Structural and mechanistic insights into the action of Plasmodium falciparum spermidine synthase.
Spermidine synthase is currently considered as a promising drug target in the malaria parasite, Plasmodium falciparum, due to the vital role of spermidine in the activation of the eukaryotic translation initiation factor (eIF5A) and cell proliferation. However, very limited information was available regarding the structure and mechanism of action of the protein at the start of this study. Structural and mechanistic insights of the P. falciparum spermidine synthase (PfSpdSyn) were obtained utilizing molecular dynamics simulations of a homology model based on the crystal structures of the Arabidopsis thaliana and Thermotoga maritima homologues. Our data are supported by in vitro site-directed mutagenesis of essential residues as well as by a crystal structure of the protein that became available recently. We provide, for the first time, dynamic evidence for the mechanism of the aminopropyltransferase action of PfSpdSyn. This characterization of the structural and mechanistic properties of the PfSpdSyn as well as the elucidation of the active site residues involved in substrate, product, and inhibitor interactions paves the way toward inhibitor selection or design of parasite-specific inhibitors.
Burger
Pieter B
PB
Bioinformatics and Computational Biology Unit, Faculty of Natural and Agricultural Sciences, University of Pretoria, Pretoria 0002, South Africa.
Birkholtz
Lyn-Marie
LM
Joubert
Fourie
F
Haider
Nashya
N
Walter
Rolf D
RD
Louw
Abraham I
AI
D000818:Animals; D001665:Binding Sites; D049109:Cell Proliferation; D003198:Computer Simulation; D009038:Motion; D016297:Mutagenesis, Site-Directed; D010448:Peptide Initiation Factors / Q000502:physiology; D010963:Plasmodium falciparum / Q000201:enzymology*; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics; D016601:RNA-Binding Proteins / Q000502:physiology; D011436:Spermidine Synthase / Q000737:chemistry* / Q000235:genetics; D000097574:Eukaryotic Translation Initiation Factor 5A
D010448:Peptide Initiation Factors; D015800:Protozoan Proteins; D016601:RNA-Binding Proteins; D011436:Spermidine Synthase; D000097574:Eukaryotic Translation Initiation Factor 5A