The Biological Functions Of

Porphyromonas Gingivalis Founction

Kgp participates in many P. gingivalis-mediated pathogenic processes by binding various targets and importantly, cleaving multiple proteins (Fig. 1).49 Kgp can bind red blood cells and many heme-containing proteins, including hemoglobin and acts as a major hemolytic enzyme to produce and store iron heme, which is a vital growth factor essential for the survival and function of P. gingivalis.50-52 The importance of Kgp in providing iron heme for P. gingivalis has been demonstrated by the...

Conclusion

Over the last 30 years, we have witnessed tremendous advances in our understanding ofthe importance and diverse functionality ofClan CA Family C1 peptidases in the biology and pathogenesis of parasitic kinetoplastids. Fundamental research with Leishmania, specifically the genetic ablation of CP genes, has elucidated the contributions of CPs to cell differentiation, virulence, modulation of the hosts' immune response and not least, the species-specific idiosyncracies that arise. The...

References

An overview of systematics and evolution of ticks. Front Biosci 2. de la Fuente J, Estrada-Pena A, Venzal JM et al. Overview Ticks as vectors of pathogens that cause disease in humans and animals. Front Biosci 2008 13 6938-6946. 3. Grandjean O, Aeschlimann A. Contribution to the study of digestion in ticks histology and fine structure of the midgut ephithelium of Ornithodorus moubata, Murray (Ixodoidea, Argasidae). Acta Trop 1973 30 193-212. 4. Obenchain FD,...

Biochemistry Of Cruzain

Cruzain belongs to the Clan CA, family C1A cysteine peptidases as described by MEROPS, an online curated database of protease information, classification and nomenclature (http merops.sanger.ac.uk ). As a member of the cathepsin L-superfamily, cruzain is described in the literature as cathepsin L-like. However, maybe a more accurate description would be to call cruzain cathepsin F-like, as it has greater sequence identity to (50.5 ) and the least sequence divergence from, the human cathepsin F...

Conor R Caffrey1 Ana Paula Lima2 and Dietmar Steverding3

1Sandler Center for Drug Discovery, California Institute for Quantitative Biosciences, Byers Hall, University of California San Francisco, San Francisco, USA 2Instituto de Biof sica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Bloco G, C.C.S., Cidade Universit ria, Ilha do Fund o, Rio de Janeiro, Brazil 3BioMedical Research Centre, School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, UK *CorrespondingAuthor Conor R. Caffrey Email caffrey...

Evolutionary Relationships Of Trematode Cysteine Proteases

Phylogenetic studies indicate that at the time of helminths emergence 480 to 540 million years ago, several cathepsin classes had evolved 9 two with endopeptidase activity (cathepsin L, F), one with both exo- and endopeptidase activity (cathepsin B) and one with dipeptidylpeptidase activity (cathepsin C).10,12,13 Sequence homologies of trematode cysteine protease mature domains reveal clustering into to three subfamilies cathepsin L-like, cathepsin B-like and cathepsin F-like indicating that...

Colin Stack1 John P Dalton2 and Mark W Robinson3

'School of Biomedical and Health Sciences, University of Western Sydney (UWS), Narellan Road, Campbelltown, NSW, Australia 2Institute of Parasitology, McDonald Campus, McGill University, St. Anne de Bellevue, Quebec, Canada 3i3 Institute (IBID), University of Technology Sydney (UTS), Ultimo, Sydney, Australia *CorrespondingAuthor Mark W. Robinson Email mark.robinson uts.edu.au Abstract Helminth parasites (nematodes, flatworms and cestodes) infect over 1 billion of the world's population causing...

Mohammed Sajid1 Stephanie A Robertson2 Linda S Brinen23 and James H McKerrow2

1Leiden University Medical Center, Afd. Parasitologie, Leiden, The Netherlands 2Sandler Center for Drug Discovery, 3Department of Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, California, USA *Corresponding Author J.H. McKerrow Email jmck cgl.ucsf.edu Abstract Cruzain is the major papain-like cysteine protease of Trypanosoma cruzi, the etiological agent causing Chagas' disease in humans in South America. Cruzain is indispensable for the survival and...

