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Amino Acids: The Forum for Amino Acid, Peptide and Protein Research (v.26, #4)

Special issue: Polyamines and transglutaminases by S. Beninati; M. Piacentini; A. Abbruzzese (pp. 305-305).

Polyamines and cancer: Minireview article by U. Bachrach (pp. 307-309).

The naturally occurring polyamines, spermine, spermidine and the diamine putrescine are widespread in nature. They have been implicated in growth and differentiation processes. Polyamines accumulate in cancerous tissues and their concentration is elevated in body fluids of cancer patients. Assays of urinary and blood polyamines have been used to detect cancer and to determine the success of therapy. Drugs which inhibit the synthesis of polyamines can prevent cancer and may also be used for therapeutic purposes. Ornithine decarboxylase, which catalyzes the rate limiting step in polyamine synthesis, can serve as a marker of proliferation. Recently, a new in vitro chemosensitivity test, based on the disappearance of ornithine decarboxylase in drug-treated cancer cells has been developed. The increasing interest in polyamines and their physiological functions may lead to a more extensive application of these compounds or their derivatives in cancer diagnosis and treatment.

Keywords: Keywords:Cancer – Polyamines – Spermine – Spermidine – Putrescine – Ornithine decarboxylase – Cancer therapy – Diagnosis and prevention

Mammary histidine decarboxylase vulnerability to enzyme antisense oligonucleotides: Histamine and polyamine systems cross-talk by W. Wagner; W. A. Fogel (pp. 311-316).

Histamine system is suggested to have a role in mammary gland growth regulation, differentiation and functioning during pregnancy and lactation. Histidine decarboxylase activity undergoes significant changes during pregnancy and lactation. Pregnancy associated elevation of HDC activity and mRNA transcript in mouse mammary gland was successfully affected by enzyme antisense oligonucleotides treatment. The enzyme activity of resting mammae was unaffected as it lacked inducible pool of HDC. The short-term mammary histamine shortage evoked influenced the mRNA expression of histamine receptors (H₁ and H₂) and ornithine decarboxylase during pregnancy. There were essentially no morphological changes in the mammary gland upon the treatment, however, adipocytes neighbouring alveolar structures were more pronounced. These findings further substantiate the role of histamine in mammary gland physiology and emphasise presence of common motifs of biogenic amines and polyamine metabolism as well as mutual interferences implicating observed “cross-talk” phenomenon.

Keywords: Keywords: Mouse mammary gland – Antisense oligonucleotides – L-Histidine decarboxylase – Ornithine decarboxylase – L-Aromatic acids decarboxylase – Histamine – Histamine receptors

How important is the oxidative degradation of spermine?: Minireview article by N. Seiler (pp. 317-319).

Spermine is a constituent of most eucaryotic cells, however, it is not of vital importance for the vertebrate organism, as is demonstrated by the existence of transgenic (Gy) mice that lack spermine and spermine synthase. In contrast its degradation appears to be of vital importance, since mice die after chronic administration of N¹,N⁴-bis(2,3-butadienyl)-1,4-butanediamine (MDL 72517). Under this condition spermine accumulates in red blood cells and blood plasma. Lethal toxicity can be avoided by intervals of MDL 72527-free periods. During these periods spermine appears to be directly degraded to spermidine without an intermediary acetylation step within the red blood cells. Since this reaction is of enormous physiological significance, it will be important to characterise the red blood cell spermine oxidase, and it will be particularly important to determine whether this oxidase is identical with the FAD-dependent polyamine oxidase that is considered to be involved in the polyamine interconversion sequence, or whether it is one of the recently characterised spermine oxidase isoenzymes.

Keywords: Keywords: Spermine – Polyamine oxidase – MDL 72527 – AcetylCoA:spermidine N¹-acetyltransferase (SAT) – Red blood cells

Arginine pathways and the inflammatory response: Interregulation of nitric oxide and polyamines: Review article by J. Satriano (pp. 321-329).

