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Query: UNIPROT:P06889 (Mol)
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A 33-kDa protein of Trypanosoma congolense is a major antigen in infected cattle and the production of antibody to this antigen appeared to correlate with enhanced resistance to trypanosomiasis [4]. Immunoelectron microscopy using a monoclonal antibody (mAb 4C5) raised against the 33-kDa antigen showed a lysosomal localisation, similar to that of a previously described 32-kDa cysteine protease of T. congolense. Both mAb 4C5 and anti-33 kDa antibody from infected cattle bound on Western blots to the cysteine protease that had been purified by affinity chromatography on cystatin-Sepharose. Sepharose-coupled mAb 4C5 was used to affinity purify the antigen from bloodstream forms of T. congolense. On sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), the affinity-purified antigen had a molecular mass of 33 kDa under non-reducing conditions, and 40 kDa under reducing conditions. Anti-33-kDa antibody from infected cattle bound to both non-reduced and reduced affinity-purified antigen on Western blots. Serum from a rabbit immunised with the biochemically purified enzyme also bound the affinity-purified antigen. The affinity-purified antigen displayed proteolytic activity in fibrinogen-containing SDS-PAGE and against Azocoll. It hydrolysed benzyloxycarbonyl-Phe-Arg-7-amino-methyl coumarin (Z-Phe-Arg-NHMec) with a Km similar to that of the biochemically purified enzyme. Proteolytic and peptidolytic activities of the antigen were inhibited by the inhibitors of cysteine proteases, cystatin and trans-epoxysuccinyl-L-leucyl-amido (4-guanidino)butane (E-64). On two-dimensional gel electrophoresis, the antigen displayed similar characteristics to those of the biochemically purified enzyme. We conclude that the 33-kDa antigen of T. congolense and the cysteine protease are the same molecule.
Mol Biochem Parasitol 1992 Nov
PMID:Identification of a 33-kilodalton immunodominant antigen of Trypanosoma congolense as a cysteine protease. 147 89

Trypanosoma brucei brucei contained a S-adenosyl-L-methionine decarboxylase (AdoMetDC) strongly activated by putrescine. The enzyme was also activated to a lesser extent by cadaverine and 1,3-diaminopropane. Spermidine and spermine had no effect on basal activity of the enzyme. However, they interfered with putrescine activation of trypanosomal AdoMetDC. The trypanosomal enzyme could not be precipitated with antiserum against human AdoMetDC. The trypanosomal AdoMetDC enzyme subunit was labeled by reaction with 35S-decarboxylated AdoMet in the presence of NaCNBH4, and found to have a molecular weight of 34 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The subunit was readily degraded on storage to a form with a molecular weight of 26 kDa. The specificity of labeling of AdoMetDC by this procedure was confirmed by the prevention of 35S-decarboxylated S-adenosylmethionine (AdoMet) binding in the presence of specific AdoMetDC inhibitors [either methylglyoxal bis(guanylhydrazone (MGBG), a reversible inhibitor, or 5'-deoxy-5'-[(2-hydrazinoethyl)methylamino]adenosine (MHZEA), an irreversible inactivator]. As compared to human AdoMetDC, the trypanosomal enzyme showed weaker binding to a column of MGBG-Sepharose and also was significantly less sensitive to inhibition by MGBG and its congener ethylglyoxal bis(guanylhydrazone) (EGBG). Thus, the trypanosomal AdoMetDC differs significantly from its mammalian and bacterial counterparts and may therefore be exploited as a specific target for chemotherapy of trypanosomiasis.
Mol Cell Biochem 1992 Nov 04
PMID:Putrescine activated S-adenosylmethionine decarboxylase from Trypanosoma brucei brucei. 148 Jan 64