O

Modeller Protein Structure

Legend A adults, E eggs, M miracidia, Sp sporocysts, C cercariae, Sc schistosomula Figure 4. 3D modelling and sequence analysis of Trichobilharzia cathepsins B1 B2. 3D Trichobilharzia regenti CB1.1 protein structure was built using Modeller 9.7 software.78 The model is based on two different template structures human pro-cathepsin B (PDB ID 3pbh)79 and bovine cathepsin B complexed with the inhibitor NS-134 (PDB ID 1sp4).80 The fluorogenic peptide substrate Z-Phe-Arg-AMC was docked at the active...

The Catalytic Mechanism Of

A detailed understanding of the mechanism by which Kgp interacts and cleaves its substrates is critical for the development of Kgp inhibitors. Since members of the gingipain family (C25) share the characteristic catalytic dyad motif, His-Gly-X-Ala-Cys, with all other familial members of the CD clan of cysteine proteases, including family 14 (caspases), family 11 (bacterial clostripains), family 13 (plant and animal legumains) and family 50 (separase), the principal catalytic mechanism is...

Zhicheng Dou and Vern B Carruthers

Department of Microbiology and Immunology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA * Corresponding Author Vern B. Carruthers Email vcarruth umich.edu Abstract Cysteine proteases are important for the growth and survival of apicomplexan parasites that infect humans. The apicomplexan Toxoplasma gondii expresses five members of the C1 family of cysteine proteases, including one cathepsin L-like (TgCPL), one cathepsin B-like (TgCPB) and three cathepsin C-like (TgCPCl, 2...

Daniel Sojka1 Ivo MB Francischetti2 Eric Calvo2 and Michalis Kotsyfakis3

Laboratory of Vector Immunology, Institute of Parasitology, Biology Centre of the Academy of Sciences of the Czech Republic, Ceske Budejovice, Czech Republic 2Laboratory of Malaria and Vector Research, National Institute ofAllergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA 3Laboratory of Genomics and Proteomics of Disease Vectors, Institute of Parasitology, Biology Centre of the Academy of Sciences of the Czech Republic, Czech Republic * Corresponding...

Histolytica Cysteine Proteases

EhCPs are referred to as cathepsin-like enzymes because their structure is similar to cathepsin-L, however their substrate specificity resembles cathepsin-B.25,34 All amoebic CPs possess the structural component (ERFNIN) motif in the pro-sequence.34-36 In addition, some ofthese proteases also possess a hydrophobic sequence near the C-terminus which facilitates binding to the extracellular membrane of the trophozoite.34 The substrate specificity for EhCPs requires two large positively charged...

Cysteine Proteases As Targets For Disease Intervention

EhCPs forms a particularly good target for disease prevention and intervention for a number of reasons. Firstly, they are essential for the parasite life cycle in terms of encystation, excystation and nutrient acquisition, so any disruption in the CPs involved in these processes would affect parasite viability. Furthermore, CPs are one of the key virulence factors involved in intestinal colonization and invasion, disruption ofhost tissue and modulation of cell-mediated immune responses,53,121...

Introduction

Malaria, particularly disease caused by Plasmodium falciparum, is one of the most important infections of humans. There is new optimism regarding malaria control, with increasing use of effective control measures, including insecticide-impregnated bednets, indoor residual spraying ofinsecticides and new efficacious drug combinations to treat and prevent malaria.1 However, the control ofmalaria continues to be challenged by resistance to most available drugs. Thus new antimalarial drugs, ideally...

Potential For Cysteine Protease Inhibitors As Antimalarial Drugs

As cysteine proteases play essential roles in erythrocytic malaria parasites, an obvious consideration is the inhibition ofthese enzymes to treat malaria. A number of older studies have supported this concept, with the demonstration that cysteine protease inhibitors have potent in vitro and in vivo antimalarial effects.6 Specifically, peptidyl fluoromethyl ketone,50,98,99 vinyl sulfone,100-102 and aldehyde103 inhibitors of falcipains blocked the development ofcultured parasites at nanomolar...

