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In silico analysis of the cyclophilin repertoire of apicomplexan parasites.

Krücken J, Greif G, von Samson-Himmelstjerna G - Parasit Vectors (2009)

Bottom Line: In addition, cyclosporine is known to exhibit anti-parasitic effects on a wide range of organisms including several apicomplexa.In order to obtain new non-immunosuppressive drugs targeting apicomplexan cyclophilins, a profound knowledge of the cyclophilin repertoire of this phylum would be necessary.The genomes of apicomplexa harbor a cyclophilin repertoire that is at least as complex as that of most fungi.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute for Parasitology, University of Veterinary Medicine Foundation, Bünteweg 17, 30559 Hannover, Germany. juergen.kruecken@tiho-hannover.de.

ABSTRACT

Background: Cyclophilins (Cyps) are peptidyl cis/trans isomerases implicated in diverse processes such as protein folding, signal transduction, and RNA processing. They are also candidate drug targets, in particular for the immunosuppressant cyclosporine A. In addition, cyclosporine is known to exhibit anti-parasitic effects on a wide range of organisms including several apicomplexa. In order to obtain new non-immunosuppressive drugs targeting apicomplexan cyclophilins, a profound knowledge of the cyclophilin repertoire of this phylum would be necessary.

Results: BLAST and maximum likelihood analyses identified 16 different cyclophilin subfamilies within the genomes of Cryptosporidium hominis, Toxoplasma gondii, Plasmodium falciparum, Theileria annulata, Theileria parva, and Babesia bovis. In addition to good statistical support from the phylogenetic analysis, these subfamilies are also confirmed by comparison of cyclophilin domain architecture. Within an individual genome, the number of different Cyp genes that could be deduced varies between 7-9 for Cryptosporidia and 14 for T. gondii. Many of the putative apicomplexan cyclophilins are predicted to be nuclear proteins, most of them presumably involved in RNA processing.

Conclusion: The genomes of apicomplexa harbor a cyclophilin repertoire that is at least as complex as that of most fungi. The identification of Cyp subfamilies that are specific for lower eukaryotes, apicomplexa, or even the genus Plasmodium is of particular interest since these subfamilies are not present in host cells and might therefore represent attractive drug targets.

No MeSH data available.


