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Query: UNIPROT:P06889 (Mol)
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Attachment of the prenyl groups farnesyl and geranylgeranyl to specific eukaryotic cell proteins by protein prenyltransferases is required for the functioning of a number of cellular processes including signal transduction. In this study it was found that previously reported inhibitors of mammalian protein farnesyltransferase (PFT) [those that mimic the substrate farnesyl pyrophosphate and those that mimic the protein acceptor of the farnesyl group (CaaX mimetic)] inhibit in vitro farnesylation catalyzed by partially purified Trypanosoma brucei (T. brucei) PFT. The most potent PFT inhibitors at concentrations of 3-10 microM inhibit the growth of insect (procyclic) and bloodstream forms of T. brucei. One of the PFT inhibitors was found to block the incorporation of radiolabeled mevalonic acid (the precursor of prenyl groups) into specific T. brucei proteins. This study also shows that protein prenylation occurs in the protozoan parasites Trypanosoma cruzi (T. cruzi) and Leishmania mexicana (L. mexicana). The growth of T. cruzi intracellular form (amastigote) is also sensitive to PFT inhibitors, whereas the insect form (epimastigote) is considerably more resistant to inhibition of protein farnesylation. On the other hand, growth of 3T3 fibroblast cells (host cells for amastigote growth) was not affected by up to 100 microM PFT inhibitors. The growth of L. mexicana insect form (promastigote) is modestly inhibited by protein farnesyltransferase inhibitors. These results suggest the potential for the development of PFT inhibitors for treating trypanosomiasis and leishmaniasis.
Mol Biochem Parasitol 1998 Jul 01
PMID:The effects of protein farnesyltransferase inhibitors on trypanosomatids: inhibition of protein farnesylation and cell growth. 971 12

Dihydrofolate reductase has successfully been used as a drug target in the area of anti-cancer, anti-bacterial and anti-malarial chemotherapy. Little has been done to evaluate it as a drug target for treatment of the trypanosomiases and leishmaniasis. A crystal structure of Leishmania major dihydrofolate reductase has been published. In this paper, we describe the modelling of Trypanosoma cruzi and Trypanosoma brucei dihydrofolate reductases based on this crystal structure. These structures and models have been used in the comparison of protozoan, bacterial and human enzymes in order to highlight the different features that can be used in the design of selective anti-protozoan agents. Comparison has been made between residues present in the active site, the accessibility of these residues, charge distribution in the active site, and the shape and size of the active sites. Whilst there is a high degree of similarity between protozoan, human and bacterial dihydrofolate reductase active sites, there are differences that provide potential for selective drug design. In particular, we have identified a set of residues which may be important for selective drug design and identified a larger binding pocket in the protozoan than the human and bacterial enzymes.
J Comput Aided Mol Des 1998 May
PMID:Dihydrofolate reductase: a potential drug target in trypanosomes and leishmania. 974 68

The effects of the antibacterial protein Drosophila cecropin A on developmental forms of Leishmania were compared with the effect of Hyalophora cecropin A in vitro. Both cecropins had a potent lytic activity on the promastigotes at concentrations not far from those occurring in vivo in the respective insect. Drosophila cecropin A had strong differential effects on the two maturation forms of Leishmania aethiopica at high concentrations: inhibiting intracellular amastigotes and stimulating extracellular promastigotes to take up thymidine. Hyalophora cecropin A also inhibited amastigotes by up to 50% at concentrations of 0.250 mg/ml, and inhibited promastigotes at high concentrations but had no enhancing effects at any of the concentrations tested. In contrast to the results with Leishmania, Drosophila cecropin A had no discernible effect on any developmental stage of P. falciparium and showed no lytic effects on haemocytes. The two enantiomers of a synthetic amphipathic peptide, D- and L-KALA, were also tested. D- and L-KALA had some in vitro antimalarial effects at 0.025 and 0.05 mg/ml respectively but both forms were haemolytic at 0.1 mg/ml. Potential uses of naturally occurring proteins and their derivatives in the control of insect born infections and topical use of cecropins against leishmaniasis are discussed.
Int J Mol Med 1998 Jan
PMID:Drosophila antibacterial protein, cecropin A, differentially affects non-bacterial organisms such as Leishmania in a manner different from other amphipathic peptides. 985 2