Info

Most variation occurs in residues at positions 67 (Leu, Tyr, Trp or Phe) and 205 (Leu, Val or Phe), however, variation can also observed at position 157 which lies at the opening of the S2 pocket.29 Interestingly, all cathepsins with the ability to degrade collagen posses a Tyr residue at position 67. Using site-directed mutagenesis, Lecaille et al substituted Tyr67 in human cathepsin K to Leu67 (creating a similar S2 subsite to that of human cathepsin L) and showed that the resulting...

D

Degradation 18, 40, 50, 55, 58, 62, 69-72, 76, 77, 87, 88, 124, 126, 128-130, 139, 146, 149, 156, 157, 163, 164, 166, 167, 169, 178, 180-183, 187, 188, 193, 197-201, 203, 212, 215, 217 Dense granule (DG) 50, 58 Diagnosis 91, 92 Digestion 50, 64, 74, 77, 129, 130, 137, 140, 143, 148-150, 155-159, 161, 162, 164, 167, 169, 170, 177-181, 185, 186, 213 Discovery 31, 43, 85, 100, 102, 132, 172 Drug 30, 31, 42, 43, 79, 84, 92, 93, 100-102, 104, 105, 110-112, 132, 136, 140, 171, 203, 219 drug target...

About The Editors

ROBINSON is a Chancellor's Postdoctoral Research Fellow at the Infection, Immunity and Innovation (i3) Institute at the University of Technology, Sydney (UTS), Australia. Robinson received a BSc (Hons) in Zoology (1999) and a PhD in molecular parasitology (2003) from Queen's University, Belfast (Northern Ireland). As a postdoctoral researcher, he worked on nematode proteomics and molecular biology at the University of Aberdeen (Scotland) until 2007 when he was awarded a prestigious Wain...

Papainlike Proteases Of Staphylococcus Aureus

Shaw2 and Jan Potempa*1,3 department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Poland 2Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, Florida, USA 3Oral Health and Systemic Disease Research Facility, University of Louisville School of Dentistry, Louisville, Kentucky, USA *Corresponding Author Jan Potempa Email jspote01 louisville.edu Abstract Staphylococcus...

I

With the host immune system.14 Therefore, it is hypothesized that cathepsin B1 could be potentially exploited for serodiagnosis of Trichobilharzia infection in humans with symptoms of cercarial dermatitis.18,24 Cysteine peptidase activity (possibly of cathepsin B1) in cercariae and schistosomula of T. regenti T. szidati was identified, but at present, only T. regenti CB1 (isoforms TrCB1.1 TrCB1.4 see below) has been produced in a recombinant form (differently glycosylated recombinant...

Christian Klotz Thomas Ziegler Emilia Danilowicz Luebert and Susanne Hartmann

Department of Molecular Parasitology, Humboldt University Berlin, Germany Corresponding Author Christian Klotz Email christian.klotz hu-berlin.de Abstract The cystatin superfamily comprises several groups of protease inhibitors. In this chapter we will focus on I25 family members, which consist predominantly of the Type 2 cystatins. Recently, a wealth of information on these molecules and their activities has been described. Parasite cystatins are shown to have dual functions via interaction...

Cooh

Entamoeba histolytica cysteine proteases structure and function - Found on the surface of amoebic trophozoite - On the cell surface as well as internal membranes in the parasite - Membrane-associated Localized to the surface of E. dispar - Located in cytoplasmic granules - Analog of EhCP exists in E. dispar - Punctuate patches on amoeba surface - Also localized to intracellular compartments Very similar to E. histolytica CP2 in structure and size Similar to E. histolytica CPl in...

Fasciola As An Example Of A Large Cysteine Protease Gene Family

The various developmental stages of F. hepatica express and secrete cathepsin L and B proteases, but not cathepsin F. In fact > 80 of proteins secreted by F. hepatica adults are cathepsin L cysteine proteases.11'21 No other class of endoprotease of exoprotease have been identified in fluke secretions, demonstrating an exclusive reliance by adult parasites on cathepsin Ls. The cathepsin L-like protease genes of F. hepatica constitute a large and well-characterised multi-gene family that belong...

