Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.5.1.3 (dihydrofolate reductase)
5,819 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transformed cells are characterized by imbalances in metabolic routes. In particular, different key enzymes of nucleotide metabolism and DNA biosynthesis, such as CTP synthetase, thymidylate synthase, dihydrofolate reductase, IMP dehydrogenase, ribonucleotide reductase, DNA polymerase, and DNA methyltransferase, are markedly up-regulated in certain tumor cells. Together with the concomitant down-modulation of the purine and pyrimidine degradation enzymes, the increased anabolic propensity supports the excessive proliferation of transformed cells. However, many types of cancer cells have maintained the ability to differentiate terminally into mature, non-proliferating cells not only in response to physiological receptor ligands, such as retinoic acid, vitamin D metabolites, and cytokines, but also following exposure to a wide variety of non-physiological agents such as antimetabolites. Interestingly, induction of tumor cell differentiation is often associated with reversal of the transformation-related enzyme deregulations. An important class of differentiating compounds comprises the antimetabolites of purine and pyrimidine nucleotide metabolism and nucleic acid synthesis, the majority being structural analogs of natural nucleosides. The CTP synthetase inhibitors cyclopentenylcytosine and 3-deazauridine, the thymidylate synthase inhibitor 5-fluoro-2'-deoxyuridine, the dihydrofolate reductase inhibitor methotrexate, the IMP dehydrogenase inhibitors tiazofurin, ribavirin, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR) and mycophenolic acid, the ribonucleotide reductase inhibitors hydroxyurea and deferoxamine, and the DNA polymerase inhibitors ara-C, 9-(2-phosphonylmethoxyethyl)adenine (PMEA), and aphidicolin, as well as several nucleoside analogs perturbing the DNA methylation pattern, have been found to induce tumor cell differentiation through impairment of DNA synthesis and/or function. Thus, by selectively targeting those anabolic enzymes that contribute to the neoplastic behavior of cancer cells, the normal cellular differentiation program may be reactivated and the malignant phenotype suppressed.
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PMID:Role of antimetabolites of purine and pyrimidine nucleotide metabolism in tumor cell differentiation. 1041 91

The 1-(1-phenylalkylideneamino)-2,4-azetidinediones are potent cytotoxic agents against the growth of human and murine leukemias, lymphoma, and suspended HeLa uterine carcinoma. In cell lines cultured from solid human tumors, the agents were more selective with only a few agents demonstrating significant activity against the growth of HCT-8 ileum adenocarcinoma, Saos-2 osteosarcoma, KB nasopharynx, MCF-7 breast effusion, and ovary 1-A9 carcinoma A mode of action study in murine L1210 lymphoid leukemia cells showed that the agents inhibited DNA and RNA syntheses after 60 min. The compounds were potent inhibitors of the de novo purine synthesis suppressing the activity of both regulatory enzymes of the pathway, i.e., PRPP-amido transferase and IMP dehydrogenase. In addition, the agents reduced the activity of ribonucleotide reductase, dihydrofolate reductase, RNA polymerases, and thymidine kinases as well as the reduction of d[NTP] pools. All of these effects would contribute to the overall reduction of DNA and RNA syntheses. The DNA molecule itself was not a target for the agents in that alkylation of nucleoide bases, intercalation between base pairs, and cross-linking of DNA strands did not occur.
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PMID:The cytotoxicity of 1-(1-phenylalkylideneamino)-2,4-azetidinediones and their mode of action in human and murine tumor cells. 1129 29

Sequencing of Mycoplasma gallisepticum genome fragment containing thymidylate synthase and ribonucleotide reductase gene clusters reveals both its unusual organization and gene content. Sequence analysis indicates the presence of a gene whose product can be considered as a fusion of two full size proteins: the N-terminal part shows significant similarity to mycoplasmal dihydrofolate reductases, while the C-terminal part of the polypeptide chain shows significant similarity to eukaryotic deoxycytidylate deaminase. Phylogenetic analysis has suggested that the C-terminal part of the M. gallisepticum fusion gene and eukaryotic deoxycytidylate deaminase genes are xenologous. No chromosomal regions encoding peptides similar to the C-terminal part of this fusion protein were found in completely sequenced genomes of Mycoplasma genitalium and Mycoplasma pneumoniae. Genes for ribonucleoside diphosphate reductase alpha chain (nrdE), NrdI protein (nrdI), and ribonucleoside diphosphate reductase beta chain (nrdF) have an opposite direction of transcription with respect to genes for thymidylate synthase (thyA), and dihydrofolate reductase-deoxycytidylate deaminase fusion protein.
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PMID:Gene re-arrangement and fusion in Mycoplasma gallisepticum thyA-nrdFEI locus. 1141 Mar 45