An early response to an acute inflammatory insult, such as wound healing or experimental glomerulonephritis, is the conversion of arginine to the cytostatic molecule nitric oxide (NO). This ‘anti-bacterial’ phase is followed by the conversion of arginine to ornithine, which is the precursor for the pro-proliferative polyamines as well as proline for the production of extracellular matrix. This latter, pro-growth phase constitutes a ‘repair’ phase response. The temporal switch of arginine as a substrate for the cytostatic iNOS/NO axis to the pro-growth arginase/ ornithine/polyamine and proline axis is subject to regulation by inflammatory cytokines as well as interregulation by the arginine metabolites themselves. Arginine is also the precursor for another biogenic amine, agmatine. Here we describe the capacity of these three arginine pathways to interregulate, and propose a model whereby agmatine has the potential to serve in the coordination of the early and repair phase pathways of arginine in the inflammatory response by acting as a gating mechanism at the transition from the iNOS/NO axis to the arginase/ODC/polyamine axis. Due to the pathophysiologic and therapeutic potential, we will further examine the antiproliferative effects of agmatine on the polyamine pathway.

Keywords: Keywords: Agmatine – Arginine – Nitric oxide – Polyamines – Antizyme

Protein-polyamine conjugation by transglutaminase in cancer cell differentiation: Review article by A. Lentini; A. Abbruzzese; M. Caraglia; M. Marra; S. Beninati (pp. 331-337).

Considerable and intense progress has been made in the understanding of the chemistry, molecular biology and cell biology of transglutaminases (TGases: EC 2.3.2.13). The knowledge that very different processes such as cell growth, reproduction and death are dependent on the presence of adequate levels of these enzymes and that the amount of both free and protein-conjugated polyamines, formed by the enzyme, are capable of modulating the differentiation and proliferative capability of several cell types, has prompted a multitude of researchers to study the role of these fascinating molecules in cancer cell differentiation.

Keywords: Keywords: Transglutaminase – Polyamine – Differentiation

Biogenic amines and apoptosis: Minireview article by A. Toninello; M. Salvi; P. Pietrangeli; B. Mondovì (pp. 339-343).

The programmed cell death is a very complex mechanism involving many factors, among them the intracellular concentration of biogenic amines (BA) appears to be important for apoptosis triggering. The mitochondrial damage is imputable to hydrogen peroxide and aldehydes, produced by amine oxidases (AO)-mediated oxidation of BA. On the other hands, the apoptosis protection observed by high BA concentration appears to be related to their scavenger effect of ROS and/or their interaction with membrane pores. Also monoamine oxidase (MAO) inhibitors, like propargylamines, preserve the mitochondria integrity by inhibiting MAO and therefore the production of H₂O₂ and aldehydes and, as cations, by regulating membrane pores, like BA.As general conclusion, apoptosis is protected by high concentration of BA and/or other cations while it is favoured by ROS produced by AOs or other mechanisms.

Keywords: Keywords: Amine oxidases – Apoptosis – Biogenic amines – Hydrogen peroxide – Aldehydes – Mitochondria

Arginine revisited: Minireview article by M. A. Grillo; S. Colombatto (pp. 345-351).

Arginine is a precursor of proteins and employed in urea synthesis. It is also the precursor of many other compounds, such as creatine, nitric oxide, polyamines, agmatine, proline. In this review, its transport and that of other basic amino acids are examined, along with its transformation into nitric oxide, agmatine and proline, and the mutual regulation of the individual pathways.

Keywords: Keywords: Arginase – Nitric oxide – Agmatine – Proline

Inhibitors of polyamine metabolism: Review article by H. M. Wallace; A. V. Fraser (pp. 353-365).

The identification of increased polyamine concentrations in a variety of diseases from cancer and psoriasis to parasitic infections has led to the hypothesis that manipulation of polyamine metabolism is a realistic target for therapeutic or preventative intervention in the treatment of certain diseases.The early development of polyamine biosynthetic single enzyme inhibitors such as α-difluoromethylornithine (DFMO) and methylglyoxal bis(guanylhydrazone) showed some interesting early promise as anticancer drugs, but ultimately failed in vivo. Despite this, DFMO is currently in use as an effective anti-parasitic agent and has recently also been shown to have further potential as a chemopreventative agent in colorectal cancer.The initial promise in vitro led to the development and testing of other potential inhibitors of the pathway namely the polyamine analogues. The analogues have met with greater success than the single enzyme inhibitors possibly due to their multiple targets. These include down regulation of polyamine biosynthesis through inhibition of ornithine decarboxylase and S-adenosylmethionine decarboxylase and decreased polyamine uptake. This coupled with increased activity of the catabolic enzymes, polyamine oxidase and spermidine/spermine N¹-acetyltransferase, and increased polyamine export has made the analogues more effective in depleting polyamine pools. Recently, the identification of a new oxidase (PAO-h1/SMO) in polyamine catabolism and evidence of induction of both PAO and PAO-h1/SMO in response to polyamine analogue treatment, suggests the analogues may become an important part of future chemotherapeutic and/or chemopreventative regimens.