Phylogram showing evolutionary relationships for Cyp and FKBP domains of FCBPs and CFBPs. Cyp domains (A) and FKBP domains (B) of FCBPs and CFBPs were aligned with related domains identified by BLAST analyses in archaebacteria, eubacteria and eukaryotes. Unrooted maximum likelihood phylograms were calculated using PhyML [34]. Statistical support for branches is given as approximate likelihood ratio at the nodes. Only likelihoods of at least 70% are presented. FCBPs of apicomplexa, ciliophora, oomyceta, chlorophyta, and archaebacteria are highlighted in red, orange, yellow, green, and purple, respectively. CFBP of spirochaetes and flavo-/proteobacteria are marked in different blue tones. Species abbreviations: Ta, Theileria annulata; Tp, Theileria parva; Tg, Toxoplasma gondii; Bb, Babesia bovis; Gj, Griffithsia japonica; Pt, Paramecium tetraurelia; Tt, Tetrahymena thermophila; Cw, Crocosphaera watsonii; Pca, Phytophora capsici; Mm, Mus musculus; Eh, Entamoeba histolytica; Ot, Ostreococcus tauri; Tc, Trypanosoma cruzi; Ss, Synechocystis spec.; Cl, Codonopsis lanceolata; Cb, Caenorhabditis briggsae; Bm, Blastupirellula marina; Sa, Stigmatella aurantiaca; Ar, uncultured archaeon GZfos18C8; Cbe, Clostridium beijerincki; Mb, Methanococcoides burtonii; Gf, Gramella forsetii; Ca, Croceibacter atlanticus; Fb, Flavobacteriales bacterium; Fba, Flavobacteria bacterium; Cs, Celluphaga spec. MED134; Lb, Leeuwenhoekiella blandensis; Dp, Desulfotalea psychrophilia; Td, Treponema denticulata; Bh, Borrelia hermsii; Hm, Haloarcula marismortui; Haloquadrantum walsbyi; Mg, Magnaporthe grisea; Pn, Phaeosphaeria nodorum; Aa, Aedes aegyptii; Lm, Leishmania major; Tn, Tetraodon nigroviridis; Py, Plasmodium yoelii; Pc, Plasmodium chabaudi; Pb, Plasmodium berghei; Pf, Plasmodium falciparum; Ec, Entodinium caudatum; Te, Trichodesmium erythraeum; No, Nitrosococcus oceani; Ps, Polaromonas spec. Js666; Yl, Yarrowia lipolytica; Gs, Geobacter spec. FRC-32; Mba, Methanosarcina barkeri; Mbu, Methanococcoides burtonii; Mt, Methanotherococcus thermolithotrophicus; Ma, Methanosarcina acetivorans; Mma, Methanoculleus marisnigri; Cf, Chlorobium ferrooxidans.
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Figure 9: Phylogram showing evolutionary relationships for Cyp and FKBP domains of FCBPs and CFBPs. Cyp domains (A) and FKBP domains (B) of FCBPs and CFBPs were aligned with related domains identified by BLAST analyses in archaebacteria, eubacteria and eukaryotes. Unrooted maximum likelihood phylograms were calculated using PhyML [34]. Statistical support for branches is given as approximate likelihood ratio at the nodes. Only likelihoods of at least 70% are presented. FCBPs of apicomplexa, ciliophora, oomyceta, chlorophyta, and archaebacteria are highlighted in red, orange, yellow, green, and purple, respectively. CFBP of spirochaetes and flavo-/proteobacteria are marked in different blue tones. Species abbreviations: Ta, Theileria annulata; Tp, Theileria parva; Tg, Toxoplasma gondii; Bb, Babesia bovis; Gj, Griffithsia japonica; Pt, Paramecium tetraurelia; Tt, Tetrahymena thermophila; Cw, Crocosphaera watsonii; Pca, Phytophora capsici; Mm, Mus musculus; Eh, Entamoeba histolytica; Ot, Ostreococcus tauri; Tc, Trypanosoma cruzi; Ss, Synechocystis spec.; Cl, Codonopsis lanceolata; Cb, Caenorhabditis briggsae; Bm, Blastupirellula marina; Sa, Stigmatella aurantiaca; Ar, uncultured archaeon GZfos18C8; Cbe, Clostridium beijerincki; Mb, Methanococcoides burtonii; Gf, Gramella forsetii; Ca, Croceibacter atlanticus; Fb, Flavobacteriales bacterium; Fba, Flavobacteria bacterium; Cs, Celluphaga spec. MED134; Lb, Leeuwenhoekiella blandensis; Dp, Desulfotalea psychrophilia; Td, Treponema denticulata; Bh, Borrelia hermsii; Hm, Haloarcula marismortui; Haloquadrantum walsbyi; Mg, Magnaporthe grisea; Pn, Phaeosphaeria nodorum; Aa, Aedes aegyptii; Lm, Leishmania major; Tn, Tetraodon nigroviridis; Py, Plasmodium yoelii; Pc, Plasmodium chabaudi; Pb, Plasmodium berghei; Pf, Plasmodium falciparum; Ec, Entodinium caudatum; Te, Trichodesmium erythraeum; No, Nitrosococcus oceani; Ps, Polaromonas spec. Js666; Yl, Yarrowia lipolytica; Gs, Geobacter spec. FRC-32; Mba, Methanosarcina barkeri; Mbu, Methanococcoides burtonii; Mt, Methanotherococcus thermolithotrophicus; Ma, Methanosarcina acetivorans; Mma, Methanoculleus marisnigri; Cf, Chlorobium ferrooxidans.

Mentions: The discontinuous distribution pattern of FCBPs and CFBPs in phylogenetically unrelated clades raises the question whether these proteins evolved multiple times independently. Alternatively, a common evolutionary origin of proteins with this domain architecture might be assumed followed by either loss from most genomes or horizontal gene transfer. In order to address this question, BLAST analyses were used to identify those Cyps and FKBPs in archaebacteria, eubacteria, and eukaryotes that show the highest similarity to the diverse FCBPs and CFBPs. All proteins used for these analyses are listed in Tables S2 and S3 in Additional file 4. Then, maximum likelihood analyses were performed independently on ClustalW2-built alignments of Cyp and FKBP domains. Results of these phylogenetic analyses are presented in Figure 9. The cyclophilin domains of all eukaryotic FCBPs are closely related (i.e. most of them are recognized as Cyp_ABH domain by CD-BLAST) and therefore form a highly significant cluster in Figure 9A (group in the dendrogram with blue background). However, they are clearly not monophyletic as there are several non-FCBP Cyps within this group and FCBP proteins have apparently evolved at least three times independently – i.e. in chlorophyta, oomycetes and alveolata. For OtCPR7 this conclusion is further supported by the fact that this FCBP does not contain any TRP repeats. Cyp domains of the putative archaebacterial FCBPs are not even closely related to this group and form a completely independent cluster. The Cyp domains of proteo-/flavobacterial CFBP proteins are monophyletic – in contrast to those of spirochaetes. However, for the latter group there are currently only members known from Treponema denticula and four Borrelia species. It is for instance possible that one of these two proteins is highly divergent from the average spirochaete CFBP due to secondary evolutionary changes. In particular, the presence of a lipoprotein anchor at the NH2-terminus of BhCFBP38 suggests an extracellular localization of the mature protein and therefore a significantly altered function.


