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Amino Acids: The Forum for Amino Acid, Peptide and Protein Research (v.33, #2)
Polyamines and their analogs in cancer and other diseases
by Enzo Agostinelli; Uriel Bachrach (pp. 173-173).
The physiological role of biogenic amines redox reactions in mitochondria. New perspectives in cancer therapy by E. Agostinelli; G. Tempera; A. Molinari; M. Salvi; V. Battaglia; A. Toninello; G. Arancia (pp. 175-187).
In tumours, polyamines and amine oxidases increase as compared to normal tissues. Cytotoxicity induced by bovine serum amine oxidase (BSAO) and spermine is attributed to H2O2 and aldehydes produced by the reaction. Increasing the incubation temperature from 37 to 42 °C enhances cytotoxicity in cells exposed to spermine metabolites. The combination BSAO/spermine prevents tumour growth, particularly well if the enzyme has been conjugated with a biocompatible hydrogel polymer. Since the tumour cells release endogenous substrates of BSAO, the administration of spermine is not required. Combination with hyperthermia improves the cytocidal effect of polyamines oxidation products. Our findings show that multidrug resistant (MDR) cells are more sensitive to spermine metabolites than their wild-type counterparts, due to an increased mitochondrial activity which induces the generation of intracellular ROS prior to the onset of mitochondrial permeability transition (MPT). It makes this new approach attractive, since the development of MDR is one of the major problems of conventional cancer therapy.
Keywords: Keywords: Polyamines – Amine oxidase – Reactive oxygen species – Multidrug resistance – Mitochondria – Cancer
Rationale for, and design of, a clinical trial targeting polyamine metabolism for colon cancer chemoprevention by E. W. Gerner; F. L. Meyskens Jr; S. Goldschmid; P. Lance; D. Pelot (pp. 189-195).
Polyamine metabolic genes are downstream targets of several genes commonly mutated in colon adenomas and cancers. Inhibitors of ornithine decarboxylase, such as difluoromethylornithine (DFMO), and agents that stimulate polyamine acetylation and export, such as non-steroidal anti-inflammatory drugs (NSAIDS), act at least additively to arrest growth in human cell models and suppress intestinal carcinogenesis in mice. These preclinical studies provided the rationale for colon cancer prevention trials in humans. A Phase IIb clinical study comparing the combination of DFMO and the NSAID sulindac versus placebo was conducted. Endpoints were colorectal tissue polyamine and prostaglandin E2 contents and overall toxicity to participants. Participants in the Phase IIb study served as a vanguard for a randomized, placebo-controlled prospective Phase III trial of the combination of DFMO and sulindac with the primary study endpoint the prevention of colon polyps. Seventy percent of participants will have completed the three years of treatment in December 2006.
Keywords: Keywords: Colon cancer – Chemoprevention – Polyamines – Difluoromethylornithine – Nonsteroidal anti-inflammatory drugs – Clinical trials
Polyamine biosynthesis as a target to inhibit apoptosis of non-tumoral cells by F. Flamigni; I. Stanic’; A. Facchini; S. Cetrullo; B. Tantini; R. M. Borzì; C. Guarnieri; C. M. Caldarera (pp. 197-202).
Growing evidence suggests a role for polyamines in apoptosis, although the relationship appears to be complex. α-Difluoromethylornithine (DFMO), a largely used ornithine decarboxylase inhibitor, is cytostatic, hardly cytotoxic and may even increase the resistance of tumour cells to some apoptotic stimuli. This may represent a problem in cancer therapy, where the killing of tumoral cells would be a desired effect, but could be an advantage in other pathological contexts related to an excess of apoptosis, such as cardiovascular diseases, stem cell transplantation, arthritis and infections. In different cellular models, polyamine depletion following treatment with polyamine biosynthesis inhibitors appears to inhibit mitochondrial and death receptor pathways of apoptosis by affecting key proteins. These studies indicate that inhibition of polyamine biosynthesis may prevent or reduce the apoptotic response triggered by a variety of stimuli in non-tumoral cells, such as cardiac cells, stem cells, chondrocytes, macrophages and intestinal epithelial cells.