Keywords: Keywords: Polyamines – Putrescine – Spermidine – Spermine – Cancer – Apoptosis – Analogues – Enzyme inhibitors – Difluoromethylornithine – Disease

The transglutaminase family: an overview: Minireview article by S. Beninati; M. Piacentini (pp. 367-372).

The knowledge that very different processes such as normal and neoplastic cell growth, reproduction and death are dependent on the presence of adequate levels of transglutaminases (TGase: EC 2.3.2.13) and that they are capable of affecting the differentiation and proliferative capability of several cell types, has prompted a multitude of researchers to study these fascinating molecules. In the following overview we intend to summarize the currently known information on the biological significance of these enzymes.

Keywords: Keywords: Transglutaminases – Cell differentiation – Pathology – Physiology – Cell death

The multifaceted role of transglutaminase in neurodegeneration: Review article by M. Karpuj; L. Steinman (pp. 373-379).

A critical role for transglutaminase [TGase] has been hypothesized in the pathogenesis of the CAG trinucleotide repeat diseases, characterized by proteins with abnormal expansions of a polyglutamine domain. In the last few years the involvement of TGase in neurodegenerative diseases [NDS], including its role in aggregate formation, has been broadened to include Alzheimer’s [AD] and Parkinson’s Disease [PD]. It is clear that reduction of TGase activity is beneficial for prolonged survival in mouse models of NDS. The pathological progression of these diseases might reflect in part increases of TGase induced aggregates, or changes in other pathways influenced by increases in TGase activity. Neurodegeneration may be influenced by increased TGase activity affecting apoptosis, modulation of GTPase activity and signal transduction. This review will focus on the leading hypotheses in relation to both old and new experimental results.

Keywords: Keywords: Transglutaminase – Neurodegeneration – Huntington disease – Alzheimer’s disease – Parkinson’s disease – Cystamine

Transglutaminase 2 in celiac disease: Minireview article by I. Caputo; A. D’Amato; R. Troncone; S. Auricchio; C. Esposito (pp. 381-386).

Celiac disease (CD) is an autoimmune pathology of the small intestine triggered, in genetically predisposed patients, by the exposition to gliadin, a flour protein, thus evoking local immune reactions and mucosal atrophy. The discovery that type 2 transglutaminase (TG2) is the main, if not the sole, target of the endomysium CD-specific autoantibodies assigned to this enzyme a master regulator role of CD. Two separated events, both based on the finding that gliadin is able to act as a TG2 substrate, have been described to indicate that TG2 is involved in both the humoral and cellular immune responses. In this paper we review the novel insights on the localization and enzymatic activity of TG2 in the small intestinal mucosa. Moreover, we report on the capability of gliadin and its peptides to act as TG2 substrates.

Keywords: Keywords: Transglutaminase 2 – Celiac disease – Gluten – Enterocytes

Tissue transglutaminase in normal and abnormal wound healing: Review article by E. A. M. Verderio; T. Johnson; M. Griffin (pp. 387-404).

A complex series of events involving inflammation, cell migration and proliferation, ECM stabilisation and remodelling, neovascularisation and apoptosis are crucial to the tissue response to injury. Wound healing involves the dynamic interactions of multiple cells types with components of the extracellular matrix (ECM) and growth factors. Impaired wound healing as a consequence of aging, injury or disease may lead to serious disabilities and poor quality of life. Abnormal wound healing may also lead to inflammatory and fibrotic conditions (such as renal and pulmonary fibrosis). Therefore identification of the molecular events underlying wound repair is essential to develop new effective treatments in support to patients and the wound care sector.Recent advances in the understating of the physiological functions of tissue transglutaminase a multi functional protein cross-linking enzyme which stabilises tissues have demonstrated that its biological activities interrelate with wound healing phases at multiple levels. This review describes our view of the function of tissue transglutaminase in wound repair under normal and pathological situations and highlights its potential as a strategic therapeutic target in the development of new treatments to improve wound healing and prevent scarring.

