Polyamine metabolism in the Microsporidia

2003 ◽  
Vol 31 (2) ◽  
pp. 420-423 ◽  
Author(s):  
C.J. Bacchi ◽  
N. Yarlett ◽  
L.M. Weiss
Keyword(s):  
Metabolic Pathways ◽  
Tumour Cells ◽  
Polyamine Metabolism ◽  
Immunocompromised Patients ◽  
Obligate Intracellular ◽  
Polyamine Analogues ◽  
Intracellular Parasites ◽  
Recent Developments ◽  
Polyamine Uptake ◽  
Block Growth

Members of the phylum Microspora are all obligate intracellular parasites. Little is known concerning metabolic pathways in these parasites, some of which pose serious problems in immunocompromised patients. We investigated polyamine metabolism in the systemic pathogen Enterocytozoon cuniculi using intact pre-emergent spores, and cell-free preparations. We found both polyamine synthetic and interconversion pathways to be operative, as evidenced by conversion of ornithine into polyamines, and production of spermidine from spermine by pre-emergent spores. Recent developments in the antitumour field have highlighted the ability of bis-ethylated polyamine analogues to reduce polyamine levels and block growth of tumour cells. In light of enhanced polyamine uptake in Enc. cuniculi, we have begun to study bis-aryl 3-7-3 and bis-ethyl oligoamine analogues as leads for chemotherapy of microsporidia.

scholarly journals A perspective of polyamine metabolism

2003 ◽  
Vol 376 (1) ◽  
pp. 1-14 ◽  
Author(s):  
Heather M. WALLACE ◽  
Alison V. FRASER ◽  
Alun HUGHES
Keyword(s):  
Tumour Cells ◽  
Polyamine Metabolism ◽  
Parasitic Infections ◽  
Proof Of Concept ◽  
Compensatory Mechanisms ◽  
Polyamine Analogues ◽  
Cellular Effects ◽  
Current Thinking ◽  
Polyamine Content ◽  
And Function

Polyamines are essential for the growth and function of normal cells. They interact with various macromolecules, both electrostatically and covalently and, as a consequence, have a variety of cellular effects. The complexity of polyamine metabolism and the multitude of compensatory mechanisms that are invoked to maintain polyamine homoeostasis argue that these amines are critical to cell survival. The regulation of polyamine content within cells occurs at several levels, including transcription and translation. In addition, novel features such as the +1 frameshift required for antizyme production and the rapid turnover of several of the enzymes involved in the pathway make the regulation of polyamine metabolism a fascinating subject. The link between polyamine content and human disease is unequivocal, and significant success has been obtained in the treatment of a number of parasitic infections. Targeting the polyamine pathway as a means of treating cancer has met with limited success, although the development of drugs such as DFMO (α-difluoromethylornithine), a rationally designed anticancer agent, has revolutionized our understanding of polyamine function in cell growth and provided ‘proof of concept’ that influencing polyamine metabolism and content within tumour cells will prevent tumour growth. The more recent development of the polyamine analogues has been pivotal in advancing our understanding of the necessity to deplete all three polyamines to induce apoptosis in tumour cells. The current thinking is that the polyamine inhibitors/analogues may also be useful agents in the chemoprevention of cancer and, in this area, we may yet see a revival of DFMO. The future will be in adopting a functional genomics approach to identifying polyamine-regulated genes linked to either carcinogenesis or apoptosis.

scholarly journals Divergent regulation of the key enzymes of polyamine metabolism by chiral α-methylated polyamine analogues

2009 ◽  
Vol 422 (2) ◽  
pp. 321-328 ◽  
Author(s):  
Mervi T. Hyvönen ◽  
Michael T. Howard ◽  
Christine B. Anderson ◽  
Nikolay Grigorenko ◽  
Alex R. Khomutov ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Upstream Open Reading Frame ◽  
Polyamine Metabolism ◽  
Therapeutic Drug ◽  
Optical Isomers ◽  
Control Mechanisms ◽  
Reading Frame ◽  
Polyamine Analogues ◽  
Novel Approach ◽  
Polyamine Uptake