Keywords: Keywords: Polyamines – Apoptosis – Signal transduction – Difluoromethylornithine – Caspases – Non-tumoral cells
Polyamine contents in current foods: a basis for polyamine reduced diet and a study of its long term observance and tolerance in prostate carcinoma patients by B. G. Cipolla; R. Havouis; J. P. Moulinoux (pp. 203-212).
Polyamine contents were assessed by mass spectrometry in 233 current foods and beverages. In order to reduce gut polyamine uptake, a polyamine reduced diet (PRD) and partial intermittent intestinal tract decontamination (PIITD) with neomycin or nifuroxazide was proposed as nutritional therapy to 33 prostate carcinoma patients, 30 of whom with hormone refractory prostate cancer (HRPC). Mean PRD observance was 22 ± 19 (median: 16; range: 3–72) months. 10, 8 and 3 patients were respectively on PRD for more than 30, 36 and 64 months. No diet toxicity was observed. 8 patients had moderate intestinal intolerance due to PIITD which was interrupted. No significant differences in body weight, blood counts or serum protein levels were observed during the follow-up of patients under PRD. Performance status and pain scores were relatively stable during the trial with improved pain scores at 6 months. A PRD associated with intermittent PIITD is a safe and well observed nutritional regimen and long term observance is possible.
Keywords: Keywords: Polyamines – Nutrition – Therapy – Prostate cancer – Pain – Performance status
Regulation of ornithine decarboxylase during oncogenic transformation: mechanisms and therapeutic potential by L. M. Shantz; V. A. Levin (pp. 213-223).
The activity of ornithine decarboxylase (ODC1), the first enzyme in polyamine biosynthesis, is induced during carcinogenesis by a variety of oncogenic stimuli. Intracellular levels of ODC and the polyamines are tightly controlled during normal cell growth, and regulation occurs at the levels of transcription, translation and protein degradation. Several known proto-oncogenic pathways appear to control ODC transcription and translation, and dysregulation of pathways downstream of ras and myc result in the constitutive elevation of ODC activity that occurs with oncogenesis. Inhibition of ODC activity reverts the transformation of cells in vitro and reduces tumor growth in several animal models, suggesting high levels of ODC are necessary for the maintenance of the transformed phenotype. The ODC irreversible inactivator DFMO has proven to be not only a valuable tool in the study of ODC in cancer, but also shows promise as a chemopreventive and chemotherapeutic agent in certain types of malignancies.
Keywords: Keywords: Ornithine decarboxylase – DFMO – Oncogenic transformation – Polyamines
Ubiquitin dependent and independent protein degradation in the regulation of cellular polyamines by C. Kahana (pp. 225-230).
Protein degradation mediated by the ubiquitin/proteasome system is the major route for the degradation of cellular proteins. In this pathway the ubiquitination of the target proteins is manifested via the concerted action of several enzymes. The ubiquinated proteins are then recognized and degraded by the 26S proteasome. There are few reports of proteins degraded by the 26S protesome without ubiquitination, with ornithine decarboxylase being the most notable representative of this group. Interestingly, while the degradation of ODC is independent of ubiquitination, the degradation of other enzymes of the polyamine biosynthesis pathway is ubiquitin dependent. The present review describes the degradation of enzymes and regulators of the polyamine biosynthesis pathway.
Keywords: Keywords: Ornithine decarboxylase – S-adenosylmethionine decarboxylase – Antizyme – Antizyme inhibitor – Protein degradation – Ubiquitin
Spermine and spermidine mediate protection against oxidative damage caused by hydrogen peroxide by J. E. Rider; A. Hacker; C. A. Mackintosh; A. E. Pegg; P. M. Woster; R. A. Casero Jr (pp. 231-240).
