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Effects of protonation on the hydrolysis of triphosphate in vacuum and the implications for catalysis by nucleotide hydrolyzing enzymes. 质子化对真空中三磷酸水解的影响及其对核苷酸水解酶催化作用的启示。
BMC Biochemistry Pub Date : 2016-06-29 DOI: 10.1186/s12858-016-0068-7
Farooq Ahmad Kiani, Stefan Fischer
{"title":"Effects of protonation on the hydrolysis of triphosphate in vacuum and the implications for catalysis by nucleotide hydrolyzing enzymes.","authors":"Farooq Ahmad Kiani, Stefan Fischer","doi":"10.1186/s12858-016-0068-7","DOIUrl":"10.1186/s12858-016-0068-7","url":null,"abstract":"<p><strong>Background: </strong>Nucleoside triphosphate (NTP) hydrolysis is a key reaction in biology. It involves breaking two very stable bonds (one P-O bond and one O-H bond of water), in either a concurrent or a sequential way. Here, we systematically examine how protonation of the triphosphate affects the mechanism of hydrolysis.</p><p><strong>Results: </strong>The hydrolysis reaction of methyl triphosphate in vacuum is computed with protons in various numbers and position on the three phosphate groups. Protonation is seen to have a strong catalytic effect, with the reaction mechanism depending highly on the protonation pattern.</p><p><strong>Conclusion: </strong>This dependence is apparently complicated, but is shown to obey a well-defined set of rules: Protonation of the α- and β-phosphate groups favors a sequential hydrolysis mechanism, whereas γ-protonation favors a concurrent mechanism, the two effects competing with each other in cases of simultaneous protonation. The rate-limiting step is always the breakup of the water molecule while it attacks the γ-phosphorus, and its barrier is lowered by γ-protonation. This step has significantly lower barriers in the sequential reactions, because the dissociated γ-metaphosphate intermediate (P<sub>γ</sub>O<sub>3</sub><sup>-</sup>) is a much better target for water attack than the un-dissociated γ-phosphate (-P<sub>γ</sub>O<sub>4</sub><sup>2-</sup>). The simple chemical logic behind these rules helps to better understand the catalytic strategy used by NTPase enzymes, as illustrated here for the catalytic pocket of myosin. A set of rules was determined that describes how protonating the phosphate groups affects the hydrolysis mechanism of methyl triphosphate: Protonation of the α- and/or β- phosphate groups promotes a sequential mechanism in which P-O bond breaking precedes the breakup of the attacking water, whereas protonation of the γ-phosphate promotes a concurrent mechanism and lowers the rate-limiting barrier of water breakup. The role played by individual protein residues in the catalytic pocket of triphosphate hydrolysing enzymes can be assigned accordingly.</p>","PeriodicalId":9113,"journal":{"name":"BMC Biochemistry","volume":"17 1","pages":"12"},"PeriodicalIF":0.0,"publicationDate":"2016-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12858-016-0068-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65930132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 9
Molecular characterization of protein kinase C delta (PKCδ)-Smac interactions. 蛋白激酶Cδ (PKCδ)-Smac相互作用的分子表征。
BMC Biochemistry Pub Date : 2016-05-23 DOI: 10.1186/s12858-016-0065-x
Christian Holmgren, Louise Cornmark, Gry Kalstad Lønne, Katarzyna Chmielarska Masoumi, Christer Larsson