Diospyrin is a plant product that has significant inhibitory effect on the growth of Leishmania donovani promastigotes. This compound inhibits the catalytic activity of DNA topoisomerase I of the parasite. Like camptothecin, it induces topoisomerase I mediated DNA cleavage in vitro. Treatment of DNA with diospyrin before addition of topoisomerase I has no effect. Preincubation of topoisomerase I with diospyrin before the addition of DNA in the relaxation reaction increases this inhibition. Our results suggest that this bis-naphthoquinone compound exerts its inhibitory effect by binding with the enzyme and stabilizing the topoisomerase I-DNA "cleavable complex." Diospyrin is a specific inhibitor of the parasitic topoisomerase I. It does not inhibit type II topoisomerase of L. donovani and requires much higher concentrations to inhibit type I topoisomerase of calf thymus. The potent inhibitory effect of diospyrin on type I DNA topoisomerase from L. donovani can be exploited for rational drug design in human leishmaniasis.
Mol Pharmacol 1998 Dec
PMID:Diospyrin, a bisnaphthoquinone: a novel inhibitor of type I DNA topoisomerase of Leishmania donovani. 985 27

Glycosylated phosphatidylinositols (GPIs) are abundant cell surface molecules of the Leishmania. Amastigote-specific GPIs AmGPI-Y and AmGPI-Z, both ethanolamine (EtN)-containing glycolipids, were identified in Leishmania amazonensis. A paucity of GPI-anchored proteins in amastigotes of L. amazonensis made the kinetoplastid suitable for evaluating the importance of free (i.e. unconjugated to protein or polysaccharide) GPIs. A strain deficient in both AmGPI-Y and AmGPI-Z was produced by stable transfection of wild-type Leishmania with a GPI-phospholipase C gene. Phosphatidylinositol deficiency was not detected in the transfectants. GPI-deficient promastigotes infected murine macrophages in vitro and differentiated into amastigotes whose growth was arrested within the host cells. Cytostasis of amastigotes was also observed during axenic culture of GPI-deficient parasites. In a hamster model of leishmaniasis, GPI-deficient promastigotes produced smaller lesions with 20-fold fewer amastigotes than infections with control parasites. Together, these observations indicate that EtN-GPIs may be essential for amastigote viability, replication, and/or virulence. Implicit in these observations is the notion that drugs targeted against the GPI biosynthetic pathway might be of value in the management of human leishmaniasis.
Mol Biochem Parasitol 1999 Mar 15
PMID:Roles of free GPIs in amastigotes of Leishmania. 1021 28

We report here the molecular cloning and characterization of two related hydrophilic antigens of Leishmania chagasi. These two antigens have predicted molecular weights of approximately 9 and 26 kDa and detect antibodies in sera of patients with kala-azar (k). Thus, to maintain consistency with nomenclature of the previously described 39 kDa diagnostic antigen of L. chagasi (k39 [1]), these antigens are being referred to as k9 and k26. A significant difference between k9 and k26 is the presence of 11 copies of a 14 amino acid repeat in the open reading frame of k26. The region flanking the repeats of k26 shares a 69% identity with the open reading frame of k9. The recombinant proteins encoded by both antigens are very hydrophilic and show aberrant migration on SDS PAGE. Results of Southern blot analysis reveal that k9 and k26 are conserved to varying degrees among various Leishmania species. Interestingly, the repeat region of k26 is specific to L. chagasi and L. donovani while the flanking region is conserved among several other species. Transcript levels of k26 are significantly upregulated in the amastigote stage of the parasite. Our results show that recombinant K26 is specific in detecting antibodies in infection sera from visceral leishmaniasis (VL) patients. Thus rK26 may complement rK39 in a more accurate diagnosis of VL in the old and the new world.
Mol Biochem Parasitol 1999 Aug 20
PMID:Cloning, characterization and serological evaluation of K9 and K26: two related hydrophilic antigens of Leishmania chagasi. 1049 81

Leishmania species of the subgenus Viannia are responsible for a large proportion of New World leishmaniasis. Here we report the development of a set of microsatellite markers which are able to discriminate between all species within the subgenus Viannia, including the closely related species pairs: Leishmania (V.) braziliensis and Leishmania (V.) peruviana; Leishmania (V.) panamensis and Leishmania (V.) guyanensis. Potential species hybrids were uncovered in the analysis. These markers are sufficiently polymorphic such that within-species epidemiological, population and genetic studies are theoretically possible for all species analyzed.
Mol Biochem Parasitol 1999 Sep 20
PMID:Intra and inter-specific microsatellite variation in the Leishmania subgenus Viannia. 1051 82