The polyamines spermidine and spermine have been hypothesized to possess different functions in the protection of DNA from reactive oxygen species. The growth and survival of mouse fibroblasts unable to synthesize spermine were compared to their normal counterparts in their native and polyamine-depleted states in response to oxidative stress. The results of these studies suggest that when present at normal or supraphysiological concentrations, either spermidine or spermine can protect cells from reactive oxygen species. However, when polyamine pools are pharmacologically manipulated to produce cells with low levels of predominately spermine or spermidine, spermine appears to be more effective. Importantly, when cells are depleted of both glutathione and endogenous polyamines, they exhibit increased sensitivity to hydrogen peroxide as compared to glutathione depletion alone, suggesting that polyamines not only play a role in protecting cells from oxidative stress but this role is distinct from that played by glutathione.
Keywords: Keywords: Polyamines – Spermine – Spermidine – Antioxidants – Hydrogen peroxide – Oxidative damage
Polyamines and mRNA stability in regulation of intestinal mucosal growth by J.-Y. Wang (pp. 241-252).
The mammalian intestinal epithelium is a rapidly self-renewing tissue in the body, and its homeostasis is preserved through strict regulation of epithelial cell proliferation, growth arrest, and apoptosis. Polyamines are necessary for normal intestinal mucosal growth and decreasing cellular polyamines inhibits cell proliferation and disrupts epithelial integrity. An increasing body of evidence indicates that polyamines regulate intestinal epithelial cell renewal by virtue of their ability to modulate expression of various genes and that growth inhibition following polyamine depletion results primarily from the activation of growth-inhibiting genes rather than a simple decrease in expression of growth-promoting genes. In this review article, we will focus on changes in expression of growth-inhibiting genes following polyamine depletion and further analyze in some detail the mechanisms through which mRNA stability is regulated by RNA-binding proteins.
Keywords: Keywords: Intestinal epithelium – Cell proliferation and growth arrest – Posttranscriptional regulation – mRNA stability – RNA-binding proteins
Enhancement of intestinal absorption of macromolecules by spermine in rats by Y. Sugita; K. Takao; Y. Toyama; A. Shirahata (pp. 253-260).
The aim of this study was to investigate the enhancing effect of polyamines on intestinal absorption of fluorescein isothiocyanate-labeled dextran (MW 4400, FD-4) in the in situ loop study and in vivo oral absorption study. Absorption of FD-4 from the jejunum was significantly enhanced by 5 mM spermine without serious membrane damage in the jejunum. An in vivo oral absorption study was also performed, and plasma FD-4 levels increased significantly after co-administration of 30 mM spermine. In the in vitro transport studies with Caco-2 cells, prolonged incubation with spermine resulted in a gradual decrease in transepithelial electrical resistance. This finding suggests that the absorption-enhancing mechanism of spermine partly includes opening the tight junctions of the epithelium via the paracellular route. These results indicate that excess oral ingestion of polyamines may have widespread health effects via the modulation of the intestinal epithelial barrier function.
Keywords: Keywords: Polyamines – Fluorescein isothiocyanate-labeled dextran – Intestinal absorption – in situ loop – Oral absorption – Caco-2 cell monolayers
Polyamine analogues – an update by H. M. Wallace; K. Niiranen (pp. 261-265).
The polyamines are growth factors in both normal and cancer cells. As the intracellular polyamine content correlates positively with the growth potential of that cell, the idea that depletion of polyamine content will result in inhibition of cell growth and, particularly tumour cell growth, has been developed over the last 15 years. The polyamine pathway is therefore a target for development of rationally designed, antiproliferative agents. Following the lessons from the single enzyme inhibitors (α-difluoromethylornithine DFMO), three generations of polyamine analogues have been synthesised and tested in vitro and in vivo. The analogues are multi-site inhibitors affecting multiple reactions in the pathway and thus prevent the up-regulation of compensatory reactions that have been the downfall of DFMO in anticancer chemotherapy. Although the initial concept was that the analogues may provide novel anticancer drugs, it now seems likely that the analogues will have wider applications in diseases involving hyperplasia.
