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)

This contribution reviews the synthesis of a range of experimental drugs designed for and aiming at antiviral chemotherapy of severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV)-induced human disease conditions. The selection of 25 test materials includes eleven trioxa-adamantane-triols (TATs) [BN, IBNCA, ABNCA, VANBA, ethylVANBA, euBN, euVANBA, ansaBN, Ehrlich BN, [6]prismaneBN, nitrodiBN], trivially termed bananins, one trioxa-adamantan-ol (TAO) THYMOBA, one bis-bananin pi-bananin (piBN), one triazaadamantane delta-bananin (deltaBN), seven potential nucleic acid-binding drugs (XBQC, INDO, PivINDO, AZTRION, AZADO, AZOCYS, AZOGALL), one potential antiviral interferon-inducer and distant nucleoside analog diazon, one potential HIV protein Vif antagonist AZODIAZON, one folic acid-diazon condensate DIAZONOFOL, and one special nucleoside analog (fructoinosine/fructovir). Four of the eleven bananins (BN, IBNCA, VANBA, euBN) were already demonstrated to constitute effective inhibitors of SARS-CoV NSP10/nsp13 RNA/DNA helicase/NTPase protein ATPase enzymatic function. Bananin (BN) was an effective inhibitor of both SARS-CoV RNA/DNA helicase nucleic acid unwinding function and SARS-CoV (Coronaviridae, Coronavirus) RNA-viral replication in cell culture. In summary, at least one selected compound of the synthesized test materials represents an interesting drug candidate for treatment of SARS-CoV-induced human disease (SARS). Viewed in aspects of organic chemistry [6]prismaneBN and nitrodiBN are the first true hexaprismane derivatives synthesized, and all reported compounds are entirely new.
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PMID:Synthesis of novel test compounds for antiviral chemotherapy of severe acute respiratory syndrome (SARS). 1610 96

GspE belongs to a secretion NTPase superfamily, members of which are involved in type II/IV secretion, type IV pilus biogenesis and DNA transport in conjugation or natural transformation. Predicted to be a cytoplasmic protein, GspE has nonetheless been shown to be membrane-associated by interacting with the N-terminal cytoplasmic domain of GspL. By taking biochemical and genetic approaches, we observed that ATP binding triggers oligomerization of Xanthomonas campestris XpsE (a GspE homolog) as well as its association with the N-terminal domain of XpsL (a GspL homolog). While isolated XpsE exhibits very low intrinsic ATPase activity, association with XpsL appears to stimulate ATP hydrolysis. Mutation at a conserved lysine residue in the XpsE Walker A motif causes reduction in its ATPase activity without significantly influencing its interaction with XpsL, congruent with the notion that XpsE-XpsL association precedes ATP hydrolysis. For the first time, functional significance of ATP binding to GspE in type II secretion system is clearly demonstrated. The implications may also be applicable to type IV pilus biogenesis.
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PMID:XpsE oligomerization triggered by ATP binding, not hydrolysis, leads to its association with XpsL. 1652 7

The TGBp1 protein, encoded in the genomes of a number of plant virus genera as the first gene of the 'triple gene block', possesses an NTPase/helicase domain characterized by seven conserved sequence motifs. It has been shown that the TGBp1 NTPase/helicase domain exhibits NTPase, RNA helicase and RNA-binding activities. In this paper, we have analysed a series of deletion and point mutants in the TGBp1 proteins encoded by Potato virus X (PVX, genus Potexvirus) and Poa semilatent virus (PSLV, genus Hordeivirus) to map functional regions responsible for their biochemical activities in vitro. It was found that, in both PVX and PSLV, the N-terminal part of the TGBp1 NTPase/helicase domain comprising conserved motifs I, Ia and II was sufficient for ATP hydrolysis, RNA binding and homologous protein-protein interactions. Point mutations in a single conserved basic amino acid residue upstream of motif I had little effect on the activities of C-terminally truncated mutants of both TGBp1 proteins. However, when introduced into the full-length NTPase/helicase domains, these mutations caused a substantial decrease in the ATPase activity of the protein, suggesting that the conserved basic amino acid residue upstream of motif I was required to maintain a reaction-competent conformation of the TGBp1 ATPase active site.
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PMID:A minimal region in the NTPase/helicase domain of the TGBp1 plant virus movement protein is responsible for ATPase activity and cooperative RNA binding. 1696 68

