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1.  α-Ketoheterocycles as inhibitors of Leishmania mexicana cysteine protease CPB 
ChemMedChem  2010;5(10):1734-1748.
Cysteine proteases of the papain superfamily are present in nearly all eukaryotes and also play pivotal roles in the biology of parasites. Inhibition of cysteine proteases is emerging as an important strategy to combat parasitic diseases such as sleeping sickness, Chagas’ disease and leishmaniasis. Inspired by the in vivo antiparasitic activity of the vinyl sulfone based cysteine protease inhibitors (CPIs), a series of α-ketoheterocycles 1-15 has been developed as reversible inhibitors of a recombinant L. mexicana cysteine protease CPB2.8. The isoxazoles 1-3 and especially the oxadiazole 15 are potent reversible inhibitors of CPB2.8, however, in vitro whole-organism screening against a panel of protozoan parasites did not fully correlate with the observed inhibition of the cysteine protease.
doi:10.1002/cmdc.201000265
PMCID: PMC3245848  PMID: 20799311
cysteine proteases; inhibitors; ketoheterocycle; parasite CPB; Trypanosoma
2.  Cysteine biosynthesis in Trichomonas vaginalis involves cysteine synthase utilizing O-phosphoserine 
The Journal of biological chemistry  2006;281(35):25062-25075.
Trichomonas vaginalis is an early divergent eukaryote with many unusual biochemical features. It is an anaerobic protozoan parasite of humans that is thought to rely heavily on cysteine as a major redox buffer, as it lacks glutathione. We report here that for synthesis of cysteine from sulphide, T. vaginalis relies upon cysteine synthase. The enzyme (TvCS1) can use as substrates either O-acetylserine or O-phosphoserine. The Kms of the enzyme for sulphide is very low (0.02 mM), suggesting that the enzyme may be a means of ensuring that sulphide in the parasite is maintained at a low level. T. vaginalis appears to lack serine acetyltransferase, the source of O-acetylserine in many cells, but has a functional 3-phosphoglycerate dehydrogenase and an O-phosphoserine aminotransferase that together result in the production of O-phosphoserine, suggesting that this is the physiological substrate. TvCS1 can also use thiosulphate as substrate. Overall, TvCS1 has substrate specificities similar to those reported for cysteine synthases of Aeropyrum pernix and Escherichia coli and this is reflected by sequence similarities around the active site. We suggest that these enzymes are classified together as type B cysteine synthases and we hypothesise that the use of O-phosphoserine is a common characteristic of these cysteine synthases. The level of cysteine synthase in T. vaginalis is regulated according to need, such that parasites growing in an environment rich in cysteine have low activity, whereas exposure to propargylglycine results in elevated cysteine synthase activity. Humans lack cysteine synthase, thus this parasite enzyme could be an exploitable drug target.
doi:10.1074/jbc.M600688200
PMCID: PMC2645516  PMID: 16735516
Trichomonas; parasite; antioxidant; cysteine synthase; desulphurase
4.  THE STRUCTURE OF LEISHMANIA MEXICANA ICP PROVIDES EVIDENCE FOR CONVERGENT EVOLUTION OF CYSTEINE PEPTIDASE INHIBITORS* 
The Journal of biological chemistry  2005;281(9):5821-5828.
Clan CA, family C1 cysteine peptidases (CPs) are important virulence factors and drug targets in parasites that cause neglected diseases. Natural CP inhibitors of the I42 family, known as ICP, occur in some protozoa and bacterial pathogens, but are absent from metazoa. They are active against both parasite and mammalian CPs, despite having no sequence similarity with other classes of CP inhibitor. Recent data suggest that L. mexicana ICP plays an important role in host-parasite interactions. We have now solved the structure of ICP from L. mexicanaby NMR and shown that it adopts a type of immunoglobulin-like fold not previously reported in lower eukaryotes or bacteria. The structure places three loops containing highly conserved residues at one end of the molecule, one loop being highly mobile. Interaction studies with CPs confirm the importance of these loops for the interaction between ICP and CPs and suggest the mechanism of inhibition. Structure-guided mutagenesis of ICP has revealed that residues in the mobile loop are critical for CP inhibition. Data-driven docking models support the importance of the loops in the ICP-CP interaction. This study provides structural evidence for the convergent evolution from an immunoglobulin fold of CP inhibitors with a cystatin-like mechanism.
doi:10.1074/jbc.M510868200
PMCID: PMC1473161  PMID: 16407198
5.  Draft Genome Sequence of the Sexually Transmitted Pathogen Trichomonas vaginalis 
Science (New York, N.Y.)  2007;315(5809):207-212.
We describe the genome sequence of the protist Trichomonas vaginalis, a sexually transmitted human pathogen. Repeats and transposable elements comprise about two-thirds of the ~160-megabase genome, reflecting a recent massive expansion of genetic material. This expansion, in conjunction with the shaping of metabolic pathways that likely transpired through lateral gene transfer from bacteria, and amplification of specific gene families implicated in pathogenesis and phagocytosis of host proteins may exemplify adaptations of the parasite during its transition to a urogenital environment. The genome sequence predicts previously unknown functions for the hydrogenosome, which support a common evolutionary origin of this unusual organelle with mitochondria.
doi:10.1126/science.1132894
PMCID: PMC2080659  PMID: 17218520

Results 1-5 (5)