Acknowledgements

Z60220518, grant No. IAA600960910, grant No. IAA600960811, and grant No. KJB600960911 from the Grant Agency of the Academy of Sciences of the Czech Republic and the Research Center No. LC06009 from the Ministry of Education, Youth and Sports of the Czech Republic. I.M.B.F., E.C. and M.K. were supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of...

To The Clinic100

Robertson, Linda S. Brinen and James H. McKerrow Current Treatments for Chagas' Biochemistry of Biological Roles of Chemical Inhibition of Cruzain First Studies and Biological The Structural Basis of Cruzain K777 The Path to the 8. THE PHYLOGENY, STRUCTURE AND FUNCTION OF TREMATODE CYSTEINE PROTEASES, WITH PARTICULAR EMPHASIS

P

Parasite 30-38, 40-44, 49-51, 55-59, 62-66, 68, 71, 72, 74, 76-79, 84, 85, 88, 90-94, 100-107, 109-111, 116-121, 123, 124, 127-132, 136, 137, 146, 148, 150, 155-157, 159-162, 166, 167, 169-172, 177, 179, 180, 184, 185, 195, 198, 200, 201, 208, 209, 211, 212, 214-219 Parasitophorous vacuole (PV) 36, 42, 50, 51, 55, 58, 59 Pathogen-associated molecular pattern (PAMP) 196, 197, 199, 217 Pathogenesis 2, 3, 15, 17, 18, 62, 63, 68, 78, 84, 93, 94, 132, 137, 150, 195, 208 pathogenicity factor 208...

Anticipated Developments

Interestingly, the intrinsic immunomodulatory activities of cystatins, in particular those expressed by parasites, might be utilized to modulate unrelated inflammatory immune responses. In this respect, we showed that a cystatin from a parasitic nematode significantly reduced allergic and inflammatory responses in two murine disease models. In a mouse model of allergic airway hyperreactivity, we showed that treatment with filarial cystatin during sensitization with a model allergen, or before...

Cysteine Proteases From Bloodfeeding Arthropod Ectoparasites 187 Conclusion

Cysteine peptidases play an important role in extracellular and intracellular protein degradation and processing in a wide range of organisms from bacteria to mammals. They have been studied in various species including bloodfeeding arthropods (Table 1). In ticks they have been shown to be the key digestive enzymes in the gut epithelium Table 1. Cysteine proteases that have been identified and functionally characterized from bloodfeeding arthropods Haemaphysalis Cathepsin L 29 longicornis...

Atomic Structure And Substrate Specificity

Although eukaryotic cathepsins are diverse at the primary sequence level, their atomic structures are remarkably conserved. We have recently solved the 3-D atomic structure of the F. hepatica FhproCLl zymogen at 1.4 , using an active site mutant FhproCLlGly 25 (PDB ID 206X).29 This structure is almost identical to that of human cathepsin L (PDB ID 1CJL), despite their primary structures exhibiting only 35 identity (and 71 similarity). The mature domain of FhproCL1Gly25 is bi-lobed the left-hand...

Virulence Factors And Immunomodulators

Over a decade of comprehensive gene deletion studies in L. mexicana, targeting CATL-A, CATL-B, CATB or various combinations thereof, has shown that they are not essential but are important as virulence factors that modulate both pathology and the host immune response.33,51,118-121 Deletion of the entire LmeCATL-B array reduced promastigote infectivity to macrophages in vitro, whereas amastigotes infected macrophages with the same kinetics as wild type parasites.51 Significant restoration of...

Contents

PAPAIN-LIKE PROTEASES OF STAPHYLOCOCCUS AUREUS 1 Tomasz Kantyka, Lindsey N. Shaw and Jan Potempa The Pathogenic Potential of S. The Proteolytic Enzymes of S. Genetic Organisation of the Staphylococcal Proteolytic Expression and Activation of S. aureus Extracellular Staphopain Activity and Its Relevance to Staphostatins are Effective Regulators of Staphopain 2. THE LYSINE-SPECIFIC GINGIPAIN OF PORPHYROMONAS GINGIVALIS IMPORTANCE TO PATHOGENICITY

History Of Kinetoplastid Cp Discovery

The early characterizations of peptidolytic activity in kinetoplastids that appeared from the late 1970s though the 1980s all pointed to the presence of significant CP activity as biochemically dissected through the use of synthetic peptidyl substrates, reducing agents (such as dithiothreitol) and protein- and peptidyl-based inhibitors.6-13 Essentially, biochemical activity similar to that of mammalian cathepsin L and localized to the endo-lysosomal system6,14-16 was responsible for the...

