Chemical Rescue of Malaria Parasites Lacking an Apicoplast Defines Organelle Function in Blood-Stage Plasmodium falciparum
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{"title"=>"Chemical rescue of malaria parasites lacking an apicoplast defines organelle function in blood-stage plasmodium falciparum", "type"=>"journal", "authors"=>[{"first_name"=>"Ellen", "last_name"=>"Yeh", "scopus_author_id"=>"27268104900"}, {"first_name"=>"Joseph L.", "last_name"=>"DeRisi", "scopus_author_id"=>"7004334309"}], "year"=>2011, "source"=>"PLoS Biology", "identifiers"=>{"scopus"=>"2-s2.0-80052308799", "doi"=>"10.1371/journal.pbio.1001138", "sgr"=>"80052308799", "isbn"=>"1545-7885", "pmid"=>"21912516", "issn"=>"15449173", "pui"=>"362471725"}, "id"=>"5c0e5e6a-c7e5-3bb8-9cae-14b0eb65d730", "abstract"=>"The only essential function of a unique plastid organelle, the apicoplast, in blood-stage P. falciparum is the production of isoprenoid precursors.", "link"=>"http://www.mendeley.com/research/chemical-rescue-malaria-parasites-lacking-apicoplast-defines-organelle-function-bloodstage-plasmodiu", "reader_count"=>240, "reader_count_by_academic_status"=>{"Unspecified"=>6, "Professor > Associate Professor"=>13, "Researcher"=>54, "Student > Doctoral Student"=>14, "Student > Ph. D. Student"=>74, "Student > Postgraduate"=>14, "Other"=>7, "Student > Master"=>27, "Student > Bachelor"=>16, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>2, "Professor"=>11}, "reader_count_by_user_role"=>{"Unspecified"=>6, "Professor > Associate Professor"=>13, "Researcher"=>54, "Student > Doctoral Student"=>14, "Student > Ph. D. Student"=>74, "Student > Postgraduate"=>14, "Other"=>7, "Student > Master"=>27, "Student > Bachelor"=>16, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>2, "Professor"=>11}, "reader_count_by_subject_area"=>{"Unspecified"=>9, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>29, "Medicine and Dentistry"=>9, "Agricultural and Biological Sciences"=>153, "Pharmacology, Toxicology and Pharmaceutical Science"=>5, "Business, Management and Accounting"=>1, "Chemical Engineering"=>2, "Chemistry"=>22, "Social Sciences"=>1, "Immunology and Microbiology"=>8}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>9}, "Chemistry"=>{"Chemistry"=>22}, "Social Sciences"=>{"Social Sciences"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>8}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>153}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>29}, "Unspecified"=>{"Unspecified"=>9}, "Environmental Science"=>{"Environmental Science"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>5}, "Chemical Engineering"=>{"Chemical Engineering"=>2}}, "reader_count_by_country"=>{"Pakistan"=>1, "United States"=>8, "Japan"=>1, "Brazil"=>1, "United Kingdom"=>4, "Ghana"=>1, "Lithuania"=>1, "France"=>3, "Portugal"=>1, "Germany"=>2, "Spain"=>1}, "group_count"=>6}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/741092"], "description"=>"<p>(Top) The essential function of the apicoplast is the production of isoprenoid precursors, IPP and DMAPP, which are exported into the cytoplasm and used to synthesize small molecule isoprenoids and prenylated proteins. Parasites that are unable to synthesize isoprenoid precursors either due to inhibition of the biosynthetic pathway by fosmidomycin or loss of the apicoplast following doxycycline inhibition can be chemically rescued by addition of exogenous IPP (red). The exogenous IPP enters the host cell through unknown membrane transporters and fulfills the missing biosynthetic function. (Bottom) Reaction scheme for MEP pathway biosynthesis of IPP and DMAPP with the enzymatic step inhibited by fosmidomycin indicated.</p>", "links"=>[], "tags"=>["apicoplast"], "article_id"=>411477, "categories"=>["Biochemistry", "Chemistry", "Infectious Diseases"], "users"=>["Ellen Yeh", "Joseph L. DeRisi"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001138.g005", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Model_of_apicoplast_function_/411477", "title"=>"Model of apicoplast function.