The natural polyamines are ubiquitous multifunctional organic cations which play important roles in regulating cellular proliferation and survival. Here we present a novel approach to investigating polyamine functions by using optical isomers of MeSpd (α-methylspermidine) and Me2Spm (α,ω-bismethylspermine), metabolically stable functional mimetics of natural polyamines. We studied the ability of MeSpd and Me2Spm to alter the normal polyamine regulation pathways at the level of polyamine uptake and the major control mechanisms known to affect the key polyamine metabolic enzymes. These include: (i) ODC (ornithine decarboxylase), which catalyses the rate-limiting step of polyamine synthesis; (ii) ODC antizyme, an inhibitor of ODC and polyamine uptake; (iii) SSAT (spermidine/spermine N1-acetyltransferase), the major polyamine catabolic enzyme; and (iv) AdoMetDC (S-adenosyl-L-methionine decarboxylase), which is required for the conversion of putrescine into spermidine, and spermidine into spermine. We show that the stereoisomers differ in their cellular uptake and ability to downregulate ODC and AdoMetDC, and to induce SSAT. These effects are mediated by the ability of the enantiomers to induce +1 ribosomal frameshifting on ODC antizyme mRNA, to suppress the translation of AdoMetDC uORF (upstream open reading frame) and to regulate the alternative splicing of SSAT pre-mRNA. The unique effects of chiral polyamine analogues on polyamine metabolism may offer novel possibilities for studying the physiological functions, control mechanisms, and targets of the natural polyamines, as well as advance therapeutic drug development in cancer and other human health-related issues.

scholarly journals Untargeted Metabolomics Uncovers the Essential Lysine Transporter in Toxoplasma gondii

Metabolites ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 476
Author(s):  
Joachim Kloehn ◽  
Matteo Lunghi ◽  
Emmanuel Varesio ◽  
David Dubois ◽  
Dominique Soldati-Favre
Keyword(s):  
Amino Acids ◽  
Toxoplasma Gondii ◽  
Rna Degradation ◽  
Major Facilitator Superfamily ◽  
Untargeted Metabolomics ◽  
Apicomplexan Parasites ◽  
Obligate Intracellular ◽  
Intracellular Parasites ◽  
Major Facilitator ◽  
Plasma Membrane Transporter

Apicomplexan parasites are responsible for devastating diseases, including malaria, toxoplasmosis, and cryptosporidiosis. Current treatments are limited by emerging resistance to, as well as the high cost and toxicity of existing drugs. As obligate intracellular parasites, apicomplexans rely on the uptake of many essential metabolites from their host. Toxoplasma gondii, the causative agent of toxoplasmosis, is auxotrophic for several metabolites, including sugars (e.g., myo-inositol), amino acids (e.g., tyrosine), lipidic compounds and lipid precursors (cholesterol, choline), vitamins, cofactors (thiamine) and others. To date, only few apicomplexan metabolite transporters have been characterized and assigned a substrate. Here, we set out to investigate whether untargeted metabolomics can be used to identify the substrate of an uncharacterized transporter. Based on existing genome- and proteome-wide datasets, we have identified an essential plasma membrane transporter of the major facilitator superfamily in T. gondii—previously termed TgApiAT6-1. Using an inducible system based on RNA degradation, TgApiAT6-1 was depleted, and the mutant parasite’s metabolome was compared to that of non-depleted parasites. The most significantly reduced metabolite in parasites depleted in TgApiAT6-1 was identified as the amino acid lysine, for which T. gondii is predicted to be auxotrophic. Using stable isotope-labeled amino acids, we confirmed that TgApiAT6-1 is required for efficient lysine uptake. Our findings highlight untargeted metabolomics as a powerful tool to identify the substrate of orphan transporters.

