Three-dimensional structures of Plasmodium falciparum spermidine synthase with bound inhibitors suggest new strategies for drug design

Acta Crystallographica. Section D, Biological Crystallography
Janina SprengerSalam Al-Karadaghi

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...Continue Reading

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Citations

Sep 4, 2015·Acta Crystallographica. Section D, Biological Crystallography·Yasushi AmanoHitoshi Sakashita
Feb 6, 2017·Experimental Parasitology·C Rojas-MartínezJ A Álvarez Martínez
Jun 27, 2017·Biochemical and Biophysical Research Communications·Huawei Zhang, Shannon Wing Ngor Au
Mar 17, 2019·The Biochemical Journal·Gabriela GuédezTiina A Salminen
Mar 28, 2017·Current Microbiology·Aslıhan Örs Gevrekci

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Methods Mentioned

BETA
X-ray
NMR
gel filtration

Software Mentioned

PHENIX
4MAN
XDS

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