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)

The effects of K2PtCl4, cis-Pt(NH3)2Cl2, and trans-Pt(NH3)2Cl2 on the activities of glyceraldehyde-3-phosphate dehydrogenase, glucose-6-phosphate dehydrogenase, dihydrofolate reductase, fructose-1,6-bisphosphate aldolase, catalase, tyrosinase, and peroxidase have been investigated. All of the enzymes which are thought to have essential sulfhydryl groups (glyceraldehyde-3-phosphate dehydrogenase, aldolase, and glucose-6-phosphate dehydrogenase) were significantly inhibited by K2PtCl4. The other four enzymes studied are not known to have essential sulfhydryl groups, and were not significantly affected by the Pt compounds under the conditions employed. Glyceraldehyde-3-phosphate dehydrogenase was the only enzyme inhibited by all three Pt compounds tested, with K2PtCl4 being the most effective and cis-Pt(NH3)2Cl2 the least effective inhibitor. Semilogarithmic plots of residual activity versus inhibition time indicated that the inhibition reactions were not simple first-order processes, except for the inhibition of glucose-6-phosphate dehydrogenase by K2PtCl4 which appeared to be first-order with respect to enzyme concentration.
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PMID:The effects of platinum complexes on seven enzymes. 11 85

Import of proteins into organelles usually requires a cis-acting targeting signal. Analysis of various hybrid proteins, consisting of mouse DHFR and parts of catalase A from Saccharomyces cerevisiae, revealed that fusion proteins containing the N-terminal 126 amino acids, or less, of catalase A remain in the cytosol whereas fusion proteins containing 140, or more, N-terminal amino acids of catalase A form large aggregates inside the cell. These protein bodies, which lack a surrounding membrane, copurified with peroxisomes on cell fractionation. The peroxisomal targeting signal of catalase A does not reside at the C-terminus or at the N-terminus.
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PMID:Fate of highly expressed proteins destined to peroxisomes in Saccharomyces cerevisiae. 224 72

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

Recent studies demonstrate that oxidative inactivation of tetrahydrobiopterin (H4B) may cause uncoupling of endothelial nitric oxide synthase (eNOS) to produce superoxide (O2*-). H4B was found recyclable from its oxidized form by dihydrofolate reductase (DHFR) in several cell types. Functionality of the endothelial DHFR, however, remains completely unknown. Here we present findings that specific inhibition of endothelial DHFR by RNA interference markedly reduced endothelial H4B and nitric oxide (NO.) bioavailability. Furthermore, angiotensin II (100 nmol/liter for 24 h) caused a H4B deficiency that was mediated by H2O2-dependent down-regulation of DHFR. This response was associated with a significant increase in endothelial O2*- production, which was abolished by eNOS inhibitor N-nitro-L-arginine-methyl ester or H2O2 scavenger polyethylene glycol-conjugated catalase, strongly suggesting H2O2-dependent eNOS uncoupling. Rapid and transient activation of endothelial NAD(P)H oxidases was responsible for the initial burst production of O2* (Rac1 inhibitor NSC 23766 but not an N-nitro-L-arginine-methyl ester-attenuated ESR O2*- signal at 30 min) in response to angiotensin II, preceding a second peak in O2*- production at 24 h that predominantly depended on uncoupled eNOS. Overexpression of DHFR restored NO. production and diminished eNOS production of O2*- in angiotensin II-stimulated cells. In conclusion, these data represent evidence that DHFR is critical for H4B and NO. bioavailability in the endothelium. Endothelial NAD(P)H oxidase-derived H2O2 down-regulates DHFR expression in response to angiotensin II, resulting in H4B deficiency and uncoupling of eNOS. This signaling cascade may represent a universal mechanism underlying eNOS dysfunction under pathophysiological conditions associated with oxidant stress.
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PMID:Endothelial dihydrofolate reductase: critical for nitric oxide bioavailability and role in angiotensin II uncoupling of endothelial nitric oxide synthase. 1594 33

Isoniazid is a key drug used in the treatment of tuberculosis. Isoniazid is a pro-drug, which, after activation by the katG-encoded catalase peroxidase, reacts nonenzymatically with NAD(+) and NADP(+) to generate several isonicotinoyl adducts of these pyridine nucleotides. One of these, the acyclic 4S isomer of isoniazid-NAD, targets the inhA-encoded enoyl-ACP reductase, an enzyme essential for mycolic acid biosynthesis in Mycobacterium tuberculosis. Here we show that the acyclic 4R isomer of isoniazid-NADP inhibits the M. tuberculosis dihydrofolate reductase (DHFR), an enzyme essential for nucleic acid synthesis. This biologically relevant form of the isoniazid adduct is a subnanomolar bisubstrate inhibitor of M. tuberculosis DHFR. Expression of M. tuberculosis DHFR in Mycobacterium smegmatis mc(2)155 protects cells against growth inhibition by isoniazid by sequestering the drug. Thus, M. tuberculosis DHFR is the first new target for isoniazid identified in the last decade.
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PMID:Mycobacterium tuberculosis dihydrofolate reductase is a target for isoniazid. 1664 61

