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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thymidine and thymidylate kinases were isolated from the gonads of scallop Mizuhopecten yessoensis. The enzymes were purified 537- and 100-fold, respectively, and were free of phosphatase and ATPase impurities. Ions of bivalent metals and ATP were necessary for both the nucleoside and nucleotide kinase activities; the pH optimum fall into the range of 7.5-8.5. KCl and NaCl at a concentration of up to 100 mM had no inhibiting effect on the activities of these scallop enzymes. Thymidine kinase catalyzed thymidine, and, at a lower rate, deoxycytidine phosphorylations did not utilize ribo- and deoxyribonucleosides, as well as pyrimidine ribonucleosides, as a phosphate acceptor. Thymidylate kinase phosphorylated TMP and dCMP with an efficiency of about 30%. In addition to ATP, these enzymes can also utilize with different efficiencies dATP, dGTP, GTP, UTP, and CTP as a donor of phosphate groups. Thymidine kinase activity was inhibited by TMP, TTP, and dCTP.
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PMID:[Thymidine and thymidylate kinases from the scallop Mizuhopecten yessoensis gonads]. 1882 69

Inhibition of H(+),K(+)-ATPase is accepted as the most effective way of controlling gastric acid secretion. However, current acid suppressant therapy for gastroesophageal reflux disease, using histamine H(2) receptor antagonists and proton pump inhibitors, does not fully meet the needs of all patients because of their mechanism of action. This study sought to characterize the in vitro and in vivo pharmacology of a novel acid pump antagonist, N-(2-Hydroxyethyl)-N,2-dimethyl-8-{[(4R)-5-methyl-3,4-dihydro-2H-chromen-4-yl]amino}imidazo[1,2-a]pyridine-6-carboxamide (PF-03716556), and to compare it with other acid suppressants. Porcine, canine, and human recombinant gastric H(+),K(+)-ATPase activities were measured by ion-leaky and ion-tight assay. The affinities for a range of receptors, ion channels, and enzymes were determined to analyze selectivity profile. Acid secretion in Ghosh-Schild rats and Heidenhain pouch dogs were measured by titrating perfusate and gastric juice samples. PF-03716556 demonstrated 3-fold greater inhibitory activity than 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine (revaprazan), the only acid pump antagonist that has been available on the market, in ion-tight assay. The compound did not display any species differences, exhibiting highly selective profile including the canine kidney Na(+),K(+)-ATPase. Kinetics experiments revealed that PF-03716556 has a competitive and reversible mode of action. More rapid onset of action than 5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]-sulfinyl}-benzimidazole (omeprazole) and 3-fold greater potency than revaprazan were observed in Ghosh-Schild rats and Heidenhain pouch dogs. PF-03716556, a novel acid pump antagonist, could improve upon or even replace current pharmacological treatment for gastroesophageal reflux disease.
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PMID:N-(2-hydroxyethyl)-N,2-dimethyl-8-{[(4R)-5-methyl-3,4-dihydro-2H-chromen-4-yl]amino}imidazo[1,2-a]pyridine-6-carboxamide (PF-03716556), a novel, potent, and selective acid pump antagonist for the treatment of gastroesophageal reflux disease. 1898 Dec 88

The chaperonin GroEL is a megadalton-sized molecular machine that plays an essential role in the bacterial cell assisting protein folding to the native state through actions requiring ATP binding and hydrolysis. A combination of medicinal chemistry and genetics has been employed to generate an orthogonal pair, a small molecule that selectively inhibits ATPase activity of a GroEL ATP-binding pocket variant. An initial screen of kinase-directed inhibitors identified an active pyrazolo-pyrimidine scaffold that was iteratively modified and screened against a collective of GroEL nucleotide pocket variants to identify a cyclopentyl carboxamide derivative, EC3016, that specifically inhibits ATPase activity and protein folding by the GroEL mutant, I493C, involving a side chain positioned near the base of ATP. This orthogonal pair will enable in vitro studies of the action of ATP in triggering activation of GroEL-mediated protein folding and might enable further studies of GroEL action in vivo. The approach originated for studying kinases by Shokat and his colleagues may thus also be used to study large macromolecular machines.
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PMID:A small molecule inhibitor selective for a variant ATP-binding site of the chaperonin GroEL. 1911 Apr 21