Keywords: Keywords: Cancer – Spermidine – Spermine – Polyamine analogues – DFMO – Disease
Antiviral activity of oxidized polyamines by U. Bachrach (pp. 267-272).
Polyamines, oxidized by serum amine oxidase, yield aminoaldehydes and hydrogen peroxide. Acrolein may be formed from the aminoaldehydes by a spontaneous β-elimination process. These oxidation products “oxidized polyamines” inhibit bacterial growth and exhibit anticancer activity. The antimicrobial activity of oxidized polyamines is not limited to bacteria; and the inactivation of bacterial viruses, plant viruses and animal viruses, was also reported. Bacteriophages of the T-odd series are permeable and were inactivated by oxidized polyamines. The inactive phages absorb to their bacterial host and injected their DNA, which formed a stable inactive complex with the aminoaldehydes. Aminoaldehydes, synthesized chemically, also inactivated viruses. The growth of the plant viruses: Tobacco mosaic virus, Potato virus X and Alfalfa mosaic virus was also inhibited by oxidized polyamines. The animal viruses, which were inactivated by oxidized polyamines included Myxoviruses (influenza and Newcastle disease viruses), West Nile, vaccinia and Sindbis viruses. These findings may have practical implications.
Keywords: Keywords: Oxidized polyamines – Aminoaldehydes – Acrolein – Inactivation of bacteriophages – Plant viruses – Animal viruses
Anticancer drugs and hyperthermia enhance cytotoxicity induced by polyamine enzymatic oxidation products by M. Marra; E. Agostinelli; G. Tempera; A. Lombardi; G. Meo; A. Budillon; A. Abbruzzese; G. Giuberti; M. Caraglia (pp. 273-281).
A correlation between regulation of cell proliferation and polyamine metabolism is described. The latter can enter protein synthesis through the modification of eukaryotic initiation factor 5A (eIF5A) and the formation of the peculiar amino acid hypusine. Specific inhibitors of hypusine formation induce apoptosis that can be potentiated by the combination with cytokines such as interferonα (IFNα) that itself decreases hypusine synthesis. We have also demonstrated that the concomitant treatment of cancer cells with IFNα and the protein synthesis inhibitor fusion protein TGFα/Pseudomonas Aeruginosa toxin synergize in inducing cancer cell growth inhibition. Another way used by polyamines to induce apoptosis is the generation of intracellular oxidative stress through the interaction with bovine serum amine oxidase (BSAO). This enzyme used simultaneously to spermine induces apoptosis, necrosis, inhibition of cell proliferation and inhibition of DNA and protein synthesis in several cell types. The enzymatic oxidation products of polyamine, H2O2 and aldehyde(s) cause these effects. We have recently found that the cytotoxicity of anti-cancer agents, either etoposide or docetaxel, in cancer cells is potentiated in the presence of BSAO/Spermine. In conclusion, polyamine metabolites could be useful in the design of new therapeutic strategies.
Keywords: Keywords: Amine oxidase – Polyamines – Multidrug resistance – Eukaryotic initiation factor 5A – Docetaxel – IFNα
Polyamines: metabolism to systems biology and beyond by R. Montañez; F. Sánchez-Jiménez; J. F. Aldana-Montes; M. Á. Medina (pp. 283-289).
Polyamines and the metabolic and physiopathological processes in which they are involved represent an active field of research that has been continuously growing since the seventies. In the last years, the trends in the focused areas of interest within this field since the 1970s have been confirmed. The impact of “-omics” in polyamine research remains too low in comparison with its deep impact on other biological research areas. These high-throughput approaches, along with systems biology and, in general, more systemic and holistic approaches should contribute to a renewal of this research area in the near future.
Keywords: Keywords: Polyamines – Systems biology – Functional genomics – Proteomics – Metabolomics – Sematic web
Antizyme and antizyme inhibitor activities influence cellular responses to polyamine analogs by J. L. A. Mitchell; T. K. Thane; J. M. Sequeira; L. J. Marton; R. Thokala (pp. 291-297).