The 3,5-pyrazolidinediones proved to be potent cytotoxic agents against the growth of a number of murine and human tumor cell lines, e.g. human THP-I monocytic leukemia, Hut-78 lymphoma, MCF-7 breast effusion, A549 lung carcinoma, U87MG glioma, Hela uterine and A431 epidermoid skin cancer. In human Tmolt4 cell leukemia, the agents substantially suppressed DNA and RNA syntheses after 60 min at 100 microM. The de novo purine biosynthetic pathway appeared to be the major target of the agents with the inhibition of both PRPP-amido transferase and IMP dehydrogenase (IMPDH) activities. Suppression of IMPDH activity was due to the inhibition of both the Type I and II isoforms through an uncompetitive mechanism; however, the Type II isoform was preferentially inhibited at lower concentrations of compounds tested (>50-150 microM). Therefore IMPDH Type II activity, which predominates in cancer cells, was selectively inhibited over the Type I isoform (208-312 microM). The activities of other enzymes examined were inhibited which added to the overall suppression of DNA synthesis, i.e., ribonucleotide reductase, dihydrofolate reductase and nucleoside kinases. The agents caused Tmolt4 DNA strand scission but the DNA molecule itself did not appear to be a target of the compounds since there was no induced cross-linking of the DNA, intercalation between base pairs or alkylation of the DNA bases.
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PMID:Cytotoxicity and mode of action of 1-(1-cyclohexenyl) and 1-unsubstituted 3,5-pyrazolidinediones in human Molt4 T cell leukemia. 1149 69

The retinoblastoma tumor suppressor, RB, is a negative regulator of the cell cycle that is inactivated in the majority of human tumors. Cell cycle inhibition elicited by RB has been attributed to the attenuation of CDK2 activity. Although ectopic cyclins partially overcome RB-mediated S-phase arrest at the replication fork, DNA replication remains inhibited and cells fail to progress to G(2) phase. These data suggest that RB regulates an additional execution point in S phase. We observed that constitutively active RB attenuates the expression of specific dNTP synthetic enzymes: dihydrofolate reductase, ribonucleotide reductase (RNR) subunits R1/R2, and thymidylate synthase (TS). Activation of endogenous RB and related proteins by p16ink4a yielded similar effects on enzyme expression. Conversely, targeted disruption of RB resulted in increased metabolic protein levels (dihydrofolate reductase, TS, RNR-R2) and conferred resistance to the effect of TS or RNR inhibitors that diminish available dNTPs. Analysis of dNTP pools during RB-mediated cell cycle arrest revealed significant depletion, concurrent with the loss of TS and RNR protein. Importantly, the effect of active RB on cell cycle position and available dNTPs was comparable to that observed with specific antimetabolites. Together, these results show that RB-mediated transcriptional repression attenuates available dNTP pools to control S-phase progression. Thus, RB employs both canonical cyclin-dependent kinase/cyclin regulation and metabolic regulation as a means to limit proliferation, underscoring its potency in tumor suppression.
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PMID:Retinoblastoma tumor suppressor targets dNTP metabolism to regulate DNA replication. 1222 Oct 87

The Crt1 (RFX1) protein in Saccharomyces cerevisiae is an effector of the DNA damage checkpoint pathway. It recognizes a 13-bp cis-regulatory element in the 5'-untranslated region (5'-UTR) of the ribonucleotide reductase genes RNR2, RNR3, and RNR4; the HUG1 gene; and itself. We calculated the weight matrix representing the Crt1p binding site motif according to analysis of the 5'-UTR sequences of the genes that are under its regulation. We subsequently searched the 5'-UTR sequences of all the genes in the yeast genome for the occurrence of this motif. The motif was found in regulatory regions of 30 genes. A statistical analysis showed that it is unlikely that a random gene cluster contains the motif conserved as well as the Crt1p binding site. Analysis of microarray data provided supporting evidence for five putative Crt1p targets: FSH3, YLR345W, UBC5, NDE2, and NTH2. We used reverse transcription-PCR to compare the expression levels of these genes in wild-type and crt1Delta strains. Our results indicated that FSH3, YLR345W, and NTH2 are indeed under the regulation of Crt1p. Sequence analysis of the FSH3p indicated that this protein may be involved in folate metabolism either by carrying serine hydrolase activity required for the novel metabolic pathway involving dihydrofolate reductase (DHFR) or by directly interacting with the DHFR enzyme. We postulate that Crt1p may influence deoxyribonucleotide synthesis not only by regulating expression of the RNR genes but also by modulating DHFR activity. FSH3p shares significant sequence similarity with the product of the human tumor suppressor gene OVCA2. YLR345Wp and NTH2p are enzymes involved in the central metabolism under stress conditions.
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PMID:Identification of new genes regulated by the Crt1 transcription factor, an effector of the DNA damage checkpoint pathway in Saccharomyces cerevisiae. 1549 96