Encystment and germination of the parasitic chytrid Rozella allomycis on host hyphae

1973 ◽  
Vol 51 (10) ◽  
pp. 1825-1835 ◽  
Author(s):  
Abraham A. Held
Keyword(s):  
Cyst Wall ◽  
Germ Tube ◽  
Light And Electron Microscopy ◽  
Multivesicular Bodies ◽  
Cell Periphery ◽  
General Sequence ◽  
Obligate Intracellular ◽  
Host Cytoplasm ◽  
Intracellular Parasites ◽  
Three Stages

Zoospores of the obligately parasitic chytrid Rozella allomycis which settle upon hyphae of the water mold host, Allomyces arbuscula, encyst and germinate before their protoplasts penetrate into the host cytoplasm. This process has been examined by light and electron microscopy. Three stages which follow the attachment to the host and the retraction of the zoospore's flagellum are described: (1) the early cyst lacks a wall; it is discoid, and its shape is maintained by the coil of the retracted axoneme which forms its rim; (2) a cyst wall is formed while multivesicular bodies occur at the cell periphery and eventually disappear; a germ tube starts to grow at the point of attachment; and (3) the firm-walled cyst is spheroidal; it has a fully developed germ tube with a specialized class of vesicles; it also forms a distal, flattened vacuole whose swelling eventually injects the Rozella protoplast into the host; at this stage the retracted axoneme has disappeared and the cell's organelles have undergone extensive changes. Electron-dense, "gamma-like" granules enclosed in vacuoles may play a major role in the formation of both the cyst wall and the distal vacuole. These granules appear to give rise to small vesicles, and thus to multivesicular bodies; the distal vacuole appears to form by coalescense of gamma-like vacuoles.The general sequence of encystment and germination resembles that found in other Chytridiomycetes, both saprophytic and parasitic. However, the distal vacuole and the vesicles in the germ tube appear to be parasitic adaptations and are shared by obligate intracellular parasites from several unrelated groups of zoosporic fungi.

Round Table Discussion

PEDIATRICS ◽  
1948 ◽  
Vol 2 (4) ◽  
pp. 469-479
Author(s):  
RUSSELL J. BLATTNER
Keyword(s):  
Inclusion Bodies ◽  
Cellular Response ◽  
Infectious Agent ◽  
Round Table ◽  
Chemotherapeutic Agents ◽  
Tissue Response ◽  
Round Table Discussion ◽  
Obligate Intracellular ◽  
Form Of Life ◽  
Intracellular Parasites

Chairman Blattner: During recent years, there has been increasing interest shown in diseases caused by filterable viruses, and significant work has been accomplished in this comparatively new and absorbing field of endeavor. With the advent of chemotherapeutic agents and antibiotics, the presence and action of these infectious agents has become more apparent. Viral diseases, therefore, have assumed increasing importance in medical literature in general and in pediatric literature in particular. By way of review, it is well to bear in mind that viruses are filter-passing agents, obligate intracellular parasites, capable of reproducing themselves and of producing disease in plants and animals, including man. While these agents cannot be seen except by the most elaborate methods, their presence can be detected by their injurious effects. The pathologic picture produced by viral agents is rather characteristic and can be recognized readily by experienced observers acquainted with tissue response. In some instances, inclusion bodies are produced which may be intranuclear or intracytoplasmic, and represent cytologic changes which are considered typical of the pathologic response to viral invasion. When inclusion bodies are present they may serve as sign posts for the recognition of the type of infectious agent. The nature of a filterable virus is as yet unknown. Viruses may be a form of life similar to bacteria, but infinitely smaller in size. It is conceivable that viruses are enzymes capable of reproducing themselves and capable of producing cellular response. They may be non-living, crystallizable substances, such as the Stanley tobacco-mosaic virus; or a form of life, the definite nature of which is as yet unrecognized. Dr. Thomas M. Rivers has stated : "Viruses are a heterogeneous collection of diverse agents which happen to induce a state of broad similarity." He points out that the reaction of the tissues in general, and of the cells in particular, determines the nature of the pathologic process about as much as the infectious agent itself.