Keywords: Keywords: Tissue transglutaminase – Wound healing – Fibrosis – Fibronectin – Collagen

Overexpressed transglutaminase 5 triggers cell death by B. Cadot; A. Rufini; V. Pietroni; S. Ramadan; P. Guerrieri; G. Melino; E. Candi (pp. 405-408).

Transglutaminases are a class of nine different proteins involved in many biological phenomena such as differentiation, tissue repair, endocytosis. Transglutaminase 5 was originally cloned from skin keratinocytes, and a partial biochemical characterization showed its involvment in skin differentiation. Here we demonstrate that transglutaminase 5 is able to induce cell death when intracellularly overexpressed. Transfected cells show enzymatic activity, as demonstrated by fluoresceincadaverine staining. Transfected cells died due to the formation of hypodiploid DNA content, indicating the induction of cell death under these pharmacological conditions. We also show that the primary sequence of transglutaminase 5 contains GTP binding domains which are similar to those in transglutaminase 2. This raises the possibility that transglutaminase 5 is regulated by GTP in a similar fashion to transglutaminase 2.

Keywords: Keywords: Transglutaminase – Cell death – Cross-links – Skin

Translational and post-translational modifications of proteins as a new mechanism of action of Alpha-Interferon: Review article by M. Caraglia; G. Vitale; M. Marra; S. Del Prete; A. Lentini; A. Budillon; S. Beninati; A. Abbruzzese (pp. 409-417).

Interferon-α (IFNα) is a recombinant protein widely used in the therapy of several neoplasms such as myeloma, renal cell carcinoma, epidermoid cervical and head and neck tumours and melanoma. IFNα, the first cytokine to be produced by recombinant DNA technology, has emerged as an important regulator of cancer cell growth and differentiation, affecting cellular communication and signal transduction pathways. However, the way by which tumour cell growth is directly suppressed by IFNα is not well known. Wide evidence exists on the possibility that cancer cells undergo apoptosis after the exposure to the cytokine. Here we will discuss data obtained by us and others on the post-translational regulation of the expression of proteins involved in the occurrence of apoptotic process such as tissue transglutaminase (tTG) or in the modulation of cell cycle such as the cyclin-dependent kinase inhibitor p27. This new way of regulation of p27 and tTG occurs through the modulation of their proteasome-dependent degradation induced by the cytokine. We will also review the involvement of protein synthesis machinery in the induction of cell growth inhibition by IFNα. In details, we will describe the effects of IFNα on the expression and activity of the protein kinase dependent from dsRNA (PKR) and on the eukaryotic initiation factor of protein synthesis 5A (eIF-5A) and their correlations with the regulation of cancer cell growth. These data strongly suggest that the antitumour activity of IFNα against human tumours could involve still unexplored mechanisms based on post-translational and translational control of the expression of proteins that regulate cell proliferation and apoptosis.

Keywords: Keywords: Interferon α – STAT – Ubiquitin – tTG – eIF-5A – Hypusine – PKR

Producing transglutaminases by molecular farming in plants: Minireview article by T. Capell; I. Claparols; S. Del Duca; L. Bassie; B. Miro; J. Rodriguez-Montesinos; P. Christou; D. Serafini-Fracassini (pp. 419-423).

Transglutaminases have a range of catalytic activities, most of which concern the post-translational modification of proteins. The most important of these activities, both in terms of biology and biotechnology, is the cross-linking of proteins into large supramolecular networks. The widespread use of transglutaminases in research, medicine and industry has increased the demand for an inexpensive, efficient and safe source of recombinant enzymes. We describe initial results concerning the production of a mammalian transglutaminase in transgenic rice plants as a first step towards the large-scale molecular farming of this enzyme.

Keywords: Keywords: Transglutaminase – Recombinant protein – Molecular farming – Plants – Biotechnology

Transglutaminase 5 is acetylated at the N-terminal end by A. Rufini; F. Vilbois; A. Paradisi; S. Oddi; R. Tartaglione; A. Leta; G. Bagetta; P. Guerrieri; A. Finazzi-Agro’; G. Melino; E. Candi (pp. 425-430).

