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Introduction
Publications
Publications (76)
Most tumor cells can use glutamine (Gln) for energy generation and biosynthetic purposes. Glutaminases (GAs) convert Gln into glutamate and ammonium. In humans, GAs are encoded by two genes: GLS and GLS2. In glioblastoma, GLS is commonly overexpressed and considered pro-oncogenic. We studied the metabolic effects of inhibiting GLS activity in T98G,...
Background
Glutaminase isoenzymes GLS and GLS2 play apparently opposing roles in cancer: GLS acts as an oncoprotein, while GLS2 (GAB isoform) has context specific tumour suppressive activity. Some microRNAs (miRNAs) have been implicated in progression of tumours, including gliomas. The aim was to investigate the effect of GLS and GAB expression on...
Glioblastoma remains one of the most challenging and devastating cancers, with only a very small proportion of patients achieving 5-year survival. The current standard of care consists of surgery, followed by radiation therapy with concurrent and maintenance chemotherapy with the alkylating agent temozolomide. To date, this drug is the only one tha...
CoFe2O4 nanoparticles (NPs) were synthesized using cobalt and iron nitrate, sucrose, and olive leaf extract by the sol-gel auto-combustion method and used to evaluate their magnetic properties. The synthesis method used in this study was eco-friendly, simple, and inexpensive. The effect of using different amounts of plant extract as a complexing ag...
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Metabolism and its regulation is one of the most complex and difficult topics for students learning biochemistry. A problem-/case-based learning (PBL) approach can be useful to help biochemistry students to fulfill the goal of acquiring an integrated view of metabolism and its regulation. The present article describes our experience enrolling volun...
Glutaminase (GA) catalyzes the first step in mitochondrial glutaminolysis playing a key role in cancer metabolic reprogramming. Humans express two types of GA isoforms: GLS and GLS2. GLS isozymes have been consistently related to cell proliferation, but the role of GLS2 in cancer remains poorly understood. GLS2 is repressed in many tumor cells and...
Background
Metabolic reprogramming of tumours is a hallmark of cancer. Among the changes in the metabolic network of cancer cells, glutaminolysis is a key reaction altered in neoplasms. Glutaminase proteins control the first step in glutamine metabolism and their expression correlates with malignancy and growth rate of a great variety of cancers. T...
In congenital hydrocephalus, cerebrospinal fluid accumulation is associated with increased intracranial pressure (ICP), ischemia/hypoxia, metabolic impairment, neuronal damage, and astrocytic reaction. The aim of this study was to identify whether a metabolite profile revealing tissue responses according to the severity of hydrocephalus can be dete...
The cover image, by Inmaculada Ruz‐Maldonado et al., is based on the Original Article LH‐21 and abnormal cannabidiol improve β‐cell function in isolated human and mouse islets through GPR55‐dependent and ‐independent signalling, DOI: 10.1111/dom.13180.
Aims:
CB1 and GPR55 are GPCRs expressed by islet β-cells. Pharmacological compounds have been used to investigate their function, but off-target effects of ligands have been reported. This study examined the effects of Abn-CBD (GPR55 agonist) and LH-21 (CB1 antagonist) on human and mouse islet function, and islets from GPR55-/- mice were used to d...
Lysophosphatidic acid (LPA) is an extracellular lipid mediator that regulates nervous system development and functions acting through G protein-coupled receptors (GPCRs). Here we explore the crosstalk between LPA1 receptor and glutamatergic transmission by examining expression of glutaminase (GA) isoforms in different brain areas isolated from wild...
Cancer cells develop and succeed by shifting to different metabolic programs compared with their normal cell counterparts. One of the classical hallmarks of cancer cells is their higher glycolysis rate and lactate production even in the presence of abundant O2 (Warburg effect). Another common metabolic feature of cancer cells is a high rate of glut...
Metabolic Biochemistry is a subject that is perceived as particularly challenging by our undergraduate
students in Biology. In fact, all the contents of its syllabus should be properly interconnected by our
students throughout their study of the subject in order to get a global insight of the complex regulatory
features controlling metabolism as a...