Close structural analogs of spermidine and spermine, polyamine mimetics, are potential chemotheraputic agents as they depress cellular polyamines required for tumor growth. Specific mimetic analogs stimulate synthesis of the regulatory protein antizyme (AZ), which not only inactivates the initial enzyme in polyamine biosynthesis but also inhibits cellular uptake of polyamines. The role of AZ induction in influencing cellular uptake of representative analogs was investigated using three analogs produced by Cellgate Inc., CGC-11047, CGC-11102, and CGC-11144, which exhibit markedly distinct AZ-inducing potential. An inverse correlation was noted between the AZ-inducing activity of a compound and the steady-state levels accumulated in cells. As some tumor cells over express AZI as a means of enhancing the polyamines required for aggressive growth, analog sensitivity was examined in transgenic CHO cells expressing exogenous antizyme inhibitor protein (AZI). Although AZI over expression increased cell sensitivity to analogs, the degree of this affect varied with the analog used.
Keywords: Keywords: Polyamines – Antizyme – Antizyme inhibitor – Polyamine mimetics – Polyamine analogs
Anthraquinone polyamines: novel channel blockers of N-methyl-d-aspartate receptors by K. Kashiwagi; K. Williams; K. Igarashi (pp. 299-304).
Polyamines, in particular spermine, as well as some natural and synthetic polyamine derivatives have been found to be blockers of N-methyl-d-aspartate receptors. We developed novel, polyamine-based channel blockers to analyze the structure of NMDA receptors. Anthraquinone polyamines block NMDA receptors with some selectivity compared to other glutamate receptors. Results using mutant NR1 and NR2 subunits identified amino acid residues that influence blockade by anthraquinone polyamines. The head group (anthraquinone) may be positioned at the selectivity filter/narrowest constriction of the channel and the polyamine tail penetrates this constriction into the inner vestibule below the level of the selectivity filter. The results are consistent with other work showing that NR1 (Asn616) and NR2B (Asn616), but not NR2B (Asn615), make the narrowest constriction of NMDA channel, and that the M3 segments from the two subunits, which form the outer vestibule, are likely staggered relative to each other in the vertical axis of the channel.
Keywords: Keywords: Polyamine derivatives – Glutamate receptor – NMDA receptor – Channel blocker
Structure-activity investigations of polyamine-anthracene conjugates and their uptake via the polyamine transporter by O. Phanstiel IV; N. Kaur; J.-G. Delcros (pp. 305-313).
A series of polyamine conjugates were synthesized and evaluated for their ability to target the polyamine transporter (PAT) in two Chinese hamster ovary (CHO) cell lines (PAT-active CHO and PAT-inactive CHOMG). This systematic study identified salient features of the polyamine architecture required to target and enter cells via the PAT. Indeed, the separation of charges, the degree of N-alkylation, and the spacer unit connecting the N1-terminus to the appended cytotoxic component (anthracene) were found to be key contributors to optimal delivery via the PAT. Using the CHO screen, the homospermidine motif (e.g., 4,4-triamine) was identified as a polyamine vector, which could enable the selective import of large N1-substituents (i.e., naphthylmethyl, anthracenylmethyl and pyrenylmethyl), which were cytotoxic to cells. The cell selectivity of this approach was demonstrated in B-16 murine melanoma cells and normal melanocytes (Mel-A). Three polyamine areas (recognition and transport, vesicle sequestration and polyamine-target interactions) were identified for future research.
Keywords: Keywords: Polyamine – Transport – Anthracene – Cytotoxicity
Development of an expression macroarray for amine metabolism-related genes by P. Chaves; F. Correa-Fiz; E. Melgarejo; J. L. Urdiales; M. A. Medina; F. Sánchez-Jiménez (pp. 315-322).