{"title":"Molecular characterization of protein kinase C delta (PKCδ)-Smac interactions.","authors":"Christian Holmgren,&nbsp;Louise Cornmark,&nbsp;Gry Kalstad Lønne,&nbsp;Katarzyna Chmielarska Masoumi,&nbsp;Christer Larsson","doi":"10.1186/s12858-016-0065-x","DOIUrl":"https://doi.org/10.1186/s12858-016-0065-x","url":null,"abstract":"<p><strong>Background: </strong>Protein kinase C δ (PKCδ) is known to be an important regulator of apoptosis, having mainly pro- but also anti-apoptotic effects depending on context. In a previous study, we found that PKCδ interacts with the pro-apoptotic protein Smac. Smac facilitates apoptosis by suppressing inhibitor of apoptosis proteins (IAPs). We previously established that the PKCδ-Smac complex dissociates during induction of apoptosis indicating a functional importance. Because the knowledge on the molecular determinants of the interaction is limited, we aimed at characterizing the interactions between PKCδ and Smac.</p><p><strong>Results: </strong>We found that PKCδ binds directly to Smac through its regulatory domain. The interaction is enhanced by the PKC activator TPA and seems to be independent of PKCδ catalytic activity since the PKC kinase inhibitor GF109203X did not inhibit the interaction. In addition, we found that C1 and C2 domains from several PKC isoforms have Smac-binding capacity.</p><p><strong>Conclusions: </strong>Our data demonstrate that the Smac-PKCδ interaction is direct and that it is facilitated by an open conformation of PKCδ. The binding is mediated via the PKCδ regulatory domain and both the C1 and C2 domains have Smac-binding capacity. With this study we thereby provide molecular information on an interaction between two apoptosis-regulating proteins.</p>","PeriodicalId":9113,"journal":{"name":"BMC Biochemistry","volume":"17 1","pages":"11"},"PeriodicalIF":0.0,"publicationDate":"2016-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12858-016-0065-x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34510428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 3
Identification and characterization of the novel nuclease activity of human phospholipid scramblase 1. 人磷脂超燃酶1新型核酸酶活性的鉴定与表征。
BMC Biochemistry Pub Date : 2016-05-20 DOI: 10.1186/s12858-016-0067-8
Ulaganathan Sivagnanam, Shweta Narayana Murthy, Sathyanarayana N Gummadi
{"title":"Identification and characterization of the novel nuclease activity of human phospholipid scramblase 1.","authors":"Ulaganathan Sivagnanam,&nbsp;Shweta Narayana Murthy,&nbsp;Sathyanarayana N Gummadi","doi":"10.1186/s12858-016-0067-8","DOIUrl":"https://doi.org/10.1186/s12858-016-0067-8","url":null,"abstract":"<p><strong>Background: </strong>Human phospholipid scramblase 1 (hPLSCR1) was initially identified as a Ca(2+) dependent phospholipid translocator involved in disrupting membrane asymmetry. Recent reports revealed that hPLSCR1 acts as a multifunctional signaling molecule rather than functioning as scramblase. hPLSCR1 is overexpressed in a variety of tumor cells and is known to interact with a number of protein molecules implying diverse functions.</p><p><strong>Results: </strong>In this study, the nuclease activity of recombinant hPLSCR1 and its biochemical properties have been determined. Point mutations were generated to identify the critical region responsible for the nuclease activity. Recombinant hPLSCR1 exhibits Mg(2+) dependent nuclease activity with an optimum pH and temperature of 8.5 and 37 °C respectively. Experiments with amino acid modifying reagents revealed that histidine, cysteine and arginine residues were crucial for its function. hPLSCR1 has five histidine residues and point mutations of histidine residues to alanine in hPLSCR1 resulted in 60 % loss in nuclease activity. Thus histidine residues could play a critical role in the nuclease activity of hPLSCR1.</p><p><strong>Conclusions: </strong>This is the first report on the novel nuclease activity of the multi-functional hPLSCR1. hPLSCR1 shows a metal dependent nuclease activity which could play a role in key cellular processes that needs to be further investigated.</p>","PeriodicalId":9113,"journal":{"name":"BMC Biochemistry","volume":"17 1","pages":"10"},"PeriodicalIF":0.0,"publicationDate":"2016-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12858-016-0067-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34568784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 7
