Peptidyl-prolyl cis–trans isomerases (immunophilins) and their roles in parasite biochemistry, host–parasite interaction and antiparasitic drug action

Abstract

Immunophilin is the collective name given to the cyclophilin and FK506-binding protein (FKBP) families. As the name suggests, these include the major binding proteins of certain immunosuppressive drugs: cyclophilins for the cyclic peptide cyclosporin A and FKBPs for the macrolactones FK506 and rapamycin. Both families, although dissimilar in sequence, possess peptidyl-prolyl cis-trans isomerase activity in vitro and can play roles in protein folding and transport, RNA splicing and the regulation of multiprotein complexes in cells. In addition to enzymic activity, many immunophilins act as molecular chaperones. This property may be conferred by the isomerase domain and/or by additional domains.

Overexpression, purification and assessment of cyclosporin binding of a family of cyclophilins and cyclophilin-like proteins of the human malarial parasite Plasmodium falciparum

“…PfCYP19A (one of three P. falciparum 19-kDa cyclophilins) [19]. After an exhaustive online search in the latest version of two main gene sequence databases PlasmoDB [28] and the National Center for Biotechnology Information [29], 12 nucleotide sequences were found to be annotated as or to have sequence similarity to cyclophilins ( Fig.…”

“…Only two gene products had been previously characterized biochemically: PfCYP19B [20] and PfCYP19A [21]. In addition, overexpression of the gene of PlasmoDB ID PF08_0121 (named PfCYP25 here, PfCYP24 previously [19]) in E. coli had been described but its product was not purified [30]. The accession numbers of the genes are listed in Table 2.…”

“…CsA exerts its action as part of a complex with its receptor, a member of the family of proteins called cyclophilins [16,17]. The mechanism(s) of antimalarial action of CsA and other cyclosporins is/are unknown but two major cyclosporin receptors have been identified, namely the parasite cyclophilins PfCYP19A and PfCYP19B [18,19]. The precise role of these two proteins in the antimalarial action of these compounds is not yet clear [19].…”

“…Regardless of their origin, the structural conservation of cyclophilins throughout evolution and the presence of peptidyl-prolyl cis-trans isomerase (PPIase) activity in most members, and molecular-chaperone activity in some, underline their importance and suggest that cyclophilins may play an important role in malarial parasite development [17,19]. So far, two recombinant P. falciparum cyclophilins PfCYP19B and PfCYP19A [20,21] (see [19] for nomenclature) have been successfully purified and biochemically characterised.…”

“…So far, two recombinant P. falciparum cyclophilins PfCYP19B and PfCYP19A [20,21] (see [19] for nomenclature) have been successfully purified and biochemically characterised.…”