A5052527219- Research on Leishmaniasis Studies
- Viral Infections and Immunology Research
- Peptidase Inhibition and Analysis
- Enzyme Production and Characterization
- Trypanosoma species research and implications
- Reproductive tract infections research
- Viral gastroenteritis research and epidemiology
- Redox biology and oxidative stress
- Bacteriophages and microbial interactions
- Toxoplasma gondii Research Studies
- Bacterial Infections and Vaccines
- Protease and Inhibitor Mechanisms
- Biochemical and Molecular Research
- Microbial Natural Products and Biosynthesis
- Plant Virus Research Studies
- Pharmacological Effects of Natural Compounds
- Insect and Pesticide Research
- Signaling Pathways in Disease
- Organoselenium and organotellurium chemistry
- Glutathione Transferases and Polymorphisms
- Toxin Mechanisms and Immunotoxins
- Cytomegalovirus and herpesvirus research
- Health, Education, and Cultural Studies
- Sulfur Compounds in Biology
- Parasitic infections in humans and animals
University of Strathclyde
2011-2024
University of Glasgow
1993-2007
Wellcome Centre for Molecular Parasitology
2006-2007
University of Maryland, College Park
2007
Technical University of Denmark
2007
Newcastle University
2007
University of Reading
1989
Institute of Virology of the Slovak Academy of Sciences
1989
University of Leicester
1984-1986
We describe the genome sequence of protist Trichomonas vaginalis , a sexually transmitted human pathogen. Repeats and transposable elements comprise about two-thirds ∼160-megabase genome, reflecting recent massive expansion genetic material. This expansion, in conjunction with shaping metabolic pathways that likely transpired through lateral gene transfer from bacteria, amplification specific families implicated pathogenesis phagocytosis host proteins may exemplify adaptations parasite...
The poliovirus type 3 Sabin oral vaccine strain P3/Leon/12a1b differs in nucleotide sequence from its neurovirulent progenitor P3/Leon/37 by just 10 point mutations. contribution of each mutation to the attenuation phenotype was determined construction a series recombinant viruses infectious cDNA clones. neurovirulence testing indicated that is two mutations: C U noncoding region at position 472 and 2034 which results serine-to-phenylalanine amino acid substitution structural protein VP3.
Metacaspases are cysteine peptidases that distantly related to the caspases, for which proteolytic processing is central their activation. Here, we show recombinant metacaspase 2 (MCA2) from Trypanosoma brucei has arginine/lysine-specific, Ca(2+)-dependent activity. Autocatalytic of MCA2 occurred after Lys55 and Lys268; however, this was shown not be required enzyme proteolytically active. The necessity Ca(2+), but processing, enzymatic activity clearly distinguishes caspases would...
Summary The growth of the Sabin strain type 3 poliovirus is reduced at high temperatures compared to that its virulent precursor Leon. Recombinant viruses have been generated from infectious cDNA clones and demonstrate temperature-sensitive (ts) phenotype mainly attributable a difference in residue 91 virion protein VP3. Examination non-ts mutants derived vitro or vivo reveals existence second site mutations some which are clearly able suppress ts phenotype. location VP3, number candidate...
The characterization of over 300 mutants, derived from two strains poliovirus type 3 and selected for resistance to neutralization by monoclonal antibodies, has led the further definition major antigenic site involved in neutralization. encompasses amino acids 89 100 VP1. A subsidiary near C-terminus VP1 been identified Sabin vaccine strain 3. Of 59 antibodies examined, 27 had virus-neutralizing activity 25 these were as directed against on (designated 1), indicating immunodominant role this...
Trichomonas is an amitochondriate parasitic protozoon specialized for anaerobic lifestyle. Nevertheless, it exposed to oxygen and able cope with the resultant oxidative stress. In absence of glutathione, cysteine has been thought be major antioxidant. We now report that parasite contains thioredoxin reductase, which functions together peroxidase detoxify potentially damaging oxidants. Thioredoxin reductase also reduce cystine so may play a role in maintaining cellular levels. The importance...
Trichomonas vaginalis is an early divergent eukaryote with many unusual biochemical features. It anaerobic protozoan parasite of humans that thought to rely heavily on cysteine as a major redox buffer, because it lacks glutathione. We report here for synthesis from sulfide, T. relies upon synthase. The enzyme (TvCS1) can use either O-acetylserine or O-phosphoserine substrates. Km values the sulfide are very low (0.02 mm), suggesting may be means ensuring in maintained at level. appears lack...
Genome mining and biochemical analyses have shown that Leishmania major possesses two pathways for cysteine synthesis--the de novo biosynthesis pathway comprising SAT (serine acetyltransferase) CS (cysteine synthase) the RTS (reverse trans-sulfuration) CBS (cystathionine beta-synthase) CGL gamma-lyase). The LmjCS (L. CS) is similar to type A CSs of bacteria catalyses synthesis using O-acetylserine sulfide with Kms 17.5 0.13 mM respectively. can use provided by action MST (mercaptopyruvate...
