Nucleosides and Nucleotides as Potential Therapeutic Agents

Abstract

and, 3) the glutamine synthetase deadenylylating enzyme. Equation 4 shows the adenylylated and unadenylylated forms of glutamine synthetase, with their respective properties, as well as the enzymes which interconvert the two forms, and their effectors.of the products of glutamine metabolism. In this form glutamine synthetase activity is thus further diminished by the accumulated nitrogenous metabolites, which has as its result the lowering of the level of glutamine in the cell. It is clear from this scheme that conditions of nitrogen starvation, with a correspondingly low nitrogen saturation ratio, lead to activation of the deadenylylating enzyme as well as to an inhibition of the adenylyltransferase, owing to the alterations in the relative levels of glutamine and a-ketoglutarate. This results in the formation of relatively unadenylylated glutamine synthetase, the form of the enzyme which is intrinsically more active and less sensitive to feedback inhibition. In this condition, ammonia will be converted into nitrogenous metabolites with high efficiency.On the other hand, with high levels of the nitrogen saturation ratio, as might be expected with a surfeit of nitrogen-containing compounds,thedeadenylylating enzyme would be inhibited and the adenylyltransferase activated. The result of this reciprocal enzyme control would be to convert the glutamine synthetase to the adenylylated form, which is less active and additionally more susceptible to inhibition by several Less active form More sensitive to feedback inhibition MnZ+ specificThe three-enzyme nitrogen regulatory system has as its most obvious role the preservation of homeostasis in cellular nitrogen metabolism; any shift away from the "normal" nitrogen saturation ratio is accompanied by adjustments in the three enzymes which tend to restore the ratio toward the preexisting level. These intricate controls have as an ancillary effect the preservation of cellular ATP, since both glutamine synthesis and adenylylation of glutamine synthetase consume ATP; in fact, the adenylylation-deadenylylation system without reciprocal controJ would be a wasteful ATPase activity. The reason for the nucleotide controls in the adenylylation and deadenylylation phenomena is as yet obscure; a possible link between glutamine synthesis and polynucleotide metabolism is suggested by the effects of ribonucleic acid species on the deadenylylating system.

Die Asymmetrie des Tricarbonsäurezyklus, aufgezeigt an Studien zur Biosynthese des Antibiotikums Showdomycin

“…Die Bedeutung der Nucleosid-Antibiotika wird augenscheinlich, wenn man die wachsende Anzahl an Veroffentlichungen, Obersichtsartikeln und Biichern betrachtet, die in den letzten Jahren tiber diese Stoffgruppe erschicnen sind (Ubersichten bei R. J. SUHADOLNIK 1970, SHEN 1970.Nucleosid-Antibiotika werden in der biochemischen Forschung hauptsachlidi als Hemmstoffe verwendet. Dieser Bericht behandelt einen Sonderfall: Show domycin (P-D-Ribofuranosyl-Maleimid) in seiner Anwendung als Studienobjekt fUr die exakte Lokalisierung von Isotopen im Krebszyklus nach deren Verfiitterung in vivo.Showdomycin wurde 1964 von der japanischen SHIONOGI-Gruppe entdeckt und identifiziert.…”

“…Die Bedeutung der Nucleosid-Antibiotika wird augenscheinlich, wenn man die wachsende Anzahl an Veroffentlichungen, Obersichtsartikeln und Biichern betrachtet, die in den letzten Jahren tiber diese Stoffgruppe erschicnen sind (Ubersichten bei R. J. SUHADOLNIK 1970, SHEN 1970.…”

Growth Inhibitors Rapidly Inactivated by the Host as Potential Antineoplastic Agents in Intra-Arterial Infusion Chemotherapy

“…In addition, thymidine analogs can be selected for trials on the basis of whether or not they exhibit the combined properties of rapid degravation to innocuous dérivâtes by the liver and nonincorporation of the nu cleoside or its free base into nucleic acids. 5-Hydroxydeoxyuridine [3,4,16] and a number of other 5-substituted deoxyuridine derivatives [41,82] may have these characteristics.…”