Suramin is a polyanionic compound which has been used in the treatment of trypanosomiasis and acquired immunodeficiency syndrome (AIDS), while preliminary success has been reported in the treatment of cancer. However, suramin also causes adrenal insufficiency. We have previously reported that suramin selectively inhibited corticotropin (ACTH)-stimulated corticosterone release by dispersed adrenal cells in a dose-dependent manner via a direct interaction with the ACTH molecule. The present study was undertaken in order to investigate the effect of suramin on hormone release by dispersed rat anterior pituitary cells. Suramin at a concentration of 100 microM inhibited both basal and secretagogue-stimulated ACTH release by cells cultured in minimal essential medium (MEM) only, while it had no effect on ACTH release by cells cultured in MEM + 10% fetal calf serum (FCS) or MEM + 0.1% bovine serum albumin (BSA). In addition, suramin also caused a parallel decrease of prolactin (PRL) and growth hormone (GH) release by cells cultured in MEM only, suggesting a toxic, rather than a selective effect of suramin on anterior pituitary cells cultured in MEM only. In addition, suramin potentiated the effect of thyrotropin-releasing hormone (TRH) on PRL release by cells cultured in MEM + 10% FCS and suppressed the inhibitory effect of dopamine (DA) on PRL release by cells cultured in MEM + 10% FCS and in MEM + 0.1% BSA. Comparable suppressive effects of suramin on growth hormone-releasing hormone (GHRH)-stimulated and somatostatin (SRIH)-inhibited GH release were found in cells cultured in MEM + 0.1% BSA but not in cells cultured in MEM + 10% FCS.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1990 Aug 20
PMID:Effects of suramin on hormone release by cultured rat anterior pituitary cells. 198 Aug 98

We have examined the reversibility of the biochemical and pathological changes induced in the spleen, kidney and lung of the suramin-treated rat which we have previously proposed as a useful model of the human condition, mucopolysaccharidosis (MPS). Rats were injected with a single intravenous dose of suramin (250 mg/kg) and allowed to survive for periods of up to 6 months. The organs were examined for suramin content, pathological changes, biochemical storage of glycosaminoglycans (GAGs) and for the blockage of the relevant hydrolytic enzymes. The extent and rate of suramin accumulation and the retention of the drug varied considerably between organs with the greatest concentration of suramin (4,000 micrograms/g) occurring in the kidney 2 weeks after injection. Suramin persisted at gradually decreasing levels in all organs for the duration of the experiment, remaining at the highest level (1,150 micrograms/g) in the kidney. The concentration of GAGs peaked 10-18 days after administration of the drug, in all organs. Within 6 months the level had returned to normal in the liver, spleen and lung, but remained elevated in the kidney. The activities of beta-glucuronidase and acid phosphatase were decreased in all organs at diminishing levels throughout the experiment. There was a significant increase in the activity of arylsulphatase B, except in the kidney, where the predominant effect was a reduction of activity. Recovery from the morphological changes was evident in all organs except the lung within 6 months of suramin administration. The reversibility of the biochemical and pathological changes in the various tissues is discussed and compared with the earlier results described for the liver (Rees et al. 1986) and the implications of using suramin for the treatment of human trypanosomiasis, onchocerciasis and AIDS are considered.
Virchows Arch B Cell Pathol Incl Mol Pathol 1986
PMID:The suramin-treated rat as a model of mucopolysaccharidosis. Variation in the reversibility of biochemical and morphological changes among different organs. 287 81

Spermidine synthase from Trypanosoma brucei brucei was characterized and found to be similar to spermidine synthase from other sources. The Km for putrescine was found to be 0.2 mM and the Km for decarboxylated S-adenosylmethionine 0.1 microM. The approximate molecular weight of the enzyme was 74 000 as determined by a combination of molecular sieve chromatography and sucrose density gradient centrifugation. Spermidine synthase activity was markedly inhibited in vitro by dicyclohexylamine (50% inhibition at 3 microM) and cyclohexylamine (50% inhibition at 15 microM); both being competitive inhibitors with respect to putrescine. S-Adenosyl-1,8-diamino-3-thiooctane, a nucleoside bisubstrate analog, was also a potent inhibitor of enzyme activity (50% inhibition at 25 microM). Administration of dicyclohexylamine to mice with trypanosomiasis resulted in no increase in survival time probably due to the lack of effect on trypanosome spermidine concentrations. Other possible inhibitors remain to be tested in vivo.
Mol Biochem Parasitol 1984 Sep
PMID:Characterization of spermidine synthase from Trypanosoma brucei brucei. 651 85