Tubulin is a molecular target of the Wnt-activating chemical probe. 微管蛋白是wnt激活化学探针的分子靶标。
BMC Biochemistry Pub Date : 2016-05-20 DOI: 10.1186/s12858-016-0066-9
Yasunori Fukuda, Osamu Sano, Kenichi Kazetani, Koji Yamamoto, Hidehisa Iwata, Junji Matsui
{"title":"Tubulin is a molecular target of the Wnt-activating chemical probe.","authors":"Yasunori Fukuda,&nbsp;Osamu Sano,&nbsp;Kenichi Kazetani,&nbsp;Koji Yamamoto,&nbsp;Hidehisa Iwata,&nbsp;Junji Matsui","doi":"10.1186/s12858-016-0066-9","DOIUrl":"https://doi.org/10.1186/s12858-016-0066-9","url":null,"abstract":"<p><strong>Background: </strong>In drug discovery research, cell-based phenotypic screening is an essential method for obtaining potential drug candidates. Revealing the mechanism of action is a key step on the path to drug discovery. However, elucidating the target molecules of hit compounds from phenotypic screening campaigns remains a difficult and troublesome process. Simple and efficient methods for identifying the target molecules are essential.</p><p><strong>Results: </strong>2-Amino-4-(3,4-(methylenedioxy)benzylamino)-6-(3-methoxyphenyl)pyrimidine (AMBMP) was identified as a senescence inducer from a phenotypic screening campaign. The compound is widely used as a Wnt agonist, although its target molecules remain to be clarified. To identify its target proteins, we compared a series of cellular assay results for the compound with our pathway profiling database. The database comprises the activities of compounds from simple assays of cellular reporter genes and cellular proliferations. In this database, compounds were classified on the basis of statistical analysis of their activities, which corresponded to a mechanism of action by the representative compounds. In addition, the mechanisms of action of the compounds of interest could be predicted using the database. Based on our database analysis, the compound was anticipated to be a tubulin disruptor, which was subsequently confirmed by its inhibitory activity of tubulin polymerization.</p><p><strong>Conclusion: </strong>These results demonstrate that tubulin is identified for the first time as a target molecule of the Wnt-activating small molecule and that this might have misled the conclusions of some previous studies. Moreover, the present study also emphasizes that our pathway profiling database is a simple and potent tool for revealing the mechanisms of action of hit compounds obtained from phenotypic screenings and off targets of chemical probes.</p>","PeriodicalId":9113,"journal":{"name":"BMC Biochemistry","volume":"17 1","pages":"9"},"PeriodicalIF":0.0,"publicationDate":"2016-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12858-016-0066-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34412565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 11
Altered activity patterns of transcription factors induced by endoplasmic reticulum stress 内质网应激诱导的转录因子活性模式改变
BMC Biochemistry Pub Date : 2016-03-24 DOI: 10.1186/s12858-016-0060-2
Sheena Jiang, E. Zhang, Rachel Zhang, Xianqiang L Li
{"title":"Altered activity patterns of transcription factors induced by endoplasmic reticulum stress","authors":"Sheena Jiang, E. Zhang, Rachel Zhang, Xianqiang L Li","doi":"10.1186/s12858-016-0060-2","DOIUrl":"https://doi.org/10.1186/s12858-016-0060-2","url":null,"abstract":"","PeriodicalId":9113,"journal":{"name":"BMC Biochemistry","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12858-016-0060-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65930002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 24
Conserved motif VIII of murine DNA methyltransferase Dnmt3a is essential for methylation activity 小鼠DNA甲基转移酶Dnmt3a的保守基序VIII对甲基化活性至关重要
BMC Biochemistry Pub Date : 2016-03-22 DOI: 10.1186/s12858-016-0064-y
