to select those cells which can use adenine but cannot use hypoxanthine as a purine source. These cells are shown to be thioguanine resistant, to be unable to incorporate exogenously added hypoxanthine into purine nucleotides, to complement our other adenine-specific purine auxotrophs, Ade-H and Ade-I but not to complement a cell isolated by virtue of thioguanine resistance, and to lack the activity of HGPRT. The use of such multiply marked mutants and cells related to them for further analysis of purine nucleotide biosynthesis and interconversion is discussed.

Animals↗