Nucleic acids metabolism studies

Studies of canavanine interaction with the tobacco hornworm and J-. miTior also revealed the marked ability of canavanine.to inhibit whole organism incorporation of [ Hjthymidine and uridine into trichloroacetic acid-precipitated materials. When canavanine is provided simultaneously with the appropriate radio-labeled precursor, ample evidence for curtailed nucleic acid metabolism emerges but protein synthesis is unaffected (Table I, exp. I). In experiment II, canavanine is allowed to assimilate... 

The knowledge of the chemistry and structure of nucleic acids as well as their metabolic and catabolic pathways has been extensively increased. However, there is very little evidence about the role of transition elements in the biochemistry of nucleic acids. Therefore, this review should emphasize the present status of the literature about studies of transition metal interactions with the monomer and polymer units of nucleic acids. Although this survey is far from being comprehensive it is hoped that the data collected here will be helpful for further investigations on the biochemical behavior of transition metals in nucleic acid metabolism. 

Among the most important reactions in biochemistry are those that involve substitution at phosphorus in phosphates. These reactions are involved in energy transduction, replication, transcription and recombination of nucleic acids, metabolic regulation, and metabolic pathways including biosyntheses of nucleotides, amino acids, proteins, complex lipids and complex carbohydrates. They are among the most intensively studied proteins in biochemistry, both because of their fundamental importance and because they present special challenges as research subjects. 

K7. Kitiyakara, A., Cytologic study of dystrophia muscularis mouse muscles. Observations on nucleic acid metabolism and nuclear distribution. Arch. Pathol. 71, 579 (1961). 

Precursor Incorporation Studies. Studies of the incorporation of tritiated precursors of the DNA, RNA, or protein synthesis, i.e. of thymidine, uridine, or leucine, into the acid-insoluble fraction of EAT cells were accomplished after in vivo as well as in vitro treatment with (C5H5)2MCl2 (M Ti, V). In all experiments, the nucleic acid metabolism turns out to be much more sensitive to the metallocene dihalide action than the protein metabolism (33, 34). In particular, treatment with vanadocene dichloride induces an extended and persistent suppression of the DNA synthesis without signs of regeneration processes (Figure 2). 

Many years ago Adamstone (1934, 1936) suggested, after extensive histopathologic study of vitamin E-deficient chickens, that the vitamin must exert some controlling influence over cellular proliferation. Mason (1944) carried this suggestion further and hypothesized that vitamin E might somehow influence the synthesis of nuclear chromatin. After these suggestions, which were made almost 30 years ago, there were no experimental studies of nucleic acid metabolism in vitamin E deficiency until the experiments to be described in this review were undertaken. 

The influence of vitamin E deficiency on nucleic acid metabolism has been investigated in rats, rabbits, and monkeys. The concentrations of both RNA and DNA are elevated in skeletal muscle and bone marrow. From studies with a variety of radioactive nucleic acid precursors it is concluded that vitamin E deficiency leads to an increased rate of DNA synthesis in rabbit skeletal muscle and in monkey skeletal muscle and bone marrow. These changes in nucleic acid metabolism may be related to the... 

Several studies have been reported on the metabolism of DMN using tissue slices. The initial studies on DMN metabolism in vitro were performed with rat and rabbit liver slices disappearance of DMN was measured polarographically (577). In subsequent investigations using this technique, conversion of [ CJDMN to C02 was determined and, in certain cases, [7- C]methyl-guanine was isolated from the tissue nucleic acids. These studies have been concerned with the effects of pretreatment on DMN metabolism and toxicity and with the comparative metabolism of DMN in various species and organs. 

Unlike many routine clinical chemistry tests, clinical analyses of lEM almost always involve a multiple metabolite analysis. The results form the basis of a metabolic profile in which both individual concentrations of metabolites and their relationship to each other can be viewed either in tabular form or in a graphical display. Perhaps the most comprehensive and historically significant test in lEM studies is gas chromatography/mass spectrometry (GC/MS) of a derivatized extract of urine. Figure 2 is a chromatogram from an infant with propionic acidemia, an organic acid disorder of leucine metabolism. Hundreds of volatile compounds of carbohydrate, amino acid, fatty acid, and nucleic acid metabolism are separated in 40 min using capillary GC. Addition... 

C5 Caldarera, C. M., Barbiroli, B., Moruzzi, M. S. and Marchetti, M. Studies on the effect of orotic acid on nucleic acid metabolism in vitamin Bi2-deficient chick liver. Biochim. Biophys. Acta, 161, 156-161 (1968)... 