Cationic amino acids are the precursors of biogenic amines, histamine from histidine, and putrescine, spermidine and spermine from arginine/ornithine (and methionine), as well as nitric oxide. These amines play important biological roles in inter- and intracellular signaling mechanisms related to inflammation, cell proliferation and neurotransmission. Biochemical and epidemiological relationships between arginine-derived products and histamine have been reported to play important roles in physiopathological problems. In this communication, we describe the construction of an expression macroarray containing more than 30 human probes for most of the key proteins involved in biogenic amines metabolisms, as well as other inflammation- and proliferation-related probes. The array has been validated on human mast HMC-1 cells. On this model, we have got further support for an inverse correlation between polyamine and histamine synthesis previously observed on murine basophilic models. These tools should also be helpful to understand the amine roles in many other inflammatory and neoplastic pathologies.
Keywords: Keywords: Expression macroarray – Polyamines – Histamine – Mast cells – Inflammation
Oxidative stress and inflammation in the pathogenesis of activated polyamine catabolism-induced acute pancreatitis by M. Merentie; A. Uimari; M. Pietilä; R. Sinervirta; T. A. Keinänen; J. Vepsäläinen; A. Khomutov; N. Grigorenko; K.-H. Herzig; J. Jänne; L. Alhonen (pp. 323-330).
The markers of oxidative stress and inflammation were studied in acute pancreatitis in transgenic rats exhibiting activated polyamine catabolism. In addition, the effect of bismethylspermine (Me2Spm) pretreatment, preventing pancreatitis in this model, on these mediators was investigated. Lipid peroxidation was increased at 6 and 24 h after induction of pancreatitis. These changes as well as the markedly decreased superoxide dismutase activity at 24 h were abolished by Me2Spm pretreatment. Glutathione level and catalase activity changed transiently, and the effect of Me2Spm was clear at 24 h. Serum inflammatory cytokine levels increased already at 4 h whereas NF-κB was distinctly activated only at 24 h. Me2Spm prevented the increase in TNF-α and IL-6 while it had no effect on NF-κB activation. These results show that typical inflammatory and, to a lesser degree, some oxidative stress mediators are involved and beneficially affected by the disease-ameliorating polyamine analogue in our pancreatitis model.
Keywords: Keywords: Spermidine/spermine N1-acetyltransferase – Inflammatory cytokines – Lipid peroxidation – Superoxide dismutase – Catalase – Glutathione
Kidney growth, hypertrophy and the unifying mechanism of diabetic complications by J. Satriano (pp. 331-339).
Michael Brownlee has proposed a ‘Unifying Mechanism’ of hyperglycemia-induced damage in diabetes mellitus. At the crux of this hypothesis is the generation of reactive oxygen species (ROS), and their impact on glycolytic pathways.Diabetes is the leading cause of chronic kidney failure. In the early phase of diabetes, prior to establishment of proteinuria or fibrosis, comes kidney growth and hyperfiltration. This early growth phase consists of an early period of hyperplasia followed by hypertrophy. Hypertrophy also contributes to cellular oxidative stress, and may precede the ROS perturbation of glycolytic pathways described in the Brownlee proposal. This increase in growth promotes hyperfiltration, and along with the hypertrophic phenotype appears required for hyperglycemia-induced cell damage and the progression of downstream diabetic complications. Here we will evaluate this growth phenomenon in the context of diabetes mellitus.
Keywords: Keywords: Type I diabetes – Hyperfiltration – Tubuloglomerular feedback – Reactive oxygen species – Polyamines – Hypertrophy
Posttranslational synthesis of hypusine: evolutionary progression and specificity of the hypusine modification by E. C. Wolff; K. R. Kang; Y. S. Kim; M. H. Park (pp. 341-350).
