Polyamine biosynthetic enzymes as drug targets in parasitic protozoa

2003 ◽  
Vol 31 (2) ◽  
pp. 415-419 ◽  
Author(s):  
O. Heby ◽  
S.C. Roberts ◽  
B. Ullman
Keyword(s):  
Chagas Disease ◽  
Ornithine Decarboxylase ◽  
Infected Patient ◽  
Drug Targets ◽  
Genetic Characterization ◽  
Biosynthetic Enzymes ◽  
Spermidine Synthase ◽  
Growth And Survival ◽  
Adenosylmethionine Decarboxylase

Molecular, biochemical and genetic characterization of ornithine decarboxylase, S-adenosylmethionine decarboxylase and spermidine synthase establishes that these polyamine-biosynthetic enzymes are essential for growth and survival of the agents that cause African sleeping sickness, Chagas' disease, leishmaniasis and malaria. These enzymes exhibit features that differ significantly between the parasites and the human host. Therefore it is conceivable that exploitation of such differences can lead to the design of new inhibitors that will selectively kill the parasites while exerting minimal, or at least tolerable, effects on the parasite-infected patient.

scholarly journals Response of enzymes involved in the metabolism of polyamines to phytohaemagglutinin-induced activation of human lymphocytes

1981 ◽  
Vol 196 (3) ◽  
pp. 733-738 ◽  
Author(s):  
H Korpela ◽  
E Hölttä ◽  
T Hovi ◽  
J Jänne
Keyword(s):  
Ornithine Decarboxylase ◽  
Human Lymphocytes ◽  
Lymphocyte Activation ◽  
Decarboxylase Activity ◽  
Spermidine Synthase ◽  
Irreversible Inhibitor ◽  
Adenosylmethionine Decarboxylase ◽  
Spermine Synthase ◽  
Diamine Oxidase Activity ◽  
Stimulation Of

The stimulation of lymphocyte ornithine decarboxylase and adenosylmethionine decarboxylase produced by phytohaemagglutinin was accompanied by an equally marked, but delayed, stimulation of spermidine synthase, which is not commonly considered as an inducible enzyme. In contrast with the marked stimulation of these biosynthetic enzymes, less marked changes were observed in the biodegradative enzymes of polyamines in response to phytohaemagglutinin. Diamine oxidase activity was undetectable during all stages of the transformation. The activity of polyamine oxidase remained either constant or was slightly decreased several days after addition of the mitogen. The activity of polyamine acetylase (employing all the natural polyamines as substrates) distinctly increased both in the cytosolic and crude nuclear preparations of the cells during later stages of mitogen activation. Difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase, although powerfully inhibiting ornithine decarboxylase, produced a gradual enhancement of adenosylmethionine decarboxylase activity during lymphocyte activation, without influencing the activities of the two propylamine transferases (spermidine synthase and spermine synthase).

scholarly journals Characterization of Trypanosoma cruzi Sirtuins as Possible Drug Targets for Chagas Disease

2015 ◽  
Vol 59 (8) ◽  
pp. 4669-4679 ◽  
Author(s):  
Nilmar Silvio Moretti ◽  
Leonardo da Silva Augusto ◽  
Tatiana Mordente Clemente ◽  
Raysa Paes Pinto Antunes ◽  
Nobuko Yoshida ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Drug Targets ◽  
Wild Type ◽  
Content Type ◽  
Damage Repair ◽  
Lysine Deacetylases

ABSTRACTAcetylation of lysine is a major posttranslational modification of proteins and is catalyzed by lysine acetyltransferases, while lysine deacetylases remove acetyl groups. Among the deacetylases, the sirtuins are NAD+-dependent enzymes, which modulate gene silencing, DNA damage repair, and several metabolic processes. As sirtuin-specific inhibitors have been proposed as drugs for inhibiting the proliferation of tumor cells, in this study, we investigated the role of these inhibitors in the growth and differentiation ofTrypanosoma cruzi, the agent of Chagas disease. We found that the use of salermide during parasite infection prevented growth and initial multiplication after mammalian cell invasion byT. cruziat concentrations that did not affect host cell viability. In addition,in vivoinfection was partially controlled upon administration of salermide. There are two sirtuins inT. cruzi, TcSir2rp1 and TcSir2rp3. By using specific antibodies and cell lines overexpressing the tagged versions of these enzymes, we found that TcSir2rp1 is localized in the cytosol and TcSir2rp3 in the mitochondrion. TcSir2rp1 overexpression acts to impair parasite growth and differentiation, whereas the wild-type version of TcSir2rp3 and not an enzyme mutated in the active site improves both. The effects observed with TcSir2rp3 were fully reverted by adding salermide, which inhibited TcSir2rp3 expressed inEscherichia coliwith a 50% inhibitory concentration (IC50) ± standard error of 1 ± 0.5 μM. We concluded that sirtuin inhibitors targeting TcSir2rp3 could be used in Chagas disease chemotherapy.