Lu KH, Winnick T. Studies of nucleic acid metabolism in embryonic tissue culture with the aid of C -labeled purines. Exp Cell Res 6 345-352, 1954. See also Lajtha CP, Oliver R, Ellis, F. Incorporation of P and adenine- C into DNA by human bone marrow cells in... 

Other Synthetic Antivirals - Clinical investigations in man have indicated that 1-allyl-3,5-diethyl-6-chlorouracil applied topically as a ifo solution is effective in the treatment of all types of recurring herpetic skin and mucous diseases including herpes genitalis and stomatitis aphthosa." The compound was first found to be active in tissue culture and then in rabbits. A study of the virostatic properties of 1-allyl-3,5-diethyl-6-chlorouracil indicated that this type of compound exerts its action through its allylic double bond and does not interfere with nucleic acid metabolism." ... 

In all studies carried out to date on enzymes of nucleic acid metabolism, MMPR-OP has shown specificity for lysine residues. Inhibition of other enzymes of nucleic acid metabolism by MMPR-OP can be taken as presumptive evidence for the presence of lysines in their active... 

Folic Acid Antagonists - Interest in antimetabolites that interfere with the synthesis of nucleic acids continues. Studies on the transport and uptake of methotrgxate ° and 2,4-diamino-5-(3,4-dichlorophenyl)-6-methylpyrimidine indicate that clinical response is related to cellular uptake of drugl and the resistance of certain cells to methotrexate appears to be due to lack of transport into these cells. Work on other resistant cell lines indicates that resistance can also be due to an increase in cellular content of folate reductase, but no correlation was observed between resistance and the level of other enzymes involved in folate metabolism. Despite these results there is evidence that the ability of methotrexate to kill cells cannot be entirely explained by its inhibition of folate reductase. Leucovorin at appropriately timed intervals improved the therapeutic index of methotrexate in the treatment of head and neck cancer, and lymphosarcoma and reticulum cell sarcoma. The use of methotrexate in the treatment of hormone-refractory metastatic breast carcinoma " and the use of intrathecal methotrexate also appear promising. Oxidation of methotrexate to 7-hydroxymethotrexate by liver aldehyde oxidase is probably a detoxification mechanism. Material previously reported to be tetrahydromethotrexate has now been found to be a mixture of di- and tetrahydromethotrexate, both of which are less effective than methotrexate in the inhibition of folate reductase, but more effective in the inhibition of thymidylate synthetase. ... 

While the studies of Boyland and Roller and Elion and co-workers, which were conducted in vivo, do suggest that urethane has a specificity for pyrimidine biosynthesis, Kaye could not demonstrate in vitro any significant inhibition by urethane of several enzymes involved in nucleic acid metabolism. Both urethane and its A -hydroxy metabolite bear a structural resemblance to carbamyl phosphate and carbamyl-L-aspartate. The enzyme aspartate transcarbamylase begins pyrimidine biosynthesis by catalyzing the formation of carbamyl-L-aspartate from carbamyl phosphate and l-aspartate. Giri and Bhide have reported that in vivo administration of urethane decreased aspartate transcarbamylase activity of lung tissue of adult male and (to a lesser extent) female mice no in vitro inhibition could be demonstrated. 

FIuazifop (2-[4-(5-trifluoromethyl-2-pyr1dyloxy)phenoxy]propionate) is a grass-specific herbicide. It is an aryloxyphenoxypropionate compound and these herbicides have been shown to kill sensitive species by causing necrosis of meristematic tissues. A number of studies on the mode of action of the aryloxyphenoxypropionates have only been able to demonstrate an inhibition of lipid metabolism. No detectable effects on CO2 fixation or carbohydrate, amino acid or nucleic acid metabolism have been shown ( Walker 1988a,). Cyclohexanedione herbicides, such as sethoxydim,... 

Martin, E. M., Malec, J., Sved, S., and Work, T. S., 1961, Studies on protein and nucleic acid metabolism in virus-infected mammalian cells. I. Encephalomyocar-ditis virus in Krebs-II mouse ascites tumour cells, Biochem. J. 80 585. 

Kristensen E. In vitro and in vivo studies on pharmacokinetics and metabolism of PNA constructs in rodents. In Peptide Nucleic Acids Methods and Protocols, Nielsen P. E. (Ed.). 2002, Humana Press (To-towa, N.J., United States) Copenhagen, pp. 259-269. 

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