The field vole, Microtus montanus, was used as a model system to evaluate the chronic effects of infection by Trypanosoma brucei gambiense on hepatic mixed-function oxidase activity. At day 28 post inoculation there was a 97% increase in liver wet weight per g body weight. A portion of the increase (21%) was accounted for by tissue edema which occurred after day 14 of infection. Total hepatic cytochrome P-450 content and related total tissue mixed-function oxidase activities were decreased to about 60% of control levels at day 28 post inoculation. The decrease in total tissue mixed-function oxidase activity was partly due to a small decrease in microsomal protein per cell, and partly to a large decrease in cytochrome P-450 concentration in the endoplasmic reticulum. Although the decrease in total liver monooxygenase activity in several substrates roughly paralleled the loss in cytochrome P-450 content, several other microsomal enzyme markers not related to cytochrome P-450 monooxygenation were elevated in proportion to total liver microsomal protein content. The results suggest that in M. montanus during trypanosomiasis, there is proliferation of hepatic cells with normal content of endoplasmic reticulum. Furthermore, there appears to be selective toxicity for hepatic cytochrome P-450 and related monooxygenase activities. This may compromise the animals' ability to metabolize and dispose of other drugs to which the animal may be exposed in the course of infection.
Mol Biochem Parasitol 1982 Jul
PMID:Hepatic microsomal alterations during chronic trypanosomiasis in the field vole, Microtus montanus. 705 Jul 1

Three days after mice were inoculated with Trypanosoma brucei gambiense, total hepatic cytochrome P-450 levels were decreased 14% from control values, while the specific mixed-function oxidase activity (per nmole of cytochrome P-450) was inhibited almost 40% in infected animals. Furthermore, drugs used to treat trypanosomiasis (Suramin and Melarsoprol B) are themselves potent in vitro inhibitors of hepatic mixed-function oxidase activity. These two trypanocides also produced a decrease in mixed-function oxidations and an increase in pentobarbital sleeping time when administered intraperitoneally in vivo. These results demonstrate that mice with trypanosomiasis or undergoing trypanosome chemotherapy have a significantly impaired capacity to metabolize foreign compounds.
Mol Biochem Parasitol 1981 Aug
PMID:Hepatic mixed-function oxidase activity in mice infected with Trypanosoma brucei gambiense or treated with trypanocides. 727 80

The effects of juvenile hormone-III (JH-III) and the juvenile hormone analogues (JHA) methoprene and fenoxycarb on the growth and macromolecular biosynthesis in Trypanosoma cruzi were studied in vitro. It was observed that JH-III and JHA blocked growth and 3H-thymidine incorporation without killing the cells within certain concentrations (< or = 1 x 10(-4) M), but they caused cellular death at concentrations over 1 x 10(-3) M. The inhibitory effect on growth was partially reversible. On the other hand, the inhibitory action of JH-III, methoprene and fenoxycarb was an unspecific effect according to the results obtained with Leishmania mexicana mexicana (promastigotes) and human peripheral blood lymphocytes. The JHA have a good possibility of being used in the control of trypanosomiasis.
J Steroid Biochem Mol Biol 1996 Dec
PMID:Activity of juvenile hormone and juvenile hormone analogues on the growth of Trypanosoma cruzi. 901 Mar 55

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

Eukaryotes modify numerous proteins, including small GTPases of the ras superfamily, with isoprenes as a mechanism for membrane attachment. Inhibition of farnesylation of ras has been successfully exploited to control cell growth, with promise in the clinic for treatment of human tumours. Using an in vitro screen of mammalian farnesyltransferase inhibitors, we have identified manumycin A as potently active against growth of both bloodstream and procyclic forms of Trypanosoma brucei. Other structural classes of farnesyltransferase inhibitors were far less effective. Exposure of T. brucei for brief periods to lethal concentrations of manumycin A resulted in subsequent cell death whilst the concentration required to achieve killing was dependent on serum concentration, suggesting partitioning of manumycin A into hydrophobic cellular sites. Manumycin A did not affect trypanosomal protein and DNA synthesis or cell cycle progression but altered incorporation of prenyl groups into several polypeptides indicating a specific effect on the prenylation without effect on other mevalonate pathway products, most importantly prenyl pyrophosphate levels. Morphological analysis indicated that manumycin A caused significant mitochondrial damage suggesting an additional site of action. Structural analogues of manumycin A containing a quinone were also highly trypanocidal and altered mitochondrial morphology, suggesting interference with electron/proton transport systems. Furthermore, manumycin A also elicited mitochondrial alterations in mammalian cells indicating that the effect is not confined to lower eukaryotes. Manumycin A is well tolerated in vivo but failed to cure experimental trypanosomiasis in mice.
Mol Biochem Parasitol 1999 Oct 25
PMID:The farnesyltransferase inhibitor manumycin A is a novel trypanocide with a complex mode of action including major effects on mitochondria. 1058 82


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