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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.


PPIH-like Cyps. Domain architecture and genomic organization of PPIH-like Cyps. Species are abbreviated as in Fig. 1. Cyp_ABH, ABH-type Cyp domain (CD accession-no.: [cd01926]); NR-rich, Asn-rich domain.
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Figure 7: PPIH-like Cyps. Domain architecture and genomic organization of PPIH-like Cyps. Species are abbreviated as in Fig. 1. Cyp_ABH, ABH-type Cyp domain (CD accession-no.: [cd01926]); NR-rich, Asn-rich domain.

Mentions: The PPIH-like Cyps represent another subfamily containing a Cyp_ABH domain that is predicted to be present in all analyzed apicomplexan genomes (Figures 1 and 7). In addition to their Cyp domain, these putative proteins have a short NH2-terminal extension which does not contain any recognizable motifs or domains. Only in PfCyp24.9 this NH2-terminal region is characterized by its richness in Asn residues. Though none of the putative apicomplexan PPIH-like Cyps contains any obvious subcellular localization signals, it should be mentioned that their human ortholog has been described to be located in the nucleus and to be associated with the splicing machinery [49,50]. Specifically, HsPPIH is able to interact independently with the factors HsPrp3 and HsPrp4 that both integrate into the U4/U6 di-snRNP particle. The binding-site of HsPrp3 and HsPrp4 for HsPPIH is highly homologous, and binding does not need enzymatic activity of PPIH since it is not impaired by the presence of CsA. PPIH-like Cyps are highly conserved between apicomplexa, fungi and mammals suggesting that the apicomplexan orthologs might carry out similar functions as well.


In silico analysis of the cyclophilin repertoire of apicomplexan parasites.

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

PPIH-like Cyps. Domain architecture and genomic organization of PPIH-like Cyps. Species are abbreviated as in Fig. 1. Cyp_ABH, ABH-type Cyp domain (CD accession-no.: [cd01926]); NR-rich, Asn-rich domain.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2713222&req=5

Figure 7: PPIH-like Cyps. Domain architecture and genomic organization of PPIH-like Cyps. Species are abbreviated as in Fig. 1. Cyp_ABH, ABH-type Cyp domain (CD accession-no.: [cd01926]); NR-rich, Asn-rich domain.
Mentions: The PPIH-like Cyps represent another subfamily containing a Cyp_ABH domain that is predicted to be present in all analyzed apicomplexan genomes (Figures 1 and 7). In addition to their Cyp domain, these putative proteins have a short NH2-terminal extension which does not contain any recognizable motifs or domains. Only in PfCyp24.9 this NH2-terminal region is characterized by its richness in Asn residues. Though none of the putative apicomplexan PPIH-like Cyps contains any obvious subcellular localization signals, it should be mentioned that their human ortholog has been described to be located in the nucleus and to be associated with the splicing machinery [49,50]. Specifically, HsPPIH is able to interact independently with the factors HsPrp3 and HsPrp4 that both integrate into the U4/U6 di-snRNP particle. The binding-site of HsPrp3 and HsPrp4 for HsPPIH is highly homologous, and binding does not need enzymatic activity of PPIH since it is not impaired by the presence of CsA. PPIH-like Cyps are highly conserved between apicomplexa, fungi and mammals suggesting that the apicomplexan orthologs might carry out similar functions as well.

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.