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-08-30 00:24:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/374101", "https://ndownloader.figshare.com/files/374127", "https://ndownloader.figshare.com/files/374140", "https://ndownloader.figshare.com/files/374166", "https://ndownloader.figshare.com/files/374192", "https://ndownloader.figshare.com/files/374210", "https://ndownloader.figshare.com/files/374242", "https://ndownloader.figshare.com/files/374293", "https://ndownloader.figshare.com/files/374337"], "description"=>"<div><p><em>Plasmodium</em> spp parasites harbor an unusual plastid organelle called the apicoplast. Due to its prokaryotic origin and essential function, the apicoplast is a key target for development of new anti-malarials. Over 500 proteins are predicted to localize to this organelle and several prokaryotic biochemical pathways have been annotated, yet the essential role of the apicoplast during human infection remains a mystery. Previous work showed that treatment with fosmidomycin, an inhibitor of non-mevalonate isoprenoid precursor biosynthesis in the apicoplast, inhibits the growth of blood-stage <em>P. falciparum</em>. Herein, we demonstrate that fosmidomycin inhibition can be chemically rescued by supplementation with isopentenyl pyrophosphate (IPP), the pathway product. Surprisingly, IPP supplementation also completely reverses death following treatment with antibiotics that cause loss of the apicoplast. We show that antibiotic-treated parasites rescued with IPP over multiple cycles specifically lose their apicoplast genome and fail to process or localize organelle proteins, rendering them functionally apicoplast-minus. Despite the loss of this essential organelle, these apicoplast-minus auxotrophs can be grown indefinitely in asexual blood stage culture but are entirely dependent on exogenous IPP for survival. These findings indicate that isoprenoid precursor biosynthesis is the only essential function of the apicoplast during blood-stage growth. Moreover, apicoplast-minus <em>P. falciparum</em> strains will be a powerful tool for further investigation of apicoplast biology as well as drug and vaccine development.</p> </div>", "links"=>[], "tags"=>["malaria", "parasites", "lacking", "apicoplast", "defines", "organelle", "blood-stage"], "article_id"=>133876, "categories"=>["Cancer", "Biochemistry", "Chemistry"], "users"=>["Ellen Yeh", "Joseph L. DeRisi"], "doi"=>["https://dx.doi.org/10.1371/journal.pbio.1001138.s001", "https://dx.doi.org/10.1371/journal.pbio.1001138.s002", "https://dx.doi.org/10.1371/journal.pbio.1001138.s003", "https://dx.doi.org/10.1371/journal.pbio.1001138.s004", "https://dx.doi.org/10.1371/journal.pbio.1001138.s005", "https://dx.doi.org/10.1371/journal.pbio.1001138.s006", "https://dx.doi.org/10.1371/journal.pbio.1001138.s007", "https://dx.doi.org/10.1371/journal.pbio.1001138.s008", "https://dx.doi.org/10.1371/journal.pbio.1001138.s009"], "stats"=>{"downloads"=>3, "page_views"=>32, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Chemical_Rescue_of_Malaria_Parasites_Lacking_an_Apicoplast_Defines_Organelle_Function_in_Blood_Stage_Plasmodium_falciparum_/133876", "title"=>"Chemical Rescue of Malaria Parasites Lacking an Apicoplast Defines Organelle Function in Blood-Stage <em>Plasmodium falciparum</em>", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-08-30 01:04:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/740892"], "description"=>"<p>Immunoblot using anti-GFP shows a time course of apicoplast-dependent protein processing of apicoplast-targeted GFP in (A) untreated, (B) doxycycline-treated, and (C) doxycycline+IPP treated parasites.</p>", "links"=>[], "tags"=>["apicoplast-targeted", "proteins", "rescued"], "article_id"=>411268, "categories"=>["Biochemistry", "Chemistry", "Infectious Diseases"], "users"=>["Ellen Yeh", "Joseph L. DeRisi"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001138.g003", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Loss_of_protein_processing_of_apicoplast_targeted_proteins_in_antibiotic_treated_rescued_parasites_/411268", "title"=>"Loss of protein processing of apicoplast-targeted proteins in antibiotic-treated, rescued parasites.