A protein with a molecular mass of 42 kDa (P42) from Mycoplasma mobile, one of several mycoplasmas that exhibit gliding motility, was shown to be a novel NTPase (nucleoside triphosphatase). Although the P42 protein lacks a common ATP-binding sequence motif (Walker A), the recombinant proteins expressed in Escherichia coli certainly hydrolysed some nucleoside triphosphates, including ATP. The results of photoaffinity labelling by an ATP analogue supported that the P42 protein contains a specific binding site for ATP (or another nucleoside triphosphate). In the M. mobile genome, the P42 gene is located downstream of gli123, gli349 and gli521 genes, and they have been reported to be polycis-tronically transcribed. As the huge proteins encoded by gli123, gli349 and gli521 play a role in gliding motility of M. mobile, P42 might also have some kind of function in the gliding motility. The gliding motility of M. mobile is driven directly by ATP hydrolysis, but the key ATPase has not been identified. Our results showed that, among these four proteins, only P42 exhibited ATPase activity. Biochemical characteristics--optimal conditions for activity, substrate specificities, and inhibiting effects by ATP analogues--of the recombinant P42 proteins were very similar to those of a putative ATPase speculated from a previous analysis with a gliding 'ghost' whose cell membrane was permeabilized by Triton X-100. These results support the hypothesis that the P42 protein is the key ATPase in the gliding motility of M. mobile.
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PMID:Identification of a novel nucleoside triphosphatase from Mycoplasma mobile: a prime candidate motor for gliding motility. 1708 28

A screen of the human cancer genome anatomy project (CGAP) database was performed to search for new proteins involved in tumorigenesis. The resulting hits were further screened for recombinant expression, solubility and protein aggregation, which led to the identification of the previously unknown human cancer-related (HCR) protein encoded by the mRNA NM_032324 as a target for structure determination by NMR. The three-dimensional structure of the protein in its complex with ATPgammaS forms a three-layered alpha/beta sandwich, with a central nine-stranded beta-sheet surrounded by five alpha-helices. Sequence and three-dimensional structure comparisons with AAA+ ATPases revealed the presence of Walker A (GPPGVGKT) and Walker B (VCVIDEIG) motifs. Using 1D (31)P-NMR spectroscopy and a coupled enzymatic assay for the determination of inorganic phosphate, we showed that the purified recombinant protein is active as a non-specific nucleoside triphosphatase, with k(cat)=7.6x10(-3) s(-1). The structural basis for the enzymatic activity of HCR-NTPase was further characterized by site-directed mutagenesis of the Walker B motif, which further contributes to making the HCR-NTPase an attractive new target for further biochemical characterization in the context of its presumed role in human tumorigenesis.
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PMID:NMR structure and functional characterization of a human cancer-related nucleoside triphosphatase. 1729 28

Dengue viruses (DENV) have 5'-capped RNA genomes of (+) polarity and encode a single polyprotein precursor that is processed into mature viral proteins. NS2B, NS3 and NS5 proteins catalyse/activate enzyme activities that are required for key processes in the virus life cycle. The heterodimeric NS2B/NS3 is a serine protease required for processing. Using a high-throughput protease assay, we screened a small molecule chemical library and identified -200 compounds having > or = 50% inhibition. Moreover, NS3 exhibits RNA-stimulated NTPase, RNA helicase and the 5'-RNA triphosphatase activities. The NTPase and the 5'-RTPase activities of NS3 are stimulated by interaction with NS5. Moreover, the conserved, positively charged motif in DENV-2 NS3, 184RKRK, is required for RNA binding and modulates the RNA-dependent enzyme activities of NS3. To study viral replication, a variety of methods are used such as the in vitro RNA-dependent RNA polymerase assays that utilize lysates from DENV-2-infected mosquito or mammalian cells or the purified NS5 along with exogenous short subgenomic viral RNAs or the replicative intracellular membrane-bound viral RNAs as templates. In addition, a cell-based DENV-2 replicon RNA encoding a luciferase reporter is also used to examine the role of cis-acting elements within the 3' UTR and the RKRK motif in viral replication.
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PMID:Multiple enzyme activities of flavivirus proteins. 1731 55