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

In our search to improve the stability and cellular absorption of tea polyphenols, we synthesized 3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin (TMECG), which showed high antiproliferative activity against melanoma. TMECG downregulates dihydrofolate reductase (DHFR) expression in melanoma cells and we detail the sequential mechanisms that result from this even. TMECG is specifically activated in melanoma cells to form a stable quinone methide (TMECG-QM). TMECG-QM has a dual action on these cells. First, it acts as a potent antifolate compound, disrupting folate metabolism and increasing intracellular oxidized folate coenzymes, such as dihydrofolate, which is a non-competitive inhibitor of dihydropterine reductase, an enzyme essential for tetrahydrobiopterin (H(4)B) recycling. Such inhibition results in H(4)B deficiency, endothelial nitric oxide synthase (eNOS) uncoupling and superoxide production. Second, TMECG-QM acts as an efficient superoxide scavenger and promotes intra-cellular H(2)O(2) accumulation. Here, we present evidence that TMECG markedly reduces melanoma H(4)B and NO bioavailability and that TMECG action is abolished by the eNOS inhibitor N(omega)-nitro-L-arginine methyl ester or the H(2)O(2) scavenger catalase, which strongly suggests H(2)O(2)-dependent DHFR downregulation. In addition, the data presented here indicate that the simultaneous targeting of important pathways for melanoma survival, such as the folate cycle, H(4)B recycling, and the eNOS reaction, could represent an attractive strategy for fighting this malignant skin pathology.
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PMID:Mechanism of dihydrofolate reductase downregulation in melanoma by 3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin. 2056 35

We studied on the proteomic characteristics of Toxoplasma gondii KI-1 tachyzoites which were originally isolated from a Korean patient, and compared with those of the well-known virulent RH strain using 2-dimensional electrophoresis (2-DE), mass spectrometry, and quantitative real-time PCR. Two-dimensional separation of the total proteins isolated from KI-1 tachyzoites revealed up to 150 spots, of which 121 were consistent with those of RH tachyzoites. Of the remaining 29 spots, 14 showed greater than 5-fold difference in density between the KI-1 and RH tachyzoites at a pH of 5.0-8.0. Among the 14 spots, 5 from the KI-1 isolate and 7 from the RH strain were identified using MALDI-TOF mass spectrometry and database searches. The spots from the KI-1 tachyzoites were dense granule proteins (GRA 2, 3, 6, and 7), hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGRPTase), and uracil phosphoribosyltransferase (UPRTase). The spots from the RH strain were surface antigen 1 (SAG 1), L-lactate dehydrogenase (LDH), actin, chorismate synthase, peroximal catalase, hexokinase, bifunctional dihydrofolate reductase-thymidylate synthase (DHTR-TS), and nucleoside-triphosphatases (NTPases). Quantitative real-time PCR supported our mass spectrometric results by showing the elevated expression of the genes encoding GRA 2, 3, and 6 and UPRTase in the KI-1 tachyzoites and those encoding GRA 7, SAG 1, NTPase, and chorismate synthase in the RH tachyzoites. These observations demonstrate that the protein compositions of KI-1 and RH tachyzoites are similar but differential protein expression is involved in virulence.
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PMID:Proteomic analysis of Toxoplasma gondii KI-1 tachyzoites. 2087 97

A growing number of insights on the biology of bacterial inclusion bodies (IBs) have revealed intriguing utilities of these protein particles. Since they combine mechanical stability and protein functionality, IBs have been already exploited in biocatalysis and explored for bottom-up topographical modification in tissue engineering. Being fully biocompatible and with tuneable bio-physical properties, IBs are currently emerging as agents for protein delivery into mammalian cells in protein-replacement cell therapies. So far, IBs formed by chaperones (heat shock protein 70, Hsp70), enzymes (catalase and dihydrofolate reductase), grow factors (leukemia inhibitory factor, LIF) and structural proteins (the cytoskeleton keratin 14) have been shown to rescue exposed cells from a spectrum of stresses and restore cell functions in absence of cytotoxicity. The natural penetrability of IBs into mammalian cells (reaching both cytoplasm and nucleus) empowers them as an unexpected platform for the controlled delivery of essentially any therapeutic polypeptide. Production of protein drugs by biopharma has been traditionally challenged by IB formation. However, a time might have arrived in which recombinant bacteria are to be engineered for the controlled packaging of therapeutic proteins as nanoparticulate materials (nanopills), for their extra- or intra-cellular release in medicine and cosmetics.
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PMID:Packaging protein drugs as bacterial inclusion bodies for therapeutic applications. 2268 40

Folic acid (FA), also named vitamin B9, is an essential cofactor for the synthesis of DNA bases and other biomolecules after bioactivation by dihydrofolate reductase (DHFR). FA is photoreactive and has been shown to generate DNA modifications when irradiated with UVA (360 nm) in the presence of DNA under cell-free conditions. To investigate the relevance of this reaction for cells and tissues, we irradiated three different cell lines (KB nasopharyngeal carcinoma cells, HaCaT keratinocytes, and a melanoma cell line) in the presence of FA and quantified cytotoxicity and DNA damage generation. The results indicate that FA is phototoxic and photogenotoxic by two different mechanisms. First, extracellular photodecomposition of FA gives rise to the generation of H2O2, which causes mostly DNA strand breaks. If this is prevented, e.g., by the presence of catalase, DNA damage generated by intracellular FA becomes evident. The damage spectrum in this case consists predominantly of oxidatively generated purine modifications sensitive to the repair glycosylase Fpg, as characteristic for type I photoreactions, and is associated with the formation of micronuclei. In KB cells, the DNA damage is strongly enhanced after pretreatment with the DHFR inhibitor methotrexate, which prevents the loss of the chromophore associated with the intracellular reduction of FA by DHFR. The results indicate that FA is photoreactive in cells and gives rise to nuclear DNA damage under irradiation.
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PMID:Photogenotoxicity of folic acid. 2397 53


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