H

Sequence-based relationships among T. gondii cathepsins. A) Molecular phylogenetic relationships among cathepsin proteases in apicomplexan parasites. The tree was generated by neighbor-joining analysis using POWER Subgroups are shaded according to their similarity to cathepsins based on homology and the presence of an ERFNIN motif (cathepsin L-like) or occluding loop (cathepsin B-like). The analysis was restricted to apicomplexan parasites with complete or nearly complete genome...

Sheila Donnelly1 John P Dalton2 and Mark W Robinson1

1 i3 Institute (formerly IBID), University of Technology, Sydney, Ultimo, Australia 2Institute of Parasitology, McDonald Campus, McGill University, St. Anne de Bellevue, Quebec, Canada Corresponding Author Sheila Donnelly Email sheila.donnelly uts.edu.au Abstract In mammals, cysteine proteases are essential for the induction and development of both innate and adaptive immune responses. These proteases play a role in antigen-and pathogen-recognition and elimination, signal processing and cell...

R

Regulation 4, 8, 11, 12, 42, 43, 55, 79, 90, 127, 128, 130, 146, 183, 195, 200, 208, 211-216 Rgp 18, 21 Schistosoma japonicum 118, 119, 136, 138-142, 147-149 Schistosoma mansoni 76, 118, 129, 130, 136, 138-141, 147-150, 168, 179, 193, 196, 198, 212, 215 Schistosomula 130, 136, 137, 139, 140, 142-144, 146, 148-150, 215 Secretion 3, 7, 20, 50, 57, 58, 62, 63, 68, 70, 71, 78, 90, 91, 117, 119, 123, 127, 128, 130-132, 139, 161, 162, 164, 170, 178, 182, 185, 186, 196, 201, 209 Secretory IgA 68, 70,...

Variation In The S2 Subsite Of The Active Site And Its Influence On Enzyme Specificity

It is well established that substrate specificity of papain-like cysteine proteases is primarily determined by the composition and arrangement of amino acids that create the S2 subsite within the active site.29-34 The deep S2 subsite is composed of residues occupying positions 67, 68, 133, 157, 160 and 205 (papain numbering) within the active site which interact with the P2 amino acid of the substrate. It is these positions which exhibit most variation among members of the papain superfamily....

Of Malaria Parasites30

Cysteine Protease Functions of Plasmodium Cysteine Proteases Determined from Inhibitor Studies 31 Falcipain Cysteine Other Clan CA Cysteine Proteases of Malaria Potential for Cysteine Protease Inhibitors as Antimalarial 4. CATHEPSIN PROTEASES IN TOXOPLASMA General Roles of Cathepsins in Biological Properties of Toxoplasma gondii and its Phylogenetic Localization, Physiological Functions and Therapeutic Conclusion and Future 5. ENTAMOEBA HISTOLYTICA CATHEPSIN-LIKE ENZYMES

C

Calpain 30, 31, 33, 41, 44, 85 Caspase 21, 22, 31, 42, 75, 76, 108, 177, Catalytic domain 21, 37-39, 42, 53, 55, 57, 64, 85, 102, 104, 105, 123, 124, 142, 170, 183, 186 Catalytic mechanism 22, 23, 25 Cathepsin 1, 2, 6, 12, 49-59, 62-64, 73, 85, 88, 89, 91, 92, 103, 104, 116-131, 136, 139-143, 145-150, 161-167, 169, 171, 178-183, 185-188, 192, 193, 195-198, 201, 202, 211-213, 215-217, 219 Cathepsin B 49-52, 54-56, 85, 88, 89, 103, 117, 118, 120, 127, 128, 139, 140, 142, 145-148, 150, 161-167,...

