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Parasite Aspartic Proteinases
The Aspartic Proteinases are a family of enzymes found in plants, fungi, vertebrates, invertebrates, viruses and recently, in bacteria.
To learn more about the structure and function of a typical aspartic proteinase, Pepsin, or the HIV proteinase, click below for Dr Berry's interactive tutorials.
>>> Aspartic Proteinase Tutorials
- Many parasites which cause serious human or livestock diseases produce aspartic proteinases which perform critical functions for parasite viability. This makes them excellent targets for the design of novel anti-parasitic drugs.
- The aspartic proteinases are particularly suitable for this since selective inhibition of several members of this class of enzyme has already been achieved, eg. HIV proteinase, Candida proteinase.
- Selectivity is clearly essential to drug development to allow potent inhibition of the target enzyme without effect on the human aspartic proteinases pepsin, gastricsin, renin, cathepsin D and cathepsin E or the recently discovered Napsins and BACE enzymes.
Malaria
The malaria parasite Plasmodium falciparum may produce up to nine aspartic proteinases (the plasmepsins) and a closely related protein -HAP.
Three of these enzymes (plasmepsins I, II and IV) are located in the parasite food vacuole and are involved in digestion of host red cell haemoglobin by the parasite. HAP is also found in this organelle but its function is presently unknown.
Inhibition of the plasmepsins can lead to parasite death.
Dr Berry's group has cloned and expressed plasmepsins I, II and IV in recombinant form and:
- has completed a full kinetic characterisation of these enzymes with a series of synthetic substrates.
- has characterised their interactions with a number of inhibitors.
- has identified a selective compound which shows significant inhibition of plasmepsin I.
- has been involved in studies to elucidate the crystal structures of the plasmepsins.
The results of these studies will facilitate the design of new inhibitory compounds as potential anti-malarial drugs.
Other Parasites
Dr Berry's group also studies the aspartic proteinases from a variety of other parasites including:
- Eimeria species which cause millions of pounds of damage in the poultry industry as causative agents of coccidiosis.
- Hookworms including Necator americanus, a serious parasite of the human gut.
- Ascaris suum and Ascaris lumbricoides.
- Various filiarial nematode parasites such as Onchocerca volvulus, (which causes African River Blindness), Brugia malayi (elephantiasis) and Dirofilaria immitis (dog heart worm).
- Leishmania parasites, which cause Leishmaniasis and the closely-related Trypanosomes, appear to encode no pepsin-like monomeric aspartic proteinases in their genomes. In common with all eukaryotes, these parasites do encode a retro-viral proteinase-like sequence related to the yeast Ddi1 protein. Studies in our laboratory on the yeast and Leishmania major proteins have identified important regions of the proteins and indicate that the Leishmania protein may be a target for the action of HIV proteinase inhibitors that are known to have activity against these parasites.
Peptide Inhibitors of Aspartic Proteinases
Protein inhibitors of aspartic proteinases are rare in nature and Dr Berry's group is involved in studies of these proteins.
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