scholarly journals Biochemical and genetic characterization of Trypanosoma cruzi N-myristoyltransferase

2014 ◽  
Vol 459 (2) ◽  
pp. 323-332 ◽  
Author(s):  
Adam J. Roberts ◽  
Leah S. Torrie ◽  
Susan Wyllie ◽  
Alan H. Fairlamb
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Genetic Characterization ◽  
Kinetic Properties

The present study shows that N-myristoyltransferase is essential for growth of Trypanosoma cruzi, the parasite responsible for Chagas’ disease. The kinetic properties of the enzyme are described along with evidence that growth is specifically inhibited by blocking N-myristoylation in the parasite.

scholarly journals Genetic Characterization of Trypanosoma cruzi Directly from Tissues of Patients with Chronic Chagas Disease

2000 ◽  
Vol 156 (5) ◽  
pp. 1805-1809 ◽  
Author(s):  
Annamaria R. Vago ◽  
Luciana O. Andrade ◽  
Adriana A. Leite ◽  
Débora d'Ávila Reis ◽  
Andrea M. Macedo ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Genetic Characterization ◽  
Chronic Chagas Disease

scholarly journals Characterization of a transgenic mouse line over-expressing the human ornithine decarboxylase gene

1991 ◽  
Vol 278 (3) ◽  
pp. 895-898 ◽  
Author(s):  
M Halmekytö ◽  
L Alhonen ◽  
J Wahlfors ◽  
R Sinervirta ◽  
T Eloranta ◽  
...  
Keyword(s):  
Transgenic Mouse ◽  
Ornithine Decarboxylase ◽  
Transgenic Animals ◽  
Metabolizing Enzymes ◽  
Transgenic Mouse Line ◽  
Adenosylmethionine Decarboxylase ◽  
Transgenic Lines ◽  
Polymerase Chain

We have produced several transgenic mouse lines over-expressing the human ornithine decarboxylase (ODC) gene. We have now characterized one of the transgenic lines as regards the tissue accumulation of the polyamines and the activities of their metabolizing enzymes. Among the tissues analysed, the polyamine pattern was most strikingly changed in testis and brain of the transgenic animals. ODC activity was greatly enhanced in all tissues, except kidney, of the transgenic animals. The most dramatic increase, 80-fold, was found in brain of the transgenic mice. The activities of S-adenosylmethionine decarboxylase and spermidine and spermine syntheses were likewise significantly increased in testis of the transgenic animals. The activities of the enzymes involved in the back-conversion of the polyamines, namely spermidine/spermine acetyltransferase and polyamine oxidase, were similar in the transgenic and non-transgenic animals. As analysed by reverse transcriptase/polymerase chain reaction, all the six tissues of the transgenic animals expressed human-specific ODC mRNA. Determination of the half-life of testicular ODC revealed a stabilization of the enzyme in the transgenic males.

scholarly journals Transgenic mice overexpressing ornithine and S-adenosylmethionine decarboxylases maintain a physiological polyamine homoeostasis in their tissues

1997 ◽  
Vol 323 (2) ◽  
pp. 457-462 ◽  
Author(s):  
Ritva HELJASVAARA ◽  
Ildiko VERESS ◽  
Maria HALMEKYTÖ ◽  
Leena ALHONEN ◽  
Juhani JÄNNE ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Ornithine Decarboxylase ◽  
Metabolic Flux ◽  
Pulse Labelling ◽  
Spermidine Synthase ◽  
Tissue Concentrations ◽  
Adenosylmethionine Decarboxylase ◽  
Normal Limits ◽  
Primary Fibroblasts ◽  
Hybrid Mice