Purine nucleotide-binding proteins build the large family of P-loop GTPases and related ATPases, which perform essential functions in all kingdoms of life. The Obg family comprises a group of ancient GTPases belonging to the TRAFAC (for translation factors) class and can be subdivided into several distinct protein subfamilies. The founding member of one of these subfamilies is the bacterial P-loop NTPase YchF, which had so far been assumed to act as GTPase. We have biochemically characterized the human homologue of YchF and found that it binds and hydrolyzes ATP more efficiently than GTP. For this reason, we have termed the protein hOLA1, for human Obg-like ATPase 1. Further biochemical characterization of YchF proteins from different species revealed that ATPase activity is a general but previously missed feature of the YchF subfamily of Obg-like GTPases. To explain ATP specificity of hOLA1, we have solved the x-ray structure of hOLA1 bound to the nonhydrolyzable ATP analogue AMPPCP. Our structural data help to explain the altered nucleotide specificity of YchF homologues and identify the Ola1/YchF subfamily of the Obg-related NTPases as an exceptional example of a single protein subfamily, which has evolved altered nucleotide specificity within a distinct protein family of GTPases.
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PMID:Human OLA1 defines an ATPase subfamily in the Obg family of GTP-binding proteins. 1743 Aug 89

The helicase-like domain of BaMV replicase possesses NTPase and RNA 5'-triphosphatase activities. In this study, mutational effects of the helicase signature motifs and residue L543 on the two activities were investigated. Either activity was inactivated by K643A-S644A, D702A, D730A, R855A, or L543P mutations. On the other hand, Q826A, D858A and L543A had activities, in terms of k(cat)/K(m), reduced by 5- to 15-fold. AMPPNP, a nonhydrolyzable ATP analogue, competitively inhibited RNA 5'-triphosphatase activity. Analogies of mutational effects on the two activities and approximation of K(i(AMPPNP)) and K(m(ATP)) suggest that the catalytic sites of the activities are overlapped. Mutational effects on the viral accumulation in Chenopodium quinoa indicated that the activities manifested by the domain are required for BaMV survival. Results also suggest that Q826 in motif V plays an additional role in preventing tight binding to ATP, which would otherwise decrease further RNA 5'-triphosphatase, leading to demise of the virus in plant.
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PMID:Mutational analysis of a helicase motif-based RNA 5'-triphosphatase/NTPase from bamboo mosaic virus. 1758 82

The optional Escherichia coli restriction tRNase PrrC represents a family of potential antiviral devices widespread among bacteria. PrrC comprises a functional C-domain of unknown structure and regulatory ABC/ATPase-like N-domain. The possible involvement of a C-domain sequence in tRNA(Lys) recognition was investigated using a matching end-protected 11-meric peptide. This mimic, termed here LARP (Lys-anticodon recognizing peptide) UV-cross-linked tRNA(Lys) anticodon stem-loop (ASL) analogs and inhibited their PrrC-catalyzed cleavage. Trimming LARP or introducing in it inactivating PrrC missense mutations impaired these activities. LARP appeared to mimic its matching protein sequence in ability to dimerize in parallel, as inferred from the following results. First, tethering Cys to the amino- or carboxy-end of LARP dramatically enhanced the ASL-cross-linking and PrrC-inhibiting activities under suitable redox conditions. Second, Cys-substitutions in a C-domain region containing the sequence corresponding to LARP elicited specific intersubunit cross-links. The parallel dimerization of PrrC's C-domains and expected head-to-tail dimerization of its N-domains further suggest that the NTPase and tRNA(Lys)-binding sites of PrrC arise during distinct assembly stages of its dimer of dimers form.
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PMID:Parallel dimerization of a PrrC-anticodon nuclease region implicated in tRNALys recognition. 1760 7

Membrane-associated ATPase constitutes an essential element common to all secretion machineries in Gram-negative bacteria. How ATP hydrolysis by these ATPases is coupled to secretion process remains unclear. Here we identified R286 as a key residue in the type II secretion system (T2SS) ATPase XpsE of Xanthomonas campestris that plays a pivotal role in coupling ATP hydrolysis to protein translocation. Mutation of R286 to alanine made XpsE hydrolyse ATP at a rate five times that of the wild-type XpsE. Yet the mutant XpsE(R286A) is non-functional in protein secretion via T2SS. Detailed analyses indicated that the mutant XpsE(R286A) lost the ability co-ordinating the N- and C-domain of XpsE. Without significantly influencing XpsE binding affinity with ATP or its oligomerization, R286A mutation however, caused XpsE lose the ability to associate with the cytoplasmic membrane via XpsL(N). As a consequence, ATP hydrolysis by XpsE was uncoupled from protein secretion. Because R286 is highly conserved among members of the secretion NTPase superfamily, we speculate that its equivalent in other homologues may also play a critical energy coupling role for T2SS, type IV pilus assembly and type IV secretion system.
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PMID:Mutation of a key residue in the type II secretion system ATPase uncouples ATP hydrolysis from protein translocation. 1763 Sep 71


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