Transglutaminases (TGases) are calcium-dependent enzymes that catalyse cross-linking between proteins by acyl transfer reaction; they are involved in many biological processes including coagulation, differentiation, and tissue repair. Transglutaminase 5 was originally cloned from keratinocytes, and a partial biochemical characterisation showed its involvement in skin differentiation, in parallel to TGase 1 and TGase 3. Here, we demonstrate, by electrospray tandem mass spectrometry that TGase 5 is acetylated at the N-terminal end. Moreover, in situ measurement of TGase activity shows that endogenous TGase 5 is active upon treatment with phorbol acetate, and the enzyme co-localises with vimentin intermediate filaments.

Keywords: Keywords: Transglutaminase – Vimentin – Cross-links – Cytoskeleton – Acetylation – Tandem mass spectrometry

Biochemical mechanisms for a possible involvement of the transglutaminase activity in the pathogenesis of the polyglutamine diseases: Minireview article by I. Pepe; E. Occhino; G. Cella; A. Luongo; F. Guardascione; V. Gentile (pp. 431-434).

Transglutaminases are a family of enzymes which show the common capacity to catalyse the cross-linking of protein substrates. Some members of this family of enzymes are also capable to catalyse other chemical reactions for the cell life. The distribution and the role of these enzymes have been studied in numerous cell types and tissues, but only recently their expression and functions started to be investigated in the Nervous System. One of the main biochemical properties of the Transglutaminase enzymes is to form large protein aggregates that are insoluble in all known protein detergents. Recently, the Transglutaminase activity has been hypothesised to be involved in the pathogenetic mechanisms responsible for the formation of cellular inclusions present in the Corea Major and in other polyglutamine diseases. In this review we describe the biochemical mechanisms by which the Transglutaminases could play a critical role in the physiopathology of the polyglutamine diseases.

Keywords: Keywords: Transglutaminases – Polyglutamine diseases – Protein aggregates – Nervous system

Acetylation of proteins as novel target for antitumor therapy: Review article by E. Di Gennaro; F. Bruzzese; M. Caraglia; A. Abruzzese; A. Budillon (pp. 435-441).

Imbalance in histone acetylation can lead to changes in chromatin structure and transcriptional dysregulation of genes that are involved in the control of proliferation, cell-cycle progression, differentiation and/or apoptosis. Histone acetyltransferases (HATs) and histone deacetylases (HDACs), are two classes of enzymes regulating histone acetylation and whose altered activity has been identified in several cancers. HATs and HDACs enzymes also target non histone protein substrates, including transcription factors, nuclear import factors, cytoskeleton and chaperon proteins. HDAC inhibitors are a novel class of anticancer agents which have been recently shown to induce growth arrest and apoptosis in a variety of human cancer cells by mechanism that cannot be solely attributed to the level of histone acetylation. Several clinical studies with HDAC inhibitors are ongoing, however the molecular basis for their tumour selectivity remains unknown and represent a challenge for the cancer research community.

Keywords: Keywords: Cancer – Chromatin – Histone – Histone deacetylase – Histone deacetylase inhibitors – Transglutaminase

The translation elongation factor 1A in tumorigenesis, signal transduction and apoptosis: Review article by A. Lamberti; M. Caraglia; O. Longo; M. Marra; A. Abbruzzese; P. Arcari (pp. 443-448).

An increasing number of evidences suggest the involvement of the eukaryotic elongation factor 1A, a core component of the protein synthesis machinery, at the onset of cell transformation. In fact, eEF1A is shown to be up-regulated in cell death; moreover, it seems to be involved in the regulation of ubiquitin-mediated protein degradation. In addition, eEF1A undergoes several post-translational modifications, mainly phosphorylation and methylation, that generally influence the activity of the protein. This article summarizes the present knowledges on the several extra-translational roles of eEF1A also in order to understand as the protein synthesis regulatory mechanisms could offer tools for cancer intervention.

Keywords: Keywords: Translation elongation factor 1A – Protein synthesis – Ubiquitin – Interferon α

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Amino Acids: The Forum for Amino Acid, Peptide and Protein Research (v.26, #4)