Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.3.5.5 (CPS)
 1,262 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

On the basis of our observation of the increased specific activities of glutamine-utilizing enzymes in purine and pyrimidine metabolism in hepatoma 3924A, and because the concentration of glutamine is ten times lower in the hepatomas than in the liver, the biochemical pharmacology of the anti-glutamine agent, acivicin, was examined. (1) Acivicin competitively inhibited the activities of amidophosphoribosyl-transferase, CTP synthetase and carbamoyl-phosphate synthetase II from extracts of liver and hepatoma 3924A. (2) In addition to the competitive inhibition exerted by acivicin, evidence was obtained that this drug also irreversibly inactivated in vitro the glutamine-utilizing enzymes. It is particularly relevant for the selectivity of acivicin that the activity of aspartate carbamoyltransferase, an enzyme present in the same complex as carbamoyl-phosphate synthetase II, was not affected by the anti-glutamine agent. (3) Acivicin in vivo brought down the activities of glutamine-utilizing enzymes in a period of 10 min to 1 hr after injection. CTP synthetase activity declined to less than 10% of that observed in the uninjected rats. The decreases were not reversible by various in vitro methods, but in vivo the activities returned to normal range in 72 hr. (4) The activity of aspartate carbamoyltransferase, which exists as a multi-enzyme complex with synthetase II, was not altered by acivicin injection. Similar results were observed in transplantable sarcoma in the rat. (5) The acivicin-induced decrease in enzymic activities could not be restored by purification of the enzymes. (6) In vitro studies indicated that addition of acivicin to liver or hepatoma extracts or purified enzymes rapidly decreased enzymic activities; the activities could not be restored. These results are consistent with an interpretation that acivicin acts either as a tight-binding inhibitor or as an inactivator through alkylation of the enzymes of glutamine utilization. (7) Acivicin in combination with actinomycin provided a synergistic kill of hepatoma cells in tissue culture and also inhibited the growth of transplantable solid hepatoma 3924A in the rat. (8) The synergistic biological results of combination chemotherapy with acivicin and actinomycin can be accounted for by the action of acivicin in inhibiting GMP and CTP synthetases, resulting in a decrease in GTP and CTP content, and by the actinomycin-caused inhibition of RNA polymerase in selectively blocking the utilization of GTP and CTP.
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PMID:Multi-enzyme-targeted chemotherapy by acivicin and actinomycin. 618 Jun 9

In rat livers and hepatomas, carbamoyl phosphate synthetase (glutamine-hydrolyzing) (EC 6.3.5.5) (synthetase II), the rate-limiting enzyme of de novo pyrimidine nucleotide biosynthesis, was separated from carbamoyl phosphate synthetase (ammonia) (EC 6.3.4.16) (synthetase I) ammonium sulfate and hydroxylapatite fractionations and gel filtration on Sephadex G-25. Both liver and hepatoma 3924A synthetase II activities were subject to feedback inhibition by UTP and to stimulation by 5-phosphoribosyl 1-pyrophosphate. UTP (0.5 mM) enhanced the apparent Km for MgATP from 2.3 to 7.6 mM, whereas 0.1 mM 5-phosphoribosyl 1-pyrophosphate reduced it to 0.5 mM. At 2 mM MgATP, 3 or 7 microM 5-phosphoribosyl 1-pyrophosphate yielded half-maximal activation (Ka) in the absence or presence of 0.5 mM UTP; UTP altered the stimulation kinetics from hyperbolic to sigmoidal. In the rat, synthetase II activities were highest in thymus, testis and spleen. In differentiating and regenerating rat livers, activities were 2.2- and 1.5-fold higher than in adult livers. In 17 hepatomas of different growth rates, synthetase II activity increased 1.3- to 9.5-fold over liver values; the rise correlated positively with tumor growth rates. Synthetase II activities also increased in a kidney tumor (5.0-fold) and in a sarcoma (18.1-fold) in the rat and in a human colon tumor (3.3-fold).
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PMID:Regulatory properties and behavior of activity of carbamoyl phosphate synthetase II (glutamine-hydrolyzing) in normal and proliferating tissues. 705 79

The specific activity of carbamoyl phosphate synthetase (glutamine-hydrolyzing), the first and rate-limiting enzyme of de novo uridine 5'-triphosphate biosynthesis, was increased in 13 transplantable hepatomas, particularly in the rapidly growing tumors (5.7- to 9.5-fold), and the rise was correlated with tumor growth rates. Thus, synthetase activity was linked with both hepatic neoplastic transformation and progression. Synthetase specific activity was so elevated in a transplantable sarcoma (18-fold) and a kidney adenocarcinoma (5-fold). The increased activity should enhance the capacity of the pathway and should confer selective advantages to cancer cells.
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PMID:Carbamoyl phosphate synthetase (glutamine-hydrolyzing): increased activity in cancer cells. 720 43