Numerous DNA mismatches and lesions activate MutS homologue (MSH) ATPase activity that is essential for mismatch repair (MMR). We have found that a mismatch embedded in a nearest-neighbor sequence context containing symmetric 3'-purines (2 x 3'-purines) enhanced, whereas symmetric 3'-pyrimidines (2 x 3'-pyrimidines) reduced, hMSH2-hMSH6 ATPase activation. The 3'-purine/pyrimidine effect was most evident for G-containing mispairs. A similar trend pervaded mismatch binding (K(D)) and the melting of unbound oligonucleotides (T(m); DeltaG). However, these latter measures did not accurately predict the hierarchy of MSH ATPase activation. NMR studies of imino proton lifetime, solvent accessibility, and NOE connectivity suggest that sequence contexts that provoke improved MSH-activation displayed enhanced localized DNA flexibility: a dynamic DNA signature that may account for the wide range of lesions that activate MSH functions.
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PMID:Sequence context effect for hMSH2-hMSH6 mismatch-dependent activation. 1923 77

Structure-based virtual screening identified pyrimidine-2,4,6-trione and 4H-1,2,4-triazole-3-thiol as novel scaffolds of Hsp90 ATPase inhibitors. Their binding modes in the ATP-binding pocket of Hsp90 were analyzed using AutoDoc program combined with molecular dynamics (MD) simulations.
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PMID:Identification of new Hsp90 inhibitors by structure-based virtual screening. 1956 Mar 53

Accessibility within chromatin is an important factor in the prompt removal of UV-induced DNA damage by nucleotide excision repair (NER). Chromatin remodeling by the SWI/SNF complex has been shown to play an important modulating role in NER in vitro and yeast in vivo. Nevertheless, the molecular basis of cross-talk between SWI/SNF and NER in mammalian cells is not fully understood. Here, we show that knockdown of Brg1, the ATPase subunit of SWI/SNF, negatively affects the elimination of cyclobutane pyrimidine dimers (CPD), but not of pyrimidine (6, 4)pyrimidone photoproducts (6-4PP) following UV irradiation of mammalian cells. Brg1-deficient cells exhibit a lower chromatin relaxation as well as impaired recruitment of downstream NER factors, XPG and PCNA, to UV lesions. However, the assembly of upstream NER factors, DDB2 and XPC, at the damage site was unaffected by Brg1 knockdown. Interestingly, Brg1 interacts with XPC within chromatin and is recruited to UV-damaged sites in a DDB2- and XPC-dependent manner. Also, postirradiation decrease of XPC levels occurred more rapidly in Brg1-deficient than normal cells. Conversely, XPC transcription remained unaltered upon Brg1 knockdown indicating that Brg1 affects the stability of XPC protein following irradiation. Thus, Brg1 facilitates different stages of NER by initially modulating UV-induced chromatin relaxation and stabilizing XPC at the damage sites, and subsequently stimulating the recruitment of XPG and PCNA to successfully culminate the repair.
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PMID:Modulation of nucleotide excision repair by mammalian SWI/SNF chromatin-remodeling complex. 1974 Jul 55

The COG database was used for a comparative genome analysis with genomes from anaerobic and aerobic microorganisms with the aim of identifying proteins specific to the anaerobic way of life. A total of 33 COGs were identified, five of which correspond to proteins of unknown function. We focused our study on TM0486 from Thermotoga maritima, which belongs to one of these COGs of unknown function, namely COG0011. The crystal structure of the protein was determined at 2 A resolution. The structure adopts a beta alpha beta beta alpha beta ferredoxin-like fold and assembles as a homotetramer. The structure also revealed the presence of a pocket in each monomer that bound an unidentified ligand. NMR and calorimetry revealed that TM0486 specifically bound thiamin with a K(d) of 1.58 microM, but not hydroxymethyl pyrimidine (HMP), which has been implicated as a potential ligand. We demonstrated that the TM0486 gene belongs to the same multicistronic unit as TM0483, TM0484 and TM0485. Although these three genes have been assigned to the transport of HMP, with TM0484 being the periplasmic thiamin/HMP-binding protein and TM0485 and TM0483 the transmembrane and the ATPase components, respectively, our results led us to conclude that this operon encodes an ABC transporter dedicated to thiamin, with TM0486 transporting charged thiamin in the cytoplasm. Given that this transcriptional unit was up-regulated when T. maritima was exposed to oxidative conditions, we propose that, by chelating cytoplasmic thiamin, TM0486 and, by extension, proteins belonging to COG0011 are involved in the response mechanism to stress that could arise during aerobic conditions.
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PMID:TM0486 from the hyperthermophilic anaerobe Thermotoga maritima is a thiamin-binding protein involved in response of the cell to oxidative conditions. 2047