Recent work has shown that transgenic mice overexpressing human ornithine decarboxylase display no marked changes in the tissue concentrations of spermidine or spermine in spite of a dramatic increase in putrescine levels. In the tissues of transgenic mice carrying the human spermidine synthase gene and in those of hybrid mice overexpressing both ornithine decarboxylase and spermidine synthase, spermidine and spermine levels remain within normal limits. To test whether the amount of the propylamine group donor, decarboxylated S-adenosylmethionine, limits the conversion of putrescine into the higher polyamines, we have produced transgenic mouse lines harbouring the rat S-adenosylmethionine decarboxylase gene in their genome. However, neither these mice nor the hybrid mice overexpressing both ornithine decarboxylase and S-adenosylmethionine decarboxylase displayed significant changes in their spermidine and spermine tissue levels. To study the mechanism by which cells maintain the constancy of the polyamine concentrations, we have determined the metabolic flux of polyamines in transgenic primary fibroblasts using pulse labelling. The results indicate that the polyamine flow is faster in transgenic primary fibroblasts than in non-transgenic fibroblasts and that the intracellular homoeostasis of higher polyamines is maintained at least partly by the acetylation of spermidine and spermine and their secretion into the medium.

scholarly journals Integrins Are the Necessary Links to Hypertrophic Growth in Cardiomyocytes

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Rebecca K. Harston ◽  
Dhandapani Kuppuswamy
Keyword(s):  
Intracellular Signaling ◽  
Drug Targets ◽  
Differential Survival ◽  
Cardiac Muscle Cells ◽  
Growth And Survival ◽  
Hypertrophic Growth ◽  
Hemodynamic Overload ◽  
Survival Signaling ◽  
Signaling Receptors

To compensate for hemodynamic overload of the heart, an event which stretches the myocardium, growth and survival signaling are activated in cardiac muscle cells (cardiomyocytes). Integrins serve as the signaling receptors of cardiomyocytes responsible for mechanotransduction toward intracellular signaling. The main integrin heterodimers on the cardiomyocyte surface are α5β1 and αvβ3, and elimination of either β1 or β3 integrins impedes pressure-induced hypertrophic signaling and leads to increased mortality. The growth signaling pathways downstream of β1 and β3 integrins are well characterized. However, new integrin pathways responsible for inhibiting apoptosis induced by hemodynamic overload are emerging. β1 and β3 integrins activate differential survival signaling, yet both integrins initiate survival signaling downstream of ubiquitination and the kinase pathway including phosphoinositol-3-kinase (PI3K)/Akt. Further characterization of these integrin-signaling mechanisms may lead to drug targets to prevent decompensation to heart failure.

scholarly journals Role of propylamine transferases in hormone-induced stimulation of polyamine biosynthesis

1980 ◽  
Vol 192 (1) ◽  
pp. 59-63 ◽  
Author(s):  
Kirsti Käpyaho ◽  
Hannu Pösö ◽  
Juhani Jänne
Keyword(s):  
Seminal Vesicle ◽  
Ornithine Decarboxylase ◽  
Ovarian Tissue ◽  
Ventral Prostate ◽  
Decarboxylase Activity ◽  
Spermidine Synthase ◽  
Polyamine Biosynthesis ◽  
Adenosylmethionine Decarboxylase ◽  
Spermine Synthase ◽  
Stimulation Of

The effect of various hormones on the activities of the four enzymes engaged with the biosynthesis of the polyamines has been investigated in the rat. Human choriogonadotropin induced a dramatic, yet transient, stimulation of l-ornithine decarboxylase (EC 4.1.1.17) activity in rat ovary, with no or only marginal changes in the activities of S-adenosyl-l-methionine decarboxylase (EC 4.1.1.50), spermidine synthase (aminopropyltransferase; EC 2.5.1.16) or spermine synthase. A single injection of oestradiol into immature rats maximally induced uterine ornithine decarboxylase at 4h after the injection. This early stimulation of ornithine decarboxylase activity was accompanied by a distinct enhancement of adenosylmethionine decarboxylase activity and a decrease in the activities of spermidine synthase and spermine synthase. In the seminal vesicle of castrated rats, testosterone treatment elicited a striking and persistent stimulation of ornithine decarboxylase and adenosylmethionine decarboxylase activities. The activity of spermidine synthase likewise rapidly increased between the first and the second day after the commencement of the hormone treatment, whereas the activity of spermine synthase remained virtually unchanged during the whole period of observation. Testosterone-induced changes in polyamine formation in the ventral prostate were comparable with those found in the seminal vesicle, with the possible exception of a more pronounced stimulation of spermidine synthase activity. It thus appears that an enhancement in one or both of the propylamine transferase (aminopropyltransferase) activities in response to hormone administration is an indicator of hormone-dependent growth (uterus and the male accessory sexual glands), and is not necessarily associated with non-proliferative hormonal responses, such as gonadotropin-induced luteinization of the ovarian tissue.

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