Conclusion And Future Perspectives

The emerging view of T. gondii cathepsins is that, like their homologs in other eukaryotes, they function in protein degradation along with playing more specialized roles in the maturation of invasion proteins. However, much remains to be done including the identification of their full range of protein substrates within the parasite, their dependency on one another for activation and their participation in similar or distinct processes within the endocytic system and parasitophorous vacuole....

Functions Of Plasmodium Cysteine Proteases Determined From Inhibitor Studies

Studies with protease inhibitors have provided valuable information regarding the functions of cysteine proteases in malaria parasites.6 Most available inhibitors are directed toward clan CA proteases, but do not offer marked specificity within this large clan. Therefore, they have been most useful to identify cysteine protease functions rather than the roles of specific enzymes. The timing of effects of cysteine protease inhibitors provides clues regarding protease functions. In a...

The Role Of Ph In Regulating Cathepsin Function In Trematodes

Once released from the gut, the extracorporeal roles oftrematode proteases are performed at physiological pH, i.e., between two and three pH units higher than the microenvironment in which the proteases function in the parasite gut. The gut lumen of F. hepatica, like that of other trematodes, is believed to be slightly acidic (around pH 5.5) however, the precise pH is unknown.77 Estimates suggest the gut lumen of S. mansoni is in the range pH 5.0-6.078 to 6.84,53 although studies by Delcroix et...

T

Th1 76, 94, 193, 195, 196, 198, 203 Th2 94, 193, 195, 196, 198 Tick 157, 177-182, 187, 188, 209, 212-216, 219 Tissue destruction 65-67 Toll-like receptor (TLR) 195 Trematode 116-119, 121, 124, 126-132, 137, 139, 140, 147, 150, 214, 215 Triatoma infestans 185, 188 Trichobilharzia regenti 136, 137, 139-150 Trichobilharzia szidati 136, 137, 139-144, 146, 148, 150 Trypanosoma 50, 72, 78, 84, 86-88, 100, 185, 193, 195, 214 Trypanosoma cruzi 72, 78, 84-86, 89-92, 100, 101, 103, 105, 107, 109-185,...

Therapeutic Potential

T. gondii cathepsins are considered potential therapeutic targets based on genetic and inhibitor studies. For example, genetic disruption of TgCPL diminishes parasite cell invasion and growth (ref.33 and Dou and Carruthers, unpublished data). Also, parasite treatment with the cathepsin inhibitor morpholinurea-leucyl-homophenyl-vinyl sulfone phenyl (LHVS, also known as K11017) impairs cell invasion by blocking secretion of adhesive proteins from parasite micronemes.31 LHVS principally targets...

The Structural Chemistry Of

The precursor ofKgp is a polyprotein consisting ofdomain components evolutionarily related to those of RgpA and RgpB17,37,49,69 (Table 1). The RgpB polyprotein does not have HA domains70 and is 72 , 99 , 52 and 51 identical in the sequences of the pro-domain, catalytic sub-domain, IgSF sub-domain and C-terminal domain, respectively, to those of the RgpA polyprotein.71 However, Kgpcat only shares 27 sequence identity to RgpAcat and RgpB.72 The C-terminal HA domains of Kgp polyprotein are highly...

Vaccines And Diagnosis

Kinetoplastid CATB and CATL enzymes are potential candidates for vaccine development, either by preventing infection or decreasing pathology.4 Immunization of cattle with recombinant TcoCATL did not prevent infection with T. congolense but the vaccinated cattle maintained or gained weight and had less-pronounced anaemia during the chronic phase of the disease.76 Injection of mice with TcrCATL DNA stimulated cytotoxic T-lymphocytes that recognized and killed T. cruzi-infected cells.77 In other...

Trematode Cysteine Proteases

Trematodes express several types of peptidases that are involved in many aspects of the host-parasite relationship.9 Of particular significance are those belonging to the papain superfamily (clan CA, family C1 CA1 peptidases) referred to as cathepsin L, B, F and C proteases.10-12 Cysteine proteases make up a large proportion of the total transcripts of each of trematode parasites studied to date. For example, nearly 15 of the transcripts derived from adult F. hepatica 10 from adult C....