O. V. Lukashevich, N. Cherepanova, Renata Z. Jurkovska, A. Jeltsch, E. Gromova
{"title":"Conserved motif VIII of murine DNA methyltransferase Dnmt3a is essential for methylation activity","authors":"O. V. Lukashevich, N. Cherepanova, Renata Z. Jurkovska, A. Jeltsch, E. Gromova","doi":"10.1186/s12858-016-0064-y","DOIUrl":"https://doi.org/10.1186/s12858-016-0064-y","url":null,"abstract":"","PeriodicalId":9113,"journal":{"name":"BMC Biochemistry","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12858-016-0064-y","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65930125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 6
Linalool isomerase, a membrane-anchored enzyme in the anaerobic monoterpene degradation in Thauera linaloolentis 47Lol 芳樟醇异构酶:一种参与厌氧单萜降解的膜锚定酶
BMC Biochemistry Pub Date : 2016-03-15 DOI: 10.1186/s12858-016-0062-0
Robert Marmulla, Barbara Safaric, S. Markert, T. Schweder, J. Harder
{"title":"Linalool isomerase, a membrane-anchored enzyme in the anaerobic monoterpene degradation in Thauera linaloolentis 47Lol","authors":"Robert Marmulla, Barbara Safaric, S. Markert, T. Schweder, J. Harder","doi":"10.1186/s12858-016-0062-0","DOIUrl":"https://doi.org/10.1186/s12858-016-0062-0","url":null,"abstract":"","PeriodicalId":9113,"journal":{"name":"BMC Biochemistry","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12858-016-0062-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65930055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 14
1,2-Dichlorobenzene affects the formation of the phosphoenzyme stage during the catalytic cycle of the Ca2+-ATPase from sarcoplasmic reticulum 1,2-二氯苯影响肌浆网Ca2+- atp酶催化循环中磷酸酶阶段的形成
BMC Biochemistry Pub Date : 2016-03-11 DOI: 10.1186/s12858-016-0061-1
Javier Vargas-Medrano, Jorge A Sierra-Fonseca, L. F. Plenge-Tellechea
{"title":"1,2-Dichlorobenzene affects the formation of the phosphoenzyme stage during the catalytic cycle of the Ca2+-ATPase from sarcoplasmic reticulum","authors":"Javier Vargas-Medrano, Jorge A Sierra-Fonseca, L. F. Plenge-Tellechea","doi":"10.1186/s12858-016-0061-1","DOIUrl":"https://doi.org/10.1186/s12858-016-0061-1","url":null,"abstract":"","PeriodicalId":9113,"journal":{"name":"BMC Biochemistry","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12858-016-0061-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65930009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 4
Substrate specificity and function of acetylpolyamine amidohydrolases from Pseudomonas aeruginosa 铜绿假单胞菌乙酰多胺酰胺水解酶的底物特异性和功能
BMC Biochemistry Pub Date : 2016-03-09 DOI: 10.1186/s12858-016-0063-z
Andreas Krämer, J. Herzer, J. Overhage, F. Meyer‐Almes
{"title":"Substrate specificity and function of acetylpolyamine amidohydrolases from Pseudomonas aeruginosa","authors":"Andreas Krämer, J. Herzer, J. Overhage, F. Meyer‐Almes","doi":"10.1186/s12858-016-0063-z","DOIUrl":"https://doi.org/10.1186/s12858-016-0063-z","url":null,"abstract":"","PeriodicalId":9113,"journal":{"name":"BMC Biochemistry","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12858-016-0063-z","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65930065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 15
BMC Biochemistry Reviewer Acknowledgement, 2015 BMC Biochemistry Reviewer Acknowledgement, 2015
BMC Biochemistry Pub Date : 2016-02-10 DOI: 10.1186/s12858-016-0058-9
Guangde Tu
{"title":"BMC Biochemistry Reviewer Acknowledgement, 2015","authors":"Guangde Tu","doi":"10.1186/s12858-016-0058-9","DOIUrl":"https://doi.org/10.1186/s12858-016-0058-9","url":null,"abstract":"","PeriodicalId":9113,"journal":{"name":"BMC Biochemistry","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12858-016-0058-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65930460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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