A naturally occurring unusual amino acid, hypusine [N ɛ-(4-amino-2-hydroxybutyl)-lysine] is a component of a single cellular protein, eukaryotic translation initiation factor 5A (eIF5A). It is a modified lysine with structural contribution from the polyamine spermidine. Hypusine is formed in a novel posttranslational modification that involves two enzymes, deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH). eIF5A and deoxyhypusine/hypusine modification are essential for growth of eukaryotic cells. The hypusine synthetic pathway has evolved in eukaryotes and eIF5A, DHS and DOHH are highly conserved, suggesting maintenance of a fundamental cellular function of eIF5A through evolution. The unique feature of the hypusine modification is the strict specificity of the enzymes toward its substrate protein, eIF5A. Moreover, DHS exhibits a narrow specificity toward spermidine. In view of the extraordinary specificity and the requirement for hypusine-containing eIF5A for mammalian cell proliferation, eIF5A and the hypusine biosynthetic enzymes present new potential targets for intervention in aberrant cell proliferation.
Keywords: Keywords: Hypusine – eIF5A – Posttranslational modification – Deoxyhypusine synthase – Deoxyhypusine hydroxylase – Polyamine
Is there a role for eIF5A in translation? by C. F. Zanelli; S. R. Valentini (pp. 351-358).
The putative translation factor eIF5A is essential for cell viability and is highly conserved from archaebacteria to mammals. This factor is the only cellular protein that undergoes an essential posttranslational modification dependent on the polyamine spermidine, called hypusination. This review focuses on the functional characterization of eIF5A. Although this protein was originally identified as a translation initiation factor, subsequent studies did not support a role for eIF5A in general translation initiation. eIF5A has also been implicated in nuclear export of HIV-1 Rev and mRNA decay, but these findings are controversial in the literature and may reflect secondary effects of eIF-5A function. Next, the involvement of eIF5A and hypusination in the control of the cell cycle and proliferation in various organisms is reviewed. Finally, recent evidence in favor of reconsidering the role of eIF5A as a translation factor is discussed. Future studies may reveal the specific mechanism by which eIF5A affects protein synthesis.
Keywords: Keywords: eIF5A – Hypusine – Ribosome – Translation – Protein synthesis
Targeting the polyamine biosynthetic enzymes: a promising approach to therapy of African sleeping sickness, Chagas’ disease, and leishmaniasis by O. Heby; L. Persson; M. Rentala (pp. 359-366).
Trypanosomatids depend on spermidine for growth and survival. Consequently, enzymes involved in spermidine synthesis and utilization, i.e. arginase, ornithine decarboxylase (ODC), S-adenosylmethionine decarboxylase (AdoMetDC), spermidine synthase, trypanothione synthetase (TryS), and trypanothione reductase (TryR), are promising targets for drug development. The ODC inhibitor α-difluoromethylornithine (DFMO) is about to become a first-line drug against human late-stage gambiense sleeping sickness. Another ODC inhibitor, 3-aminooxy-1-aminopropane (APA), is considerably more effective than DFMO against Leishmania promastigotes and amastigotes multiplying in macrophages. AdoMetDC inhibitors can cure animals infected with isolates from patients with rhodesiense sleeping sickness and leishmaniasis, but have not been tested on humans. The antiparasitic effects of inhibitors of polyamine and trypanothione formation, reviewed here, emphasize the relevance of these enzymes as drug targets. By taking advantage of the differences in enzyme structure between parasite and host, it should be possible to design new drugs that can selectively kill the parasites.
Keywords: Keywords: African sleeping sickness – Chagas’ disease – Leishmaniasis – Polyamines
Unique polyamines produced by an extreme thermophile, Thermus thermophilus by T. Oshima (pp. 367-372).
