Three-dimensional structures of Plasmodium falciparum spermidine synthase with bound inhibitors suggest new strategies for drug design.
(2015) In Acta Crystallographica. Section D: Biological Crystallography 71(Pt 3). p.484-493- Abstract
- The enzymes of the polyamine-biosynthesis pathway have been proposed to be promising drug targets in the treatment of malaria. Spermidine synthase (SpdS; putrescine aminopropyltransferase) catalyzes the transfer of the aminopropyl moiety from decarboxylated S-adenosylmethionine to putrescine, leading to the formation of spermidine and 5'-methylthioadenosine (MTA). In this work, X-ray crystallography was used to examine ligand complexes of SpdS from the malaria parasite Plasmodium falciparum (PfSpdS). Five crystal structures were determined of PfSpdS in complex with MTA and the substrate putrescine, with MTA and spermidine, which was obtained as a result of the enzymatic reaction taking place within the crystals, with dcAdoMet and the... (More)
- The enzymes of the polyamine-biosynthesis pathway have been proposed to be promising drug targets in the treatment of malaria. Spermidine synthase (SpdS; putrescine aminopropyltransferase) catalyzes the transfer of the aminopropyl moiety from decarboxylated S-adenosylmethionine to putrescine, leading to the formation of spermidine and 5'-methylthioadenosine (MTA). In this work, X-ray crystallography was used to examine ligand complexes of SpdS from the malaria parasite Plasmodium falciparum (PfSpdS). Five crystal structures were determined of PfSpdS in complex with MTA and the substrate putrescine, with MTA and spermidine, which was obtained as a result of the enzymatic reaction taking place within the crystals, with dcAdoMet and the inhibitor 4-methylaniline, with MTA and 4-aminomethylaniline, and with a compound predicted in earlier in silico screening to bind to the active site of the enzyme, benzimidazol-(2-yl)pentan-1-amine (BIPA). In contrast to the other inhibitors tested, the complex with BIPA was obtained without any ligand bound to the dcAdoMet-binding site of the enzyme. The complexes with the aniline compounds and BIPA revealed a new mode of ligand binding to PfSpdS. The observed binding mode of the ligands, and the interplay between the two substrate-binding sites and the flexible gatekeeper loop, can be used in the design of new approaches in the search for new inhibitors of SpdS. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/5264706
- author
- Sprenger, Janina LU ; Svensson, Bo LU ; Hålander, Jenny ; Carey, Jannette LU ; Persson, Lo LU and Al-Karadaghi, Salam
- organization
- publishing date
- 2015
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Acta Crystallographica. Section D: Biological Crystallography
- volume
- 71
- issue
- Pt 3
- pages
- 484 - 493
- publisher
- John Wiley & Sons Inc.
- external identifiers
-
- pmid:25760598
- wos:000351155400007
- scopus:84924765182
- pmid:25760598
- ISSN
- 1399-0047
- DOI
- 10.1107/S1399004714027011
- language
- English
- LU publication?
- yes
- id
- 3f2660ed-d03a-4675-b184-00619d56ba3d (old id 5264706)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/25760598?dopt=Abstract
- date added to LUP
- 2016-04-01 13:24:21
- date last changed
- 2022-04-14 01:03:32
@article{3f2660ed-d03a-4675-b184-00619d56ba3d,
abstract = {{The enzymes of the polyamine-biosynthesis pathway have been proposed to be promising drug targets in the treatment of malaria. Spermidine synthase (SpdS; putrescine aminopropyltransferase) catalyzes the transfer of the aminopropyl moiety from decarboxylated S-adenosylmethionine to putrescine, leading to the formation of spermidine and 5'-methylthioadenosine (MTA). In this work, X-ray crystallography was used to examine ligand complexes of SpdS from the malaria parasite Plasmodium falciparum (PfSpdS). Five crystal structures were determined of PfSpdS in complex with MTA and the substrate putrescine, with MTA and spermidine, which was obtained as a result of the enzymatic reaction taking place within the crystals, with dcAdoMet and the inhibitor 4-methylaniline, with MTA and 4-aminomethylaniline, and with a compound predicted in earlier in silico screening to bind to the active site of the enzyme, benzimidazol-(2-yl)pentan-1-amine (BIPA). In contrast to the other inhibitors tested, the complex with BIPA was obtained without any ligand bound to the dcAdoMet-binding site of the enzyme. The complexes with the aniline compounds and BIPA revealed a new mode of ligand binding to PfSpdS. The observed binding mode of the ligands, and the interplay between the two substrate-binding sites and the flexible gatekeeper loop, can be used in the design of new approaches in the search for new inhibitors of SpdS.}},
author = {{Sprenger, Janina and Svensson, Bo and Hålander, Jenny and Carey, Jannette and Persson, Lo and Al-Karadaghi, Salam}},
issn = {{1399-0047}},
language = {{eng}},
number = {{Pt 3}},
pages = {{484--493}},
publisher = {{John Wiley & Sons Inc.}},
series = {{Acta Crystallographica. Section D: Biological Crystallography}},
title = {{Three-dimensional structures of Plasmodium falciparum spermidine synthase with bound inhibitors suggest new strategies for drug design.}},
url = {{https://lup.lub.lu.se/search/files/3347965/8055240}},
doi = {{10.1107/S1399004714027011}},
volume = {{71}},
year = {{2015}},
}