Adaptive Immune Responses

The immunity and pathology occurring in response to infection with any pathogen is predominantly mediated by T-lymphocytes. In general, control of infection and healing is associated with a polarized Th1 type response whereas the induction of interleukin (IL)-4-dominated Th2 responses are largely suboptimal against a number of pathogens. Induction of Th2 Immune Responses and or Suppression of Th1 Responses In certain protozoan infections, cysteine proteases are critical for the induction of Th2...

The Proteolytic Enzymes Of S Aureus

Amongst the proteins secreted by S. aureus are proteolytic enzymes belonging to three distinct catalytic classes, namely metallo- (aureolysin), serine (V8, Spl proteases, epidermiolytic toxins) and cysteine (staphopain A, StpA and staphopain B, StpB) proteases.20-24 Based on in vitro studies, staphylococcal proteases are considered potentially important virulence factors. They possess the ability to degrade critical components of the host defence system, such as elements of the complement...

Interference With Antigen Processing And Presentation

Many immunological processes rely on extracellular and intracellular activities of proteases and their respective inhibitors. In particular, cysteine proteases are involved in processes such as antigen processing and presentation and regulation of pattern recognition receptor (PRR) signalling.44 These proteases are mainly localized within the endolysosomal compartment and are regulated by a variety of endogenous inhibitors, including cystatins.1,2 Most parasite cystatins are potent inhibitors...

Genomic Organization And Control Of Gene Expression

In trypanosomatids, key differences from other eukaryotes include the organization ofthe genome into polycistronic gene clusters,44-46 a simplified transcriptional machinery and mRNA trans-splicing coupled with polyadenylation.47 In T. cruzi, 12 ofprotein-encoding genes are found in clusters (of more than two genes), 46 of which (3836 genes) contain 20 or more paralogues. For example, many housekeeping genes occur in highly-conserved tandem clusters throughout the genome.45 In Leishmania major,...

Properties Of Toxoplasma Gondii And Its Cathepsins

T. gondii is a ubiquitous apicomplexan parasite that infects a wide range of warm-blooded animals. It is estimated that almost one-third of the human population is infected by this parasite.24 Infection with Toxoplasma can lead to encephalitis, chorioretinitis and congenital birth defects. AIDS and immunocompromised patients are at especially high risk of developing toxoplasmosis. As an obligate intracellular parasite, T. gondii must invade host cells to survive and expand the infection. Unlike...

Saltzer 1999- Reference About Helminthes

Hotez PJ, Molyneux DH, Stillwaggon E et al. Neglected tropical diseases and HIV AIDS. Lancet 2006 2. Robinson M, Dalton JP. Zoonotic helminth infections with particular emphasis on fasciolosis and other trematodes. Philos Trans R Soc B Biol Sci 2009 364 2763-2776. 3. Engels D, Chitsulo L, Montresor A et al. The global epidemiological situation of schistosomiasis and new approaches to control and research. Acta Trop 2002 82 139-146. 4. Gryseels B, Polman K, Clerinx J et al. Human...

Drug Targets

The few drugs that are available to treat kinetoplastid diseases suffer from a variety of problems, including limited efficacy, toxicity, the need for parenteral administration and the establishment of drug resistance.1 New options for safe, effective and orally-administered treatments are urgently needed. Since the first proof-of-principle study in 1993,88 Family C1 peptidases have been validated as drug targets in many parasitic organisms, including kinetoplastids.89-91 At first, the idea...

Staphopain Activity And Its Relevance To Virulence

The elaborate and unusual mechanism of controlling proteolytic activity in S. aureus strongly suggests that extracellular proteases and staphopains in particular, are very important factors for growth and survival. Each step in releasing staphopain activity is strictly regulated, starting at the level of gene transcription, through to preproprotein secretion and folding and finally zymogen activation and control of mature enzyme activity by specific inhibitors. Such complicated mechanisms have...

Biological Roles Of Cruzain

Cruzain is expressed in all life-cycle stages and has been localized to the lysosome, the prelysosomal 'reservasome', the flagellar pocket and to the plasma membrane in both epimastigotes and amastogites.22'30'37-40 In addition to contributing to general protein turnover as well as nutrient processing, cruzain may play a number of additional essential roles. Cruzain's role in invasion was proposed as Fab fragments of antibodies that targeted cruzain markedly reduced the invasion...