In addition to their well-known anti-malarial activity, artemisinin and its derivatives (1,2,4-trioxanes) possess potent activity against tumor cells in the nano- to micromolar range. Candidate genes that may contribute to the sensitivity and resistance of tumor cells to artemisinins were identified by pharmacogenomic and molecular pharmacological approaches. Target validation was performed using cell lines transfected with candidate genes or corresponding knockout cells. These genes are from classes with different biological function; for example, regulation of proliferation (BUB3, cyclins, CDC25A), angiogenesis (vascular endothelial growth factor and its receptor, matrix metalloproteinase-9, angiostatin, thrombospondin-1) or apoptosis (BCL-2, BAX). Artesunate triggers apoptosis both by p53-dependent and -independent pathways. Anti-oxidant stress genes (thioredoxin, catalase, gamma-glutamyl-cysteine synthetase, glutathione S-transferases) as well as the epidermal growth factor receptor confer resistance to artesunate. Cell lines over-expressing genes that confer resistance to established anti-tumor drugs (MDR1, MRP1, BCRP, dihydrofolate reductase, ribonucleotide reductase) were not cross-resistant to artesunate, indicating that this drug has a different target and is not subject to multidrug resistance. The Plasmodium translationally controlled tumor protein (TCTP) represents a known target protein of artemisinin and its derivatives in the malaria parasite. The microarray-based mRNA expression of human TCTP correlated with sensitivity to artesunate in tumor cells, suggesting that human TCTP contributes to response of tumor cells to the drug. The multi-factorial nature of cellular response to artemisinin and its derivatives may be beneficial to treat otherwise drug-resistant tumors and may explain why resistance development has not been observed in either cancer or malaria.
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PMID:Mechanistic perspectives for 1,2,4-trioxanes in anti-cancer therapy. 1587 3

Secondary metabolites from plants serve as defense against herbivores, microbes, viruses, or competing plants. Many medicinal plants have pharmacological activities and may, thus, be a source for novel treatment strategies. During the past 10 years, we have systematically analyzed medicinal plants used in traditional Chinese medicine and focused our interest on Artemisia annua L. (qinhao, sweet wormwood). We found that the active principle of Artemisia annua L., artemisinin, exerts not only antimalarial activity but also profound cytotoxicity against tumor cells. The inhibitory activity of artemisinin and its derivatives towards cancer cells is in the nano- to micromolar range. Candidate genes that may contribute to the sensitivity and resistance of tumor cells to artemisinins were identified by pharmacogenomic and molecular pharmacological approaches. Target validation was performed using cell lines transfected with candidate genes or corresponding knockout cells. The identified genes are from classes with diverse biological functions; for example, regulation of proliferation (BUB3, cyclins, CDC25A), angiogenesis (vascular endothelial growth factor and its receptor, matrix metalloproteinase-9, angiostatin, thrombospondin-1) or apoptosis (BCL-2, BAX, NF-kappaB). Artesunate triggers apoptosis both by p53-dependent and -independent pathways. Antioxidant stress genes (thioredoxin, catalase, gamma-glutamylcysteine synthetase, glutathione S-transferases) as well as the epidermal growth factor receptor confer resistance to artesunate. Cell lines overexpressing genes that confer resistance to established antitumor drugs (MDR1, MRP1, BCRP, dihydrofolate reductase, ribonucleotide reductase) were not cross-resistant to artesunate, indicating that artesunate is not involved in multidrug resistance. The anticancer activity of artesunate has also been shown in human xenograft tumors in mice. First encouraging experience in the clinical treatment of patients suffering from uveal melanoma calls for comprehensive clinical trials with artesunate for cancer treatment in the near future.
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PMID:Willmar Schwabe Award 2006: antiplasmodial and antitumor activity of artemisinin--from bench to bedside. 1735 63

The SWI/SNF chromatin remodeling complex plays a critical role in the coordination of gene expression with physiological stimuli. The synthetic enzymes ribonucleotide reductase, dihydrofolate reductase, and thymidylate synthase are coordinately regulated to ensure appropriate deoxyribonucleotide triphosphate levels. Particularly, these enzymes are actively repressed as cells exit the cell cycle through the action of E2F transcription factors and the retinoblastoma tumor suppressor/p107/p130 family of pocket proteins. This process is found to be highly dependent on SWI/SNF activity as cells deficient in BRG-1 and Brm subunits fail to repress these genes with activation of pocket proteins, and this deficit in repression can be complemented, via the ectopic expression of BRG-1. The failure to repress transcription does not involve a blockade in the association of E2F or pocket proteins p107 and p130 with promoter elements. Rather, the deficit in repression is due to a failure to mediate histone deacetylation of ribonucleotide reductase, dihydrofolate reductase, and thymidylate synthase promoters in the absence of SWI/SNF activity. The basis for this is found to be a failure to recruit mSin3B and histone deacetylase proteins to promoters. Thus, the coordinate repression of deoxyribonucleotide triphosphate metabolic enzymes is dependent on the action of SWI/SNF in facilitating the assembly of repressor complexes at the promoter.
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PMID:SWI/SNF activity is required for the repression of deoxyribonucleotide triphosphate metabolic enzymes via the recruitment of mSin3B. 1751 60

We report the construction and testing of a combinatorial multicomponent plug mixer (CMPM) chip that generates a large number of mix ratios. The CMPM chip has been designed to study ribonucleotide reductase (RNR) protein-protein/protein-ligand interaction networks. The 4-component chip is capable of 5400 different combinations in a 30 plug cycle. CMPM chips were tested producing fluorescent dye and dihydrofolate reductase NADPH/MX mixtures with plug lengths of 2 mm.
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PMID:A combinatorial multicomponent plug mixer for systems chemistry. 2041 59


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