Recent research progress on polyamines in extreme thermophiles is reviewed. Extreme thermophiles produce two types of unique polyamines; one is longer polyamines such as caldopentamine and caldohexamine, and the other is branched polyamines such as tetrakis(3-aminopropyl)ammonium. The protein synthesis catalyzed by a cell-free extract of Thermus thermophilus, an extreme thermophile, required the presence of a polyamine and the highest activity was found in the presence of tetrakis(3-aminopropyl)ammonium. In vitro experiments, longer polyamines efficiently stabilized double stranded nucleic acids and a branched polyamine, tetrakis(3-aminropyl)ammonium, stabilized stem-and-loop structures. In T. thermophilus, polyamines are synthesized from arginine by a new metabolic pathway; arginine is converted to agmatine and then agmatine is aminopropylated to N1-aminopropylagmatine which is converted to spermidine by an enzyme coded by a gene homologous to speB (a gene for agmatinase). In this new pathway spermidine is not synthesized from putrescine. Reverse genetic studies indicated that the unique polyamines are synthesized from spermidine.
Keywords: Keywords: Archaeon – Caldopentamine – Cell-free protein synthesis – Hyperthermophile – Tetrakis(3-aminopropyl)ammonium
Tissue transglutaminase in tumour progression: friend or foe? by P. Kotsakis; M. Griffin (pp. 373-384).
Basic biological processes in which tissue transglutaminase (TG2, tTG) is thought to be important including apoptosis, cell adhesion and migration, ECM homeostasis and angiogenesis are key stages in the multistage tumour progression cascade. Studies undertaken with primary tumours and experimental models suggest that TG2 expression and activity in the tumour body and surrounding matrix generally decreases with tumour progression, favouring matrix destabilisation, but supporting angiogenesis and tumour invasion. In contrast, in the secondary metastatic tumour TG2 is often highly expressed whereby its potential roles in cell survival both at the intra- and extracellular level become important. In the following review the underlying molecular basis for the selection of these different phenotypes in tumour types and the anomaly for the requirement of TG2 is discussed in relation to the complex events of tumour progression.
Keywords: Keywords: Enzyme – Tissue transglutaminase – Tumour growth – Angiogenesis – Extracellular matrix – Review
Tissue transglutaminase and the stress response by R. Ientile; D. Caccamo; M. Griffin (pp. 385-394).
The expression of the protein crosslinking enzyme tissue transglutaminase (TG2, tTG), the ubiquitous member of transglutaminase family, can be regulated by multiple factors. Although it has been suggested that TG2 can be involved in apoptotic cell death, high levels of enzyme have also been associated with cell survival in response to different stimuli. Furthermore, evidence indicates that increases in TG2 production cause enzyme translocation to cell membrane. Cell stress can also lead to TG2 accumulation on the cell surface and in the extracellular matrix resulting in changes in cell-matrix interactions.Here, we discuss the underlying mechanisms of TG2 up-regulation induced by various stimuli including glutamate exposure, calcium influx, oxidative stress, UV, and inflammatory cytokines.These findings agree with a postulated role for transglutaminases in molecular mechanisms involved in several diseases suggesting that cross-linking reactions could be a relevant part of the biochemical changes observed in pathological conditions.
Keywords: Keywords: Transglutaminases – Tissue transglutaminase – Neurodegeneration – Oxidative stress – Inflammation – Extracellular matrix
Programmed cell death: similarities and differences in animals and plants. A flower paradigm by M. Della Mea; D. Serafini-Fracassini; S. Del Duca (pp. 395-404).
After an overview of the criteria for the definition of cell death in the animal cell and of its different types of death, a comparative analysis of PCD in the plant cell is reported. The cytological characteristics of the plant cell undergoing PCD are described.The role of plant hormones and growth factors in the regulation of this event is discussed with particular emphasis on PCD activation or prevention by polyamine treatment (doses, timing and developmental stage of the organism) in a Developmental cell death plant model: the Nicotiana tabacum (tobacco) flower corolla. Some of the effects of polyamines might be mediated by transglutaminase catalysis. The activity of this enzyme was examined in different parts of the corolla during its life span showing an acropetal trend parallel to the cell death wave. The location of transglutaminase in some sub-cellular compartments suggests that it exerts different functions in the corolla DCD.
Keywords: Keywords: Programmed cell death – Polyamines – Transglutaminase – Flower – Cell wall – Tobacco