Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:O15067 (FGAM synthetase)
 19 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A study on the oncolytic activity of the L-cysteine derivative L-cysteine, ethyl ester, S-(N-methylcarbamate) monohydrochloride (NSC 303861), revealed that the drug caused complete regression of the MX-1 human mammary tumor xenograft. The compound also exhibited moderate antitumor activity against murine leukemia P388 (T/C value of 169% at a daily dose of 400 mg/kg) and against M5076 sarcoma (T/C value of 135% at a daily dose of 600 mg/kg). The drug was inactive against B16 melanoma, Lewis lung, colon 38 and CD8F1 mammary carcinomas. The compound exhibited significant cytotoxicity against hepatoma 3924A cells in culture (LC50 = 6 microM). Studies on the mechanism of action revealed that the cytotoxicity of the drug could be partially abrogated by protecting hepatoma 3924A cells in culture with L-glutamine. At 6 h after injection of the compound (400 mg/kg) into rats bearing hepatoma 3924A, the pools of L-glutamine and L-glutamate in the tumor decreased to 33% and 71%, respectively, of control levels; the drug selectively inhibited the activities of L-glutamine-requiring enzymes of purine nucleotide biosynthesis, amidophosphoribosyltransferase, FGAM synthase, and GMP synthase, to 21%, 1%, and 69%, respectively, without significantly altering the activities of pyrimidine biosynthetic enzymes, carbamoylphosphate synthase II and CTP synthase. Measurement of the nucleotide concentrations further corroborated the actions of the drug on the purine nucleotide biosynthetic enzyme activities. Drug injection (400 mg/kg) in the hepatoma 3924A-bearing rats reduced the concentrations of IMP in the tumor to 52%, those of total adenylates to 52%, those of total guanylates to 57%, and those of NAD to 73%, without significantly perturbing the pyrimidine nucleotide pools. Studies on the mechanism of action of the L-cysteine derivative suggested that the compound behaved as an L-glutamine antagonist, selectively acting on the enzymes of purine nucleotide biosynthesis.
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PMID:Oncolytic activity and mechanism of action of a novel L-cysteine derivative, L-cysteine, ethyl ester, S-(N-methylcarbamate) monohydrochloride. 234 42

The glutamine antagonists, acivicin (NSC 163501), azaserine (NSC 742), and 6-diazo-5-oxo-L-norleucine (DON) (NSC 7365), are potent inhibitors of many glutamine-dependent amidotransferases in vitro. Experiments performed with mouse L1210 leukemia growing in culture show that each antagonist has different sites of inhibition in nucleotide biosynthesis. Acivicin is a potent inhibitor of CTP and GMP synthetases and partially inhibits N-formylglycineamidine ribotide (FGAM) synthetase of purine biosynthesis. DON inhibits FGAM synthetase, CTP synthetase, and glucosamine-6-phosphate isomerase. Azaserine inhibits FGAM synthetase and glucosamine-6-phosphate isomerase. Large accumulations of FGAR and its di- and triphosphate derivatives were observed for all three antagonists which could interfere with the biosynthesis of nucleic acids, providing another mechanism of cytotoxicity. Acivicin, azaserine, and DON are not potent inhibitors of carbamyl phosphate synthetase II (glutamine-hydrolyzing) and amidophosphoribosyltransferase in leukemia cells growing in culture although there are reports of such inhibitions in vitro. Blockade of de novo purine biosynthesis by these three antagonists results in a "complementary stimulation" of de novo pyrimidine biosynthesis.
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PMID:Cytotoxic mechanisms of glutamine antagonists in mouse L1210 leukemia. 235 67

Aim of this study was to elucidate insulin regulatory effects on purine and pyrimidine metabolism. Livers of alloxan diabetic and insulin treated rats were freeze clamped and nucleotide pools measured using HPLC techniques. Activities of key enzymes of de novo and salvage pathways were analyzed with radioassays. In diabetic liver nucleotide triphosphate pools were reduced between 46 and 75% of controls, nucleotide monophosphate concentrations increased. Activities of de novo biosynthetic enzymes amidophosphoribosyltransferase, FGAM synthase, IMP dehydrogenase, GMP synthase, carbamoylphosphate synthase II were curtailed by 16-61%, those of salvage enzymes hypoxanthine-guanine-phosphoribosyltransferase, adenine-phosphoribosyltransferase, thymidine kinase also decreased to 31-58%. Insulin treatment for 2 and 7 days normalized nucleotide pools, activities of key enzymes of de novo and salvage pathways were increased between 2.4 and 4.1 fold compared to diabetic untreated. Activation of nucleic acid metabolism by insulin can be explained by the requirement for high energy phosphates of certain anabolic key enzymes in carbohydrate and lipid metabolism. Impaired synthesis in insulin deficiency of end products of guanylate and pyrimidine pathway required as substrates for a variety of enzymes synthesising membrane structures throw new light on the pathogenesis of some late complications of diabetic disease.
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PMID:Insulin regulatory effects on purine- and pyrimidine metabolism in alloxan diabetic rat liver. 304 17

Extensive circadian (daily) control over gene expression in the cyanobacterium Synechococcus sp. strain PCC 7942 is programmed into at least two differentially phased groups. The transcriptional activity of the smaller group of genes is maximal at about dawn and minimal at about dusk. We identified one of the genes belonging to this latter group as purF, which encodes the key regulatory enzyme in the de novo purine synthetic pathway, glutamine PRPP amidotransferase (also known as amidophosphoribosyltransferase). Its expression pattern as a function of circadian time was confirmed by both luminescence from a purF::luxAB reporter strain and the abundance of purF mRNA. By fusing sequences upstream of the purF coding region to promoterless luxAB genes, we identified a limited upstream region, which potentially regulates purF circadian expression patterns in vivo. We also identified the purL gene immediately upstream of purF. The purL gene encodes FGAM synthetase, the fourth enzyme in the purine nucleotide biosynthesis pathway. Although these genes are expressed as part of a larger operon in other bacteria, reporter gene fusions revealed that purF and purL are transcribed independently in Synechococcus and that they are expressed at different phases of the circadian cycle. This differential expression pattern may be related to the oxygen sensitivity of amidophosphoribosyltransferase.
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PMID:Circadian expression of genes involved in the purine biosynthetic pathway of the cyanobacterium Synechococcus sp. strain PCC 7942. 880 59