Skip to main content

Binding and Inhibition of Spermidine Synthase from Plasmodium falciparum and Implications for In Vitro Inhibitor Testing

Author(s): Sprenger, Janina; Carey, Jannette; Svensson, Bo; Wengel, Verena; Persson, Lo

Download
To refer to this page use: http://arks.princeton.edu/ark:/88435/pr13512
Full metadata record
DC FieldValueLanguage
dc.contributor.authorSprenger, Janina-
dc.contributor.authorCarey, Jannette-
dc.contributor.authorSvensson, Bo-
dc.contributor.authorWengel, Verena-
dc.contributor.authorPersson, Lo-
dc.date.accessioned2020-10-30T19:14:07Z-
dc.date.available2020-10-30T19:14:07Z-
dc.date.issued2016-09-01en_US
dc.identifier.citationSprenger, Janina, Carey, Jannette, Svensson, Bo, Wengel, Verena, Persson, Lo. (2016). Binding and Inhibition of Spermidine Synthase from Plasmodium falciparum and Implications for In Vitro Inhibitor Testing. PLOS ONE, 11 (9), e0163442 - e0163442. doi:10.1371/journal.pone.0163442.en_US
dc.identifier.urihttp://arks.princeton.edu/ark:/88435/pr13512-
dc.descriptionPLoS ONE. Volume 11, Issue 9, September 2016, Article number e0163442.en_US
dc.description.abstractThe aminopropyltransferase spermidine synthase (SpdS) is a promising drug target in cancer and in protozoan diseases including malaria. Plasmodium falciparum SpdS (PfSpdS) transfers the aminopropyl group of decarboxylated S-adenosylmethionine (dcAdoMet) to putrescine or to spermidine to form spermidine or spermine, respectively. In an effort to understand why efficient inhibitors of PfSpdS have been elusive, the present study uses enzyme activity assays and isothermal titration calorimetry with verified or predicted inhibitors of PfSpdS to analyze the relationship between binding affinity as assessed by KD and inhibitory activity as assessed by IC50. The results show that some predicted inhibitors bind to the enzyme with high affinity but are poor inhibitors. Binding studies with PfSpdS substrates and products strongly support an ordered sequential mechanism in which the aminopropyl donor (dcAdoMet) site must be occupied before the aminopropyl acceptor (putrescine) site can be occupied. Analysis of the results also shows that the ordered sequential mechanism adequately accounts for the complex relationship between IC50 and KD and may explain the limited success of previous efforts at structure-based inhibitor design for PfSpdS. Based on PfSpdS active-site occupancy, we suggest a classification of ligands that can help to predict the KD-IC50 relations in future design of new inhibitors. The present findings may be relevant for other drug targets that follow an ordered sequential mechanism. © 2016 Sprenger et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.format.extent11.9:e0163442-1 - e0163442-17en_US
dc.language.isoenen_US
dc.relation.ispartofPLOS ONEen_US
dc.rightsFinal published version. This is an open access article.en_US
dc.titleBinding and Inhibition of Spermidine Synthase from Plasmodium falciparum and Implications for In Vitro Inhibitor Testingen_US
dc.typeJournal Articleen_US
dc.identifier.doidoi:10.1371/journal.pone.0163442-
dc.date.eissued2016-09-23en_US
dc.identifier.eissn1932-6203-
pu.type.symplectichttp://www.symplectic.co.uk/publications/atom-terms/1.0/journal-articleen_US

Files in This Item:
File Description SizeFormat 
journal.pone.0163442.PDF2.7 MBAdobe PDFView/Download


Items in OAR@Princeton are protected by copyright, with all rights reserved, unless otherwise indicated.