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Crystal structure of Plasmodium falciparum spermidine synthase in complex with the substrate decarboxylated S-adenosylmethionine and the potent inhibitors 4MCHA and AdoDATO

Tamu Dufe, Veronica LU ; Qiu, Wei; Mueller, Ingrid B.; Hui, Raymond; Walter, Rolf D. and Al-Karadaghi, Salam LU (2007) In Journal of Molecular Biology 373(1). p.167-177
Abstract
Plasmodium falciparum is the causative agent of the most severe type of malaria, a life-threatening disease affecting the lives of over three billion people. Factors like widespread resistance against available drugs and absence of an effective vaccine are seriously compounding control of the malaria parasite. Thus, there is an urgent need for the identification and validation of new drug targets. The enzymes of the polyamine biosynthesis pathway have been suggested as possible targets for the treatment of malaria. One of these enzymes is spermidine synthase (SPDS, putrescine aminopropyltransferase), which catalyzes the transfer of an aminopropyl moiety from decarboxylated S-adenosylmethionine (dcAdoMet) to putrescine, leading to the... (More)
Plasmodium falciparum is the causative agent of the most severe type of malaria, a life-threatening disease affecting the lives of over three billion people. Factors like widespread resistance against available drugs and absence of an effective vaccine are seriously compounding control of the malaria parasite. Thus, there is an urgent need for the identification and validation of new drug targets. The enzymes of the polyamine biosynthesis pathway have been suggested as possible targets for the treatment of malaria. One of these enzymes is spermidine synthase (SPDS, putrescine aminopropyltransferase), which catalyzes the transfer of an aminopropyl moiety from decarboxylated S-adenosylmethionine (dcAdoMet) to putrescine, leading to the formation of spermidine and 5 '-methylthioadenosine. Here we present the three-dimensional structure of P falciparum spermidine synthase (pfSPDS) in apo form, in complex with dcAdoMet and two inhibitors, S-adenosyl-1,8-diamino-3-thio-octane (AdoDATO) and trans-4-methylcyclohexylamine (4MCHA). The results show that binding of dcAdoMet to pfSPDS stabilizes the conformation of the flexible gatekeeper loop of the enzyme and affects the conformation of the active-site amino acid residues, preparing the protein for binding of the second substrate. The complexes of AdoDATO and 4MCHA with pfSPDS reveal the mode of interactions of these compounds with the enzyme. While AdoDATO essentially fills the entire active-site pocket, 4MCHA only occupies part of it, which suggests that simple modifications of this compound may yield more potent inhibitors of pfSPDS. (C) 2007 Elsevier Ltd. All rights reserved. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
spermidine synthase, polyamine synthesis, enzyme inhibition, malaria, inhibitor design
in
Journal of Molecular Biology
volume
373
issue
1
pages
167 - 177
publisher
Elsevier
external identifiers
  • wos:000249948800013
  • scopus:34548587312
ISSN
1089-8638
DOI
10.1016/j.jmb.2007.07.053
language
English
LU publication?
yes
id
e493df56-4536-4d3e-b5e8-cc0fd5ba5d65 (old id 654300)
date added to LUP
2007-12-07 13:32:07
date last changed
2017-07-30 04:29:49
@article{e493df56-4536-4d3e-b5e8-cc0fd5ba5d65,
  abstract     = {Plasmodium falciparum is the causative agent of the most severe type of malaria, a life-threatening disease affecting the lives of over three billion people. Factors like widespread resistance against available drugs and absence of an effective vaccine are seriously compounding control of the malaria parasite. Thus, there is an urgent need for the identification and validation of new drug targets. The enzymes of the polyamine biosynthesis pathway have been suggested as possible targets for the treatment of malaria. One of these enzymes is spermidine synthase (SPDS, putrescine aminopropyltransferase), which catalyzes the transfer of an aminopropyl moiety from decarboxylated S-adenosylmethionine (dcAdoMet) to putrescine, leading to the formation of spermidine and 5 '-methylthioadenosine. Here we present the three-dimensional structure of P falciparum spermidine synthase (pfSPDS) in apo form, in complex with dcAdoMet and two inhibitors, S-adenosyl-1,8-diamino-3-thio-octane (AdoDATO) and trans-4-methylcyclohexylamine (4MCHA). The results show that binding of dcAdoMet to pfSPDS stabilizes the conformation of the flexible gatekeeper loop of the enzyme and affects the conformation of the active-site amino acid residues, preparing the protein for binding of the second substrate. The complexes of AdoDATO and 4MCHA with pfSPDS reveal the mode of interactions of these compounds with the enzyme. While AdoDATO essentially fills the entire active-site pocket, 4MCHA only occupies part of it, which suggests that simple modifications of this compound may yield more potent inhibitors of pfSPDS. (C) 2007 Elsevier Ltd. All rights reserved.},
  author       = {Tamu Dufe, Veronica and Qiu, Wei and Mueller, Ingrid B. and Hui, Raymond and Walter, Rolf D. and Al-Karadaghi, Salam},
  issn         = {1089-8638},
  keyword      = {spermidine synthase,polyamine synthesis,enzyme inhibition,malaria,inhibitor design},
  language     = {eng},
  number       = {1},
  pages        = {167--177},
  publisher    = {Elsevier},
  series       = {Journal of Molecular Biology},
  title        = {Crystal structure of Plasmodium falciparum spermidine synthase in complex with the substrate decarboxylated S-adenosylmethionine and the potent inhibitors 4MCHA and AdoDATO},
  url          = {http://dx.doi.org/10.1016/j.jmb.2007.07.053},
  volume       = {373},
  year         = {2007},
}