Unusual aspects of the polyamine transport system affect the design of strategies for use of polyamine analogues in chemotherapy

2007 ◽  
Vol 35 (2) ◽  
pp. 318-321 ◽  
Author(s):  
J.L.A. Mitchell ◽  
T.K. Thane ◽  
J.M. Sequeira ◽  
R. Thokala
Keyword(s):  
Regulatory Protein ◽  
Feedback System ◽  
Uptake System ◽  
Polyamine Synthesis ◽  
Polyamine Analogues ◽  
Binding Partners ◽  
Polyamine Transport ◽  
Polyamine Uptake ◽  
Tumour Cell Growth

One strategy for inhibiting tumour cell growth is the use of polyamine mimetics to depress endogenous polyamine levels and, ideally, obstruct critical polyamine-requiring reactions. Such polyamine analogues make very unusual drugs, in that extremely high intracellular concentrations are required for growth inhibition or cytotoxicity. Cells exposed to even sub-micromolar concentrations of such analogues can achieve effective intracellular levels because these compounds are incorporated by the very aggressive polyamine uptake system. Once incorporated to these levels, many of these analogues induce the synthesis of a regulatory protein, antizyme, which inhibits both polyamine synthesis and the transporter they used to enter the cell. Thus this feedback system allows steady-state maintenance of effective cellular doses of such analogues. Accordingly, effective cellular levels of polyamine analogues are generally inversely related to their capacity to induce antizyme. Antizyme activity is down-regulated by interaction with several binding partners, most notably antizyme inhibitor, and at least a few tumour tissues exhibit deficiencies in antizyme expression. Our studies explore the role of antizyme induction by several polyamine analogues in their physiological response and the possibility that cell-to-cell differences in antizyme expression may contribute to variable sensitivities to these agents.

scholarly journals A metabolic dependency for host isoprenoids in the obligate intracellular pathogenRickettsia parkeriunderlies a sensitivity for the statin class of host-targeted therapeutics

2019 ◽  
Author(s):  
Vida Ahyong ◽  
Charles A. Berdan ◽  
Daniel K. Nomura ◽  
Matthew D. Welch
Keyword(s):  
Cell Wall ◽  
Host Cell ◽  
Bacterial Growth ◽  
Spotted Fever ◽  
Intracellular Pathogens ◽  
Biosynthetic Pathways ◽  
Targeted Therapeutics ◽  
Rickettsia Parkeri ◽  
Obligate Intracellular ◽  
Intracellular Parasites

AbstractGram-negative bacteria in the order Rickettsiales are obligate intracellular parasites that cause human diseases such typhus and spotted fever. They have evolved a dependence on essential nutrients and metabolites from the host cell as a consequence of extensive genome streamlining. However, it remains largely unknown which nutrients they require and whether their metabolic dependency can be exploited therapeutically. Here, we describe a genetic rewiring of bacterial isoprenoid biosynthetic pathways in the Rickettsiales that has resulted from reductive genome evolution. We further investigated whether the spotted fever groupRickettsiaspeciesRickettsia parkeriscavenges isoprenoid precursors directly from the host. Using targeted mass spectrometry in uninfected and infected cells, we found decreases in host isoprenoid products and concomitant increases in bacterial isoprenoid metabolites. Additionally, we report that bacterial growth is prohibited by inhibition of the host isoprenoid pathway with the statins class of drugs. We show that growth inhibition correlates with changes in bacterial size and shape that mimic those caused by antibiotics that inhibit peptidoglycan biosynthesis, suggesting statins inhibit cell wall synthesis. Altogether, our results describe an Achilles’ heel of obligate intracellular pathogens that can be exploited with host-targeted therapeutics that interfere with metabolic pathways required for bacterial growth.ImportanceObligate intracellular parasites, which include viruses as well as certain bacteria and eukaryotes, extract essential nutrients and metabolites from their host cell. As a result, these pathogens have often lost essential biosynthetic pathways and are metabolically dependent on the host. In this study, we describe a metabolic dependency of the bacterial pathogenRickettsia parkerion host isoprenoid molecules that are used in the biosynthesis of downstream products including cholesterol, steroid hormones, and heme. Bacteria make products from isoprenoids such as an essential lipid carrier for making the bacterial cell wall. We show that bacterial metabolic dependency can represent an Achilles’ heel, and that inhibiting host isoprenoid biosynthesis with the FDA-approved statin class of drugs inhibits bacterial growth by interfering with the integrity of the cell wall. This work highlights a potential to treat infections by obligate intracellular pathogens through inhibition of host biosynthetic pathways that are susceptible to parasitism.