A series of pyrimidine derivatives as acid pump antagonists (APAs) was synthesized and the inhibitory activities against H(+)/K(+) ATPase isolated from hog gastric mucosa were determined. After elaborating on substituents at C2 and C4 position of the pyrimidine scaffold, we have observed that the compound 7h is a potent APA with H(+)/K(+) ATPase, IC(50) = 52 nM.
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PMID:Novel pyrimidines as acid pump antagonists (APAs). 2081 Feb 80

The UvrA protein is the initial DNA damage-sensing protein in bacterial nucleotide excision repair and detects a wide variety of structurally unrelated lesions. After initial recognition of DNA damage, UvrA loads the UvrB protein onto the DNA. This protein then verifies the presence of a lesion, after which UvrA is released from the DNA. UvrA contains two ATPase domains, both belonging to the ABC ATPase superfamily. We have determined the activities of two mutants, in which a single domain was deactivated. Inactivation of either one ATPase domain in Escherichia coli UvrA results in a complete loss of ATPase activity, indicating that both domains function in a cooperative way. We could show that this ATPase activity is not required for the recognition of bulky lesions by UvrA, but it does promote the specific binding to the less distorting cyclobutane-pyrimidine dimer (CPD). The two ATPase mutants also show a difference in UvrB-loading, depending on the length of the DNA substrate. The ATPase domain I mutant was capable of loading UvrB on a lesion in a 50 bp fragment, but this loading was reduced on a longer substrate. For the ATPase domain II mutant the opposite was found: UvrB could not be loaded on a 50 bp substrate, but this loading was rescued when the length of the fragment was increased. This differential loading of UvrB by the two ATPase mutants could be related to different interactions between the UvrA and UvrB subunits.
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PMID:Role of the two ATPase domains of Escherichia coli UvrA in binding non-bulky DNA lesions and interaction with UvrB. 2086 19

The most detrimental responses of the UV-exposed skin are triggered by cyclobutane pyrimidine dimers (CPDs). Although placental mammals rely solely on nucleotide excision repair (NER) to eliminate CPDs, none of the core NER factors are apparently able to distinguish this hazardous lesion from native DNA, raising the question of how CPDs are circumscribed to define correct excision boundaries. A key NER intermediate involves unwinding of the damaged duplex by transcription factor TFIIH, a reaction that requires xeroderma pigmentosum group D (XPD) protein. This study was prompted by the observation that the ATPase/helicase activity of XPD is necessary for an effective anchoring of this subunit to UV lesions in mammalian nuclei. The underlying mechanism by which XPD impinges on damaged DNA has been probed with a monomeric archaeal homolog, thus revealing that the collision with a single CPD inhibits the helicase but stimulates its ATPase activity. Restriction and glycosylase protection assays show that the XPD helicase remains firmly bound to a CPD situated in the translocated strand along which the enzyme moves with 5'-3' polarity. Competition assays confirm that a stable complex is formed when the XPD helicase encounters a CPD in the translocated strand. Instead, the enzyme dissociates from the substrate after running into a CPD in the complementary 3'-5' strand. These results disclose a damage verification and demarcation process that takes place by strand-selective immobilization of the XPD helicase and its conversion to a site-specific ATPase at DNA lesions.
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PMID:Strand- and site-specific DNA lesion demarcation by the xeroderma pigmentosum group D helicase. 2087 34


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