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

Bell, A., Monaghan, P. and Page, A. (2006) Peptidyl-prolyl cis-trans isomerases (immunophilins) and their roles in parasite biochemistry, host-parasite interaction and antiparasitic drug action. International Journal for Parasitology, 36(3), pp. 261-276. (doi:10.1016/j.ijpara.2005.11.003)

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Abstract

Immunophilin is the collective name given to the cyclophilin and FK506-binding protein families. As the name suggests, these include the major binding proteins of certain immunosuppressive drugs: cyclophilins for the cyclic peptide cyclosporin A and FK506-binding proteins 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 multi-protein 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. Recent years have seen a great increase in the number of known immunophilin genes in parasitic protozoa and helminths and in many cases their products have been characterised biochemically and their temporal and spatial expression patterns have been examined. Some of these genes represent novel types: one example is a Toxoplasma gondii gene encoding a protein with both cyclophilin and FK506-binding protein domains. Likely roles in protein folding and oligomerisation, RNA splicing and sexual differentiation have been suggested for parasite immunophilins. In addition, unexpected roles in parasite virulence (Mip FK506-binding protein of Trypanosoma cruzi) and host immuno-modulation (e.g. 18-kDa cyclophilin of T. gondii) have been established. Furthermore, in view of the potent antiparasitic activities of cyclosporins, macrolactones and non-immunosuppressive derivatives of these compounds, immunophilins may mediate drug action and/or may themselves represent potential drug targets. Investigation of the mechanisms of action of these agents may lead to the design of potent and selective antimalarial and other antiparasitic drugs. This review discusses the properties of immunophilins in parasites and the ‘animal model’ Caenorhabditis elegans and relates these to our understanding of the roles of these proteins in cellular biochemistry, host–parasite interaction and the antiparasitic mechanisms of the drugs that bind to them.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Page, Professor Tony
Authors: Bell, A., Monaghan, P., and Page, A.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:International Journal for Parasitology
Publisher:Elsevier
ISSN:0020-7519
ISSN (Online):1879-0135
Published Online:07 December 2005

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
229993The Molecular Enzymology of Collagen Assembly and Post-Translational Modification: a Nematode Model SystemAntony PageMedical Research Council (MRC)G117/476Infection Immunity and Inflammation Life Sciences