Cruzain

In the mid to late 1970s, a number of protease activities, including cysteine protease (CP) activities, were described in crude T. cruzi extracts.7,8 By the 1980s, CPs had been localized to the lysosome and purified to homogeneity from parasite extracts.9-11 The last two decades have seen a progressive increase in the detailed molecular, biochemical, structural and drug-targeting of cruzain as evidenced by the publication output (Fig. 1). The enzyme was originally termed cruzipain as it was the...

The Pathogenic Potential Of S Aureus

Staph Aureus Quorum Sensing

Despite the progress in the disciplines of infectious medicine and pharmacology, S. aureus continues to be a major human pathogen. Infections caused by this micro-organism range from superficial lesions, such as wound infections and abscesses, to life-threatening syndromes, including bacteremia, endocarditis, meningitis and osteomyelitis. The increasing prevalence of antibiotic-resistant strains, especially methicillin resistant S. aureus (MRSA) and the emergence of vancomycin resistant S....

Expression And Activation Of S Aureus Extracellular Proteases

Staphylococcal proteolytic enzymes are expressed as preproproteins, with a large propeptide domain. Firstly, signal sequences target the polypeptide chains for translocation across the cell membrane. Subsequently, in the extracellular environment, the proproteins are folded into enzymatically inert zymogens, most likely in the vicinity of the bacterial cell surface. Figure 4. Diagrammatic representation of the posttranslational steps of activation of extracellular proteases of S. aureus. Broken...

Innate Immune Responses

Substantial evidence supports the view that cysteine proteases secreted by a range of pathogens specifically prevent cells of the innate immune response promoting Th1-adaptive immune responses.10,25-27 The mechanisms are varied and depend on the substrate specificity ofthe protease and ofthe location ofthe pathogen within the host. The innate immune system constitutes the first line ofhost defence during infection and plays a crucial role in the early recognition ofinvading pathogens. Unlike...

Peptidases Of Trichobilharzia

Trichobilharzia Spezies

Although members of the genus Trichobilharzia parasitize bird definitive hosts exclusively, their strategies of exploiting enzymatic equipment are, in general, similar to the well described human schistosomes, such as Schistosoma mansoni, S. japonicum Figure 2. Cercaria A and schistosomulum B of Trichobilharzia regenti. PG postacetabular glands stained by lithium carmine . G gut. Photo B taken by Katerina Blazova, MSc. Figure 2. Cercaria A and schistosomulum B of Trichobilharzia regenti. PG...

Modulation Of Cytokine Responses And Nitric Oxide Production

An intrinsic feature ofendogenous and parasite cystatins is the modification ofthe cytokine and nitric oxide NO production of APCs, such as macrophages.5 Thereby, the presence or absence of pro-inflammatory stimuli such as IFN-y and TNF-a or an anti-inflammatory mediator like IL-10 define the modulatory features of cystatins. Stimulation of IFN-y-primed peritoneal macrophages with chicken cystatin drastically increases NO production by a mechanism that is independent of the protease inhibitory...

The Structural Basis Of Cruzain Inhibition

Cysteinprotease Vinylsulfone

As described above, cruzain is a papain-family cysteine protease that is folded into two domains. One is predominantly alpha-helical and the other consists of extensive antiparallel beta sheet interactions. The active site is found in the cleft at the interface of the two domains and within this cleft is, expectedly, the catalytic triad of residues Cys 25, His159 and Asnra and extended substrate binding sites. Note cruzain numbering adheres to the numbering used in the original cruzain X-ray...

Host Defence And Amoeba Cysteine Proteases

Mucin Release Goblet

Amoebae CPs are critical in invasion due their ability to dismantle both innate and adaptive host defence mechanisms Figs. 2 and 3 . EhCPs cleave a wide range of host molecules that result in de-polymerization of the mucus layer, destruction of the colonic epithelium with its accompanying tight junctions, inactivation of immunoglobulins and either activation or inactivation of components of the complement cascade. The intestinal mucus layer forms the first line of host defence against enteric...