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-08-30 00:21:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/740809"], "description"=>"<p>(A) Survival of parasites over 4 life cycles treated with (1) doxycyline only, (2) doxycycline+IPP, or (3) doxycycline+IPP for three cycles followed by removal of both. Parasitemia is normalized to that of an untreated control. (B) Apicoplast∶nuclear and (C) mitochondria∶nuclear genome ratio of doxycycline only and doxycycline+IPP treated parasites over the same time course. Genome ratios are normalized to an untreated control. Data from three separate passages are shown.</p>", "links"=>[], "tags"=>["antibiotic", "delayed", "apicoplast", "genome"], "article_id"=>411179, "categories"=>["Biochemistry", "Chemistry", "Infectious Diseases"], "users"=>["Ellen Yeh", "Joseph L. DeRisi"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001138.g002", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Rescue_of_antibiotic_delayed_death_and_apicoplast_genome_loss_/411179", "title"=>"Rescue of antibiotic delayed death and apicoplast genome loss.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-08-30 00:19:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/741167"], "description"=>"<p>ND, not determined.</p>a<p>Represented as mean (95% confidence interval).</p>b<p>50% inhibition above highest assayed concentration.</p>", "links"=>[], "tags"=>["apicoplast-specific", "inhibition"], "article_id"=>411548, "categories"=>["Biochemistry", "Chemistry", "Infectious Diseases"], "users"=>["Ellen Yeh", "Joseph L. DeRisi"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001138.t001", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Rescue_of_apicoplast_specific_growth_inhibition_by_antibiotics_/411548", "title"=>"Rescue of apicoplast-specific growth inhibition by antibiotics.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-08-30 00:25:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/740737"], "description"=>"<p>(A) Growth inhibition by fosmidomycin (0–100 µM) in media supplemented with 200 µM IPP, DMAPP, or both IPP and DMAPP. (B) Concentration dependence of IPP rescue.</p>", "links"=>[], "tags"=>["fosmidomycin", "inhibition", "ipp"], "article_id"=>411108, "categories"=>["Biochemistry", "Chemistry", "Infectious Diseases"], "users"=>["Ellen Yeh", "Joseph L. DeRisi"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001138.g001", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Chemical_rescue_of_fosmidomycin_inhibition_with_IPP_precursors_/411108", "title"=>"Chemical rescue of fosmidomycin inhibition with IPP precursors.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-08-30 00:18:28"}
  • {"files"=>["https://ndownloader.figshare.com/files/740985"], "description"=>"<p>Widefield epifluorescence microscopy for apicoplast (ACP<sub>L</sub>-GFP) and nucleus (Hoescht 33342) comparing ring, trophozoite, and schizont in untreated parasites and chloramphenicol+IPP treated parasites. To right, confocal 3-D reconstruction of untreated parasites and chloramphenicol+IPP treated early trophozoite stage parasites.</p>", "links"=>[], "tags"=>["localization", "apicoplast-targeted", "proteins", "rescued"], "article_id"=>411359, "categories"=>["Biochemistry", "Chemistry", "Infectious Diseases"], "users"=>["Ellen Yeh", "Joseph L. DeRisi"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001138.g004", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Loss_of_localization_of_apicoplast_targeted_proteins_in_antibiotic_treated_rescued_parasites_/411359", "title"=>"Loss of localization of apicoplast-targeted proteins in antibiotic-treated, rescued parasites.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-08-30 00:22:39"}

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Relative Metric

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