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Background  Hypusination is an essential post-translational modification in eukaryotes. The two enzymes required for this modification, namely deoxyhypusine synthase (DHS) and deoxyhypusine hydrolase are also conserved.  Plasmodium falciparum  human malaria parasites possess genes for both hypusination enzymes, which are hypothesized to be targets of antimalarial drugs.    Methods  Transgenic  P. falciparum  parasites with modification of the PF3D7_1412600 gene encoding  Pf DHS enzyme were created by insertion of the  glmS  riboswitch or the M9 inactive variant. The  Pf DHS protein was studied in transgenic parasites by confocal microscopy and Western immunoblotting. The biochemical function of  Pf DHS enzyme in parasites was assessed by hypusination and nascent protein synthesis assays. Gene essentiality was assessed by competitive growth assays and chemogenomic profiling.    Results  Clonal transgenic parasites with integration of  glmS  riboswitch downstream of the  Pf DHS gene were established.  Pf DHS protein was present in the cytoplasm of transgenic parasites in asexual stages. The  Pf DHS protein could be attenuated fivefold in transgenic parasites with an active riboswitch, whereas  Pf DHS protein expression was unaffected in control transgenic parasites with insertion of the riboswitch-inactive sequence. Attenuation of  Pf DHS expression for 72 h led to a significant reduction of hypusinated protein; however, global protein synthesis was unaffected. Parasites with attenuated  Pf DHS expression showed a significant growth defect, although their decline was not as rapid as parasites with attenuated dihydrofolate reductase-thymidylate synthase ( Pf DHFR-TS) expression.  Pf DHS-attenuated parasites showed increased sensitivity to  N  1 -guanyl-1,7-diaminoheptane, a structural analog of spermidine, and a known inhibitor of DHS enzymes.    Discussion  Loss of  Pf DHS function leads to reduced hypusination, which may be important for synthesis of some essential proteins. The growth defect in parasites with attenuated  Pf  DHS expression suggests that this gene is essential. However, the slower decline of  Pf DHS mutants compared with  Pf DHFR-TS mutants in competitive growth assays suggests that  Pf DHS is less vulnerable as an antimalarial target. Nevertheless, the data validate  Pf DHS as an antimalarial target which can be inhibited by spermidine-like compounds.

Validation ofPlasmodium falciparumdeoxyhypusine synthase as an antimalarial target