title: Target evaluation of deoxyhypusine synthase from Theileria parva the neglected animal parasite and its relationship to Plasmodium.
abstract: East Coast fever (ECF) is a tick-borne disease caused by the parasite Theileria parva which infects cattle. In Sub-Saharan Africa it leads to enormous economic costs. After a bite of a tick, sporozoites invade the host lymphocytes and develop into schizonts. At this stage the parasite transforms host lymphocytes resulting in the clonal expansion of infected lymphocytes. Animals develop a lymphoma like disorder after infection which is rapidly fatal. Hitherto, a few drugs of the quinone type can cure the disease. However, therapy can only be successful after early diagnosis. The genera Theileria and Plasmodium, which includes the causative agent of human malaria, are closely related apicomplexan parasites. Enzymes of the hypusine pathway, a posttranslational modification in eukaryotic initiation factor EIF-5A, have shown to be druggable targets in Plasmodium. We identified the first enzyme of the hypusine pathway from T. parva, the deoxyhypusine synthase (DHS), which is located on chromosome 2 of the Muguga strain. Transcription is significantly increased in schizonts. The expressed T. parva DHS reveals an open reading frame (ORF) of 370 amino acids after expression in Escherichia coli Rosetta cells with a molecular size of 41.26 kDa and a theoretical pI of 5.26. Screening of the Malaria Box which consists of 400 active compounds resulted in a novel heterocyclic compound with a guanyl spacer which reduced the activity of T. parva DHS to 45%. In sum, the guanyl residue seems to be an important lead structure for inhibition of Theileria DHS. Currently, more different guanyl analogues from the Malaria Box are tested in inhibitor experiments to determine their efficacy.
authors.affiliation: Institute for Pharmacogenetics, Medical Research Centre, University Duisburg-Essen, Germany.
authors.forename: James T
authors.initials: JT
authors.lastname: Njuguna
authors.affiliation: Institute for Pharmacogenetics, Medical Research Centre, University Duisburg-Essen, Germany.
authors.forename: Imke
authors.initials: I
authors.lastname: von Koschitzky
authors.affiliation: Pharmaceutical Analytics, Pharmaceutical Institute, Eberhard-Karls-University Tübingen, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Gerhardt
authors.affiliation: Pharmaceutical Analytics, Pharmaceutical Institute, Eberhard-Karls-University Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Lämmerhofer
authors.affiliation: Institute for Pharmacogenetics, Medical Research Centre, University Duisburg-Essen, Germany.
authors.forename: Ali
authors.initials: A
authors.lastname: Choucry
authors.affiliation: Occupational Medicine, Friedrich Alexander-University Erlangen, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Pink
authors.affiliation: Occupational Medicine, Friedrich Alexander-University Erlangen, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Schmitz-Spahnke
authors.affiliation: Research Center Borstel, Leibniz Center for Medicine and Biosciences Borstel, Germany.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Bakheit
authors.affiliation: Institute for Parasitology, University of Veterinary Medicine Hannover, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Strube
authors.affiliation: Institute for Pharmacogenetics, Medical Research Centre, University Duisburg-Essen, Germany. Electronic address: annette.kaiser@uk-essen.de.
authors.forename: Annette
authors.initials: A
authors.lastname: Kaiser
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D003001:Cloning, Molecular; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism; D006147:Guanine / Q000737:chemistry; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008214:Lymphocytes / Q000469:parasitology; D008969:Molecular Sequence Data; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010961:Plasmodium / Q000201:enzymology* / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D016415:Sequence Alignment; D016797:Theileria parva / Q000201:enzymology* / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D011994:Recombinant Proteins; D006147:Guanine; D000587:Oxidoreductases Acting on CH-NH Group Donors; C063507:deoxyhypusine synthase
keywords: Deoxyhypusine synthase; East Coast fever; Hypusine; Theileria parva