Trivalent antimony (SB3+) in the form of potassium antimony tartrate was found to be an inhibitor of glutathione-S-transferases (GST) from human erythrocytes with a 50% inhibition concentration (IC50) of 0.05 mM. The inhibition was, however, incomplete with 15-20% of the GST activity remaining unaffected. In comparison, ethacrynic acid, a known inhibitor of GST, was tenfold more potent and affected close to 100% inhibition. Pentavalent antimony (SB5+) in the form of sodium stibogluconate had no effect on GST. Group V metalloids such as arsenite was slightly inhibitory, and arsenate was noninhibitory. When compared with five heavy metals, the inhibitory potency followed the order of SB3+ > Hg2+, Cu2+ > Cd 2+ > Cr3+ > Fe2+ x SB3+ inhibition of GST was competitive against the substrate 1-chloro-2,4-dinitrobenzene (CDNB) with an apparent Ki of 0.018 mM. Increasing the glutathione (GSH) concentration, however, produced a biphasic response: at concentrations below 1 mM, GSH was noncompetitive against SB3+, but at 1 mM and higher it was apparently competitive. A concurrent study of interactions between GSH, CDNB, and SB3+ showed that there was a significant nonenzymatic conjugation of CDNB at high GSH concentrations, which was suppressed by SB3+. The presence of albumin (500 mg/dL), or up to 5 mM N-acetylcysteine, cysteine, or ethylenediamine tetraacetic acid (EDTA) did not protect GST from the inhibitory effect of SB3+. The ability of erythrocyte GST to conjugate CDNB, which was measured directly by the formation of dinitrophenyl-glutathione (DNP-glutathione), was reduced by approximately 20 and 33%, respectively, in the presence of 2 and 10 mM SB3+, and nearly abolished with the addition of 0.2 mM ethacrynic acid. Based on these inhibition characteristics and the preferential accumulation of SB3+ in mammalian erythrocytes, it may be deduced that in the case of high antimonial intake, for example, during therapeutic treatment of Leishmaniasis, SB3+ levels in erythrocytes may be high enough to depress GST activity, which might compromise the ability of erythrocytes to detoxify electrophilic xenotbiotics.
J Biochem Mol Toxicol 2000
PMID:Effects of trivalent antimony on human erythrocyte glutathione-S-transferases. 1071 33

Maxadilan is a small ( approximately 7 kDa) protein found in the saliva of sand fly species in the Lutzomyia longipalpis complex, vectors of the parasite causing visceral leishmaniasis, Leishmania chagasi. It is a potent vasodilator and also has immunomodulatory affects. Maxadilan recovered from different sibling species of the Lu. longipalpis complex differ in amino acid content by as much as 23%, however all variants possess equivalent vasodilatory activity. Therefore, the dramatic differences in vasodilatory activity of the saliva from different sibling species is probably due to differences in the amounts of maxadilan in their saliva. This is significant because it has been suggested that maxadilan may influence the pathogenesis of leishmanial infections. In this study we measured the amount of maxadilan messenger RNA (mRNA) per pair of salivary glands from individual sand flies by quantitative reverse transcription polymerase chain reaction (RT-PCR) using a competitive method. We report a method using the gene of interest, in this case maxadilan, amplified by the PCR from genomic DNA, as a competitor in the quantitative RT-PCR, taking advantage of differences in the size of these products due to the presence of an intron. Significant differences in amounts of maxadilan mRNA among colonies from Central and South America are described. We found a strong correlation between the amount of maxadilan mRNA detected in salivary glands of different Lu. longipalpis sibling species and previously described differences in the size of erythemas produced by the bite of these species. Therefore, variation in the amount of mRNA suggests that differences in the vasodilatory properties of saliva among the different sibling species are the result of differences in the amount of maxadilan present in the saliva and not differences in the potency of maxadilan peptide variants. The geographical distribution of species with high or low levels of maxadilan gene expression are concordant with the distribution of atypical cutaneous leishmaniasis resulting from infection with Le. chagasi, lending credence to earlier suggestions that maxadilan may be involved with visceralization of this parasite.
Insect Mol Biol 2000 Jun
PMID:Sibling species in the Llutzomyia longipalpis complex differ in levels of mRNA expression for the salivary peptide, maxadilan. 1088 15

Trypanosomatids, unicellular organisms responsible for several global diseases, contain unique organelles called glycosomes in which the first seven glycolytic enzymes are sequestered. We report the crystal structures of glycosomal fructose-1,6-bisphosphate aldolase from two major tropical pathogens, Trypanosoma brucei and Leishmania mexicana, the causative agents of African sleeping sickness and one form of leishmaniasis, respectively. Unlike mammalian aldolases, the T. brucei and L. mexicana aldolases contain nonameric N-terminal type 2 peroxisomal targeting signals (PTS2s) to direct their import into the glycosome. In both tetrameric trypanosomatid aldolases, the PTS2s from two different subunits form two closely intertwined structures. These "PTS2 dimers", which have very similar conformations in the two aldolase structures, are the first reported conformations of a glycosomal or peroxisomal PTS2, and provide opportunities for the design of trypanocidal compounds.
J Mol Biol 2000 Jul 21
PMID:Structures of type 2 peroxisomal targeting signals in two trypanosomatid aldolases. 1089 Dec 64


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