Comparative genomic analyses of Leishmania species have revealed relatively minor heterogeneity amongst recognised housekeeping genes and yet the cause distinct infections pathogenesis in their mammalian hosts. To gain greater information on biochemical variation between species, insights into possible metabolic mechanisms underpinning visceral cutaneous leishmaniasis, we undertaken this study a comparative analysis metabolomes promastigotes L. donovani, major mexicana. The 64 metabolites...
Cysteine peptidase inhibitor genes ( ICP ) of the chagasin family have been identified in protozoan Leishmania mexicana and Trypanosoma brucei bacterial Pseudomonas aeruginosa pathogens. The encoded proteins low sequence identities with each other no significant identity cystatins or known cysteine inhibitors. Recombinant forms inhibit mammalian clan CA, C1 peptidases but do not CD caspase 3, serine trypsin aspartic pepsin thrombin. functional homology between ICPs implies a common...
Thiol-dependent reductase I (TDR1), an enzyme found in parasitic Leishmania species and Trypanosoma cruzi , is implicated deglutathionylation activation of antimonial prodrugs used to treat leishmaniasis. The 2.3 Å resolution structure TDR1 reveals a unique trimer subunits each containing two glutathione-S-transferase (GST) domains. similarities individual domains comparisons with GST classes suggest that evolved by gene duplication, diversification, fusion; combination events previously...
Toxoplasma gondii can actively invade almost any mammalian cell type including phagocytes. Early events in phagocytic cells such as dendritic are key to establishing parasite infection, but conversely play a pivotal role initiating host immunity. It is now recognised that addition changes canonical immune markers and mediators, alteration metabolism occurs upon activation of cells. These metabolic important for supporting the developing response, affect availability nutrients intracellular...
The tandemly arranged CPB genes ofLeishmania mexicana are polycistronically transcribed and encode cysteine proteases that differentially stage-specific;CPB1 CPB2 expressed predominantly in metacyclics, whereas CPB3–CPB18 mainly amastigotes. mechanisms responsible for this differential expression have been studied via gene analysis re-integration of individual genes, variants thereof, into aCPB-deficient parasite mutant. Comparison the nucleotide sequences repeat units CPB1 CPB2with CPB2.8...
Abstract Cysteine proteases of the papain superfamily are present in nearly all eukaryotes and also play pivotal roles biology parasites. Inhibition cysteine is emerging as an important strategy to combat parasitic diseases such sleeping sickness, Chagas disease, leishmaniasis. Inspired by vivo antiparasitic activity vinylsulfone‐based protease inhibitors, a series α‐ketoheterocycles were developed reversible inhibitors recombinant L. mexicana protease, CPB2.8. Three isoxazoles especially...
Trichomonas vaginalis and Tritrichomonas foetus are pathogens that parasitise, respectively, human bovine urogenital tracts causing disease. Using LC-MS, reference metabolomic profiles were obtained for both species stable isotope labelling with D-[U-13C6] glucose was used to analyse central carbon metabolism. This facilitated a comparison of the metabolic pathways T. foetus, extending earlier targeted biochemical studies. 43 metabolites, whose identities confirmed by their retention times...
Understanding the mechanism(s) underpinning drug resistance could lead to novel treatments reverse increased tolerance of a pathogen. In this study, paromomycin (PMM) (PMMr) was induced in three Nepalese clinical strains Leishmania donovani with different inherent susceptibilities antimony (Sb) drugs by stepwise exposure promastigotes PMM. Exposure PMM resulted production mixed populations parasites, even though single cloned population used at start selection. 50% inhibitory concentration...
We investigated the use of infectious cDNA for production poliovirus type 1-type 3 recombinants. One such recombinant virus was produced, but a second construct involving transfer part capsid protein region not infectious. Our results suggest that approach may prove valuable all constructs will give rise to viable viruses.
Leishmania ISPs are ecotin-like natural peptide inhibitors of trypsin-family serine peptidases, enzymes that absent from the genome. This led to proposal inhibit host peptidases and we have recently shown ISP2 inhibits neutrophil elastase, thereby enhancing parasite survival in murine macrophages. In this study show ISP1 has less peptidase inhibitory activity than ISP2, promastigotes both generally located cytosol along flagellum. However, haptomonad there is a prominent accumulation...
Cysteine biosynthesis is a potential target for drug development against parasitic Leishmania species; these protozoa are responsible range of serious diseases. To improve understanding this aspect biology, crystallographic and biochemical study L. major cysteine synthase has been undertaken, seeking to understand its structure, enzyme activity modes inhibition. Active was purified, assayed crystallized in an orthorhombic form with dimer the asymmetric unit. Diffraction data extending 1.8 Å...