Subversion of host cell signalling by the protozoan parasiteLeishmania

Parasitology ◽  
2005 ◽  
Vol 130 (S1) ◽  
pp. S27-S35 ◽  
Author(s):  
D. J. GREGORY ◽  
M. OLIVIER
Keyword(s):  
Nitric Oxide ◽  
Reactive Oxygen Species ◽  
Cell Signalling ◽  
Protein Tyrosine Phosphatases ◽  
Innate Immune ◽  
Signalling Pathways ◽  
Oxygen Species ◽  
Obligate Intracellular ◽  
Intracellular Parasites ◽  
Intracellular Ca

The protozoaLeishmaniaspp. are obligate intracellular parasites that inhabit the macrophages of their host. Since macrophages are specialized for the identification and destruction of invading pathogens, both directly and by triggering an innate immune response,Leishmaniahave evolved a number of mechanisms for suppressing some critical macrophage activities. In this review, we discuss how various species ofLeishmaniadistort the host macrophage's own signalling pathways to repress the expression of various cytokines and microbicidal molecules (nitric oxide and reactive oxygen species), and antigen presentation. In particular, we describe how MAP Kinase and JAK/STAT cascades are repressed, and intracellular Ca2+and the activities of protein tyrosine phosphatases, in particular SHP-1, are elevated.

scholarly journals Pathway swapping: Toward modular engineering of essential cellular processes

2016 ◽  
Vol 113 (52) ◽  
pp. 15060-15065 ◽  
Author(s):  
Niels G. A. Kuijpers ◽  
Daniel Solis-Escalante ◽  
Marijke A. H. Luttik ◽  
Markus M. M. Bisschops ◽  
Francine J. Boonekamp ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Metabolic Pathways ◽  
Applied Research ◽  
Central Metabolism ◽  
Microbial Genomes ◽  
Cellular Processes ◽  
Recent Developments ◽  
One Step ◽  
Saccharomyces Kudriavzevii

Recent developments in synthetic biology enable one-step implementation of entire metabolic pathways in industrial microorganisms. A similarly radical remodelling of central metabolism could greatly accelerate fundamental and applied research, but is impeded by the mosaic organization of microbial genomes. To eliminate this limitation, we propose and explore the concept of “pathway swapping,” using yeast glycolysis as the experimental model. Construction of a “single-locus glycolysis” Saccharomyces cerevisiae platform enabled quick and easy replacement of this yeast’s entire complement of 26 glycolytic isoenzymes by any alternative, functional glycolytic pathway configuration. The potential of this approach was demonstrated by the construction and characterization of S. cerevisiae strains whose growth depended on two nonnative glycolytic pathways: a complete glycolysis from the related yeast Saccharomyces kudriavzevii and a mosaic glycolysis consisting of yeast and human enzymes. This work demonstrates the feasibility and potential of modular, combinatorial approaches to engineering and analysis of core cellular processes.

scholarly journals Suicidal Leishmania

Pathogens ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 79 ◽  
Author(s):  
Lucie Podešvová ◽  
Tereza Leštinová ◽  
Eva Horáková ◽  
Julius Lukeš ◽  
Petr Volf ◽  
...  
Keyword(s):  
Cell Death ◽  
Phospholipase A2 ◽  
Cutaneous Leishmaniasis ◽  
Human Pathogen ◽  
Leishmania Mexicana ◽  
Macrophage Infection ◽  
Obligate Intracellular ◽  
Intracellular Parasites ◽  
Tropical Infections

Leishmania are obligate intracellular parasites known to have developed successful ways of efficient immunity evasion. Because of this, leishmaniasis, a disease caused by these flagellated protists, is ranked as one of the most serious tropical infections worldwide. Neither prophylactic medication, nor vaccination has been developed thus far, even though the infection has usually led to strong and long-lasting immunity. In this paper, we describe a “suicidal” system established in Leishmania mexicana, a human pathogen causing cutaneous leishmaniasis. This system is based on the expression and (de)stabilization of a basic phospholipase A2 toxin from the Bothrops pauloensis snake venom, which leads to the inducible cell death of the parasites in vitro. Furthermore, the suicidal strain was highly attenuated during macrophage infection, regardless of the toxin stabilization. Such a deliberately weakened parasite could be used to vaccinate the host, as its viability is regulated by the toxin stabilization, causing a profoundly reduced pathogenesis.

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