In silico analysis of the cyclophilin repertoire of apicomplexan parasites.

Krücken J, Greif G, von Samson-Himmelstjerna G - Parasit Vectors (2009)

Phylogram showing evolutionary relationships for Cyp and FKBP domains of FCBPs and CFBPs. Cyp domains (A) and FKBP domains (B) of FCBPs and CFBPs were aligned with related domains identified by BLAST analyses in archaebacteria, eubacteria and eukaryotes. Unrooted maximum likelihood phylograms were calculated using PhyML [34]. Statistical support for branches is given as approximate likelihood ratio at the nodes. Only likelihoods of at least 70% are presented. FCBPs of apicomplexa, ciliophora, oomyceta, chlorophyta, and archaebacteria are highlighted in red, orange, yellow, green, and purple, respectively. CFBP of spirochaetes and flavo-/proteobacteria are marked in different blue tones. Species abbreviations: Ta, Theileria annulata; Tp, Theileria parva; Tg, Toxoplasma gondii; Bb, Babesia bovis; Gj, Griffithsia japonica; Pt, Paramecium tetraurelia; Tt, Tetrahymena thermophila; Cw, Crocosphaera watsonii; Pca, Phytophora capsici; Mm, Mus musculus; Eh, Entamoeba histolytica; Ot, Ostreococcus tauri; Tc, Trypanosoma cruzi; Ss, Synechocystis spec.; Cl, Codonopsis lanceolata; Cb, Caenorhabditis briggsae; Bm, Blastupirellula marina; Sa, Stigmatella aurantiaca; Ar, uncultured archaeon GZfos18C8; Cbe, Clostridium beijerincki; Mb, Methanococcoides burtonii; Gf, Gramella forsetii; Ca, Croceibacter atlanticus; Fb, Flavobacteriales bacterium; Fba, Flavobacteria bacterium; Cs, Celluphaga spec. MED134; Lb, Leeuwenhoekiella blandensis; Dp, Desulfotalea psychrophilia; Td, Treponema denticulata; Bh, Borrelia hermsii; Hm, Haloarcula marismortui; Haloquadrantum walsbyi; Mg, Magnaporthe grisea; Pn, Phaeosphaeria nodorum; Aa, Aedes aegyptii; Lm, Leishmania major; Tn, Tetraodon nigroviridis; Py, Plasmodium yoelii; Pc, Plasmodium chabaudi; Pb, Plasmodium berghei; Pf, Plasmodium falciparum; Ec, Entodinium caudatum; Te, Trichodesmium erythraeum; No, Nitrosococcus oceani; Ps, Polaromonas spec. Js666; Yl, Yarrowia lipolytica; Gs, Geobacter spec. FRC-32; Mba, Methanosarcina barkeri; Mbu, Methanococcoides burtonii; Mt, Methanotherococcus thermolithotrophicus; Ma, Methanosarcina acetivorans; Mma, Methanoculleus marisnigri; Cf, Chlorobium ferrooxidans.
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Figure 9: Phylogram showing evolutionary relationships for Cyp and FKBP domains of FCBPs and CFBPs. Cyp domains (A) and FKBP domains (B) of FCBPs and CFBPs were aligned with related domains identified by BLAST analyses in archaebacteria, eubacteria and eukaryotes. Unrooted maximum likelihood phylograms were calculated using PhyML [34]. Statistical support for branches is given as approximate likelihood ratio at the nodes. Only likelihoods of at least 70% are presented. FCBPs of apicomplexa, ciliophora, oomyceta, chlorophyta, and archaebacteria are highlighted in red, orange, yellow, green, and purple, respectively. CFBP of spirochaetes and flavo-/proteobacteria are marked in different blue tones. Species abbreviations: Ta, Theileria annulata; Tp, Theileria parva; Tg, Toxoplasma gondii; Bb, Babesia bovis; Gj, Griffithsia japonica; Pt, Paramecium tetraurelia; Tt, Tetrahymena thermophila; Cw, Crocosphaera watsonii; Pca, Phytophora capsici; Mm, Mus musculus; Eh, Entamoeba histolytica; Ot, Ostreococcus tauri; Tc, Trypanosoma cruzi; Ss, Synechocystis spec.; Cl, Codonopsis lanceolata; Cb, Caenorhabditis briggsae; Bm, Blastupirellula marina; Sa, Stigmatella aurantiaca; Ar, uncultured archaeon GZfos18C8; Cbe, Clostridium beijerincki; Mb, Methanococcoides burtonii; Gf, Gramella forsetii; Ca, Croceibacter atlanticus; Fb, Flavobacteriales bacterium; Fba, Flavobacteria bacterium; Cs, Celluphaga spec. MED134; Lb, Leeuwenhoekiella blandensis; Dp, Desulfotalea psychrophilia; Td, Treponema denticulata; Bh, Borrelia hermsii; Hm, Haloarcula marismortui; Haloquadrantum walsbyi; Mg, Magnaporthe grisea; Pn, Phaeosphaeria nodorum; Aa, Aedes aegyptii; Lm, Leishmania major; Tn, Tetraodon nigroviridis; Py, Plasmodium yoelii; Pc, Plasmodium chabaudi; Pb, Plasmodium berghei; Pf, Plasmodium falciparum; Ec, Entodinium caudatum; Te, Trichodesmium erythraeum; No, Nitrosococcus oceani; Ps, Polaromonas spec. Js666; Yl, Yarrowia lipolytica; Gs, Geobacter spec. FRC-32; Mba, Methanosarcina barkeri; Mbu, Methanococcoides burtonii; Mt, Methanotherococcus thermolithotrophicus; Ma, Methanosarcina acetivorans; Mma, Methanoculleus marisnigri; Cf, Chlorobium ferrooxidans.
Mentions: The discontinuous distribution pattern of FCBPs and CFBPs in phylogenetically unrelated clades raises the question whether these proteins evolved multiple times independently. Alternatively, a common evolutionary origin of proteins with this domain architecture might be assumed followed by either loss from most genomes or horizontal gene transfer. In order to address this question, BLAST analyses were used to identify those Cyps and FKBPs in archaebacteria, eubacteria, and eukaryotes that show the highest similarity to the diverse FCBPs and CFBPs. All proteins used for these analyses are listed in Tables S2 and S3 in Additional file 4. Then, maximum likelihood analyses were performed independently on ClustalW2-built alignments of Cyp and FKBP domains. Results of these phylogenetic analyses are presented in Figure 9. The cyclophilin domains of all eukaryotic FCBPs are closely related (i.e. most of them are recognized as Cyp_ABH domain by CD-BLAST) and therefore form a highly significant cluster in Figure 9A (group in the dendrogram with blue background). However, they are clearly not monophyletic as there are several non-FCBP Cyps within this group and FCBP proteins have apparently evolved at least three times independently – i.e. in chlorophyta, oomycetes and alveolata. For OtCPR7 this conclusion is further supported by the fact that this FCBP does not contain any TRP repeats. Cyp domains of the putative archaebacterial FCBPs are not even closely related to this group and form a completely independent cluster. The Cyp domains of proteo-/flavobacterial CFBP proteins are monophyletic – in contrast to those of spirochaetes. However, for the latter group there are currently only members known from Treponema denticula and four Borrelia species. It is for instance possible that one of these two proteins is highly divergent from the average spirochaete CFBP due to secondary evolutionary changes. In particular, the presence of a lipoprotein anchor at the NH2-terminus of BhCFBP38 suggests an extracellular localization of the mature protein and therefore a significantly altered function.