Glutamate is the principal excitatory neurotransmitter in the central nervous system and its actions are related to the behavioral effects of psychostimulant drugs. In the last two decades, basic neuroscience research and preclinical studies with animal models are suggesting a critical role for glutamate transmission in drug reward, reinforcement,...
La Bioquímica es una materia que, organizada en sus múltiples asignaturas, se imparte a lo largo del currículo de algunos grados de Ciencias (Biología, Química, Bioquímica). Es habitual que la primera aproximación a esta disciplina que el alumnado afronta sea cursando una asignatura de Fundamentos de Bioquímica o Bioquímica General, que a su vez pu...
La Bioquímica es una materia que, organizada en sus múltiples asignaturas, se imparte a lo largo del currículo de algunos grados de Ciencias (Biología, Química, Bioquímica). Es habitual que la primera aproximación a esta disciplina que el alumnado afronta sea cursando una asignatura de Fundamentos de Bioquímica o Bioquímica General, que a su vez pu...
The expression of glutaminase in glial cells has been a controversial issue and matter of debate for many years. Actually, glutaminase is essentially considered as a neuronal marker in brain. Astrocytes are endowed with efficient and high capacity transport systems to recapture synaptic glutamate which seems to be consistent with the absence of glu...
Metabolism is fundamental to cell survival, growth, and behavior. Tumor cells have an enhanced demand for nutrients which provide biosynthetic building blocks and cellular energy to sustain their proliferative status. Altered metabolism is a hallmark of cancer. The term metabolic reprogramming has been coined to describe the whole range of metaboli...
Mammalian glutaminase (GA; EC 3.5.1.2) is the main enzyme involved in brain generation of glutamate (Glu). This amino acid acts as an excitatory neurotransmitter within the CNS, and it is also implicated in behavioral sensitization through the mesolimbic pathway. Two different GA genes have been described: Gls that encodes the isozymes KGA and GAC,...
Unlabelled:
Mitochondrial glutaminase (GA) plays an essential role in cancer cell metabolism, contributing to biosynthesis, bioenergetics, and redox balance. Humans contain several GA isozymes encoded by the GLS and GLS2 genes, but the specific roles of each in cancer metabolism are still unclear. In this study, glioma SFxL and LN229 cells with si...
Tumor cells suffer a metabolic reprogramming which allows them to use metabolic fuels (glucose, glutamine, lipids) through anabolic fates to support their enhanced proliferation and other carcinogenesis-related features. The present review tries to address and summarize the broad and growing information available about this reprogramming, whose pie...
Cancer cells require a robust supply of reduced nitrogen to produce nucleotides, non-essential amino acids and a high cellular redox activity. Glutamine provides a major substrate for respiration as well as nitrogen for the production of proteins, hexosamines, and macromolecules. Therefore, glutamine is one of key molecules in cancer metabolism dur...
The oxygen paradox tells us that oxygen is both necessary for aerobic life and toxic to all life forms. Reactive oxygen species (ROS) touch every biological and medical discipline, especially those involving proliferative status, supporting the idea that active oxygen may be increased in tumor cells. In fact, metabolism of oxygen and the resulting...
Glutaminase is expressed in most mammalian tissues and cancer cells, but the regulation of its expression is poorly understood. An essential step to accomplish this goal is the characterization of its species- and cell-specific isoenzyme pattern of expression. Our aim was to identify and characterize transcript variants of the mammalian glutaminase...
Comparison of N-terminal amino acid sequences of LGA and GAB proteins from mouse, rat and human tissues. Sequence alignment of the N-termini of the indicated proteins were done using Multalin program (http://multalin.toulouse.inra.fr/multalin/). For the sake of clarity, the same order as in the nucleotide sequence comparison shown in Fig. 2 was mai...
Oligonucleotide sequences used for real-time RT-PCR of GAB- and LGA-specific amplicons in brain and liver tissues from rat and mouse. The nucleotide sequences for sense (forward) and antisense (reverse) primers used in the real-time RT-PCR experiments are shown. Mouse primers are indicated with the abbreviation “m” and rat primers with “r”. Primers...
The altered metabolism of tumors