Bottom Line: In addition, cyclosporine is known to exhibit anti-parasitic effects on a wide range of organisms including several apicomplexa.In order to obtain new non-immunosuppressive drugs targeting apicomplexan cyclophilins, a profound knowledge of the cyclophilin repertoire of this phylum would be necessary.The genomes of apicomplexa harbor a cyclophilin repertoire that is at least as complex as that of most fungi.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute for Parasitology, University of Veterinary Medicine Foundation, Bünteweg 17, 30559 Hannover, Germany. juergen.kruecken@tiho-hannover.de.

ABSTRACT

Background: Cyclophilins (Cyps) are peptidyl cis/trans isomerases implicated in diverse processes such as protein folding, signal transduction, and RNA processing. They are also candidate drug targets, in particular for the immunosuppressant cyclosporine A. In addition, cyclosporine is known to exhibit anti-parasitic effects on a wide range of organisms including several apicomplexa. In order to obtain new non-immunosuppressive drugs targeting apicomplexan cyclophilins, a profound knowledge of the cyclophilin repertoire of this phylum would be necessary.

Results: BLAST and maximum likelihood analyses identified 16 different cyclophilin subfamilies within the genomes of Cryptosporidium hominis, Toxoplasma gondii, Plasmodium falciparum, Theileria annulata, Theileria parva, and Babesia bovis. In addition to good statistical support from the phylogenetic analysis, these subfamilies are also confirmed by comparison of cyclophilin domain architecture. Within an individual genome, the number of different Cyp genes that could be deduced varies between 7-9 for Cryptosporidia and 14 for T. gondii. Many of the putative apicomplexan cyclophilins are predicted to be nuclear proteins, most of them presumably involved in RNA processing.

Conclusion: The genomes of apicomplexa harbor a cyclophilin repertoire that is at least as complex as that of most fungi. The identification of Cyp subfamilies that are specific for lower eukaryotes, apicomplexa, or even the genus Plasmodium is of particular interest since these subfamilies are not present in host cells and might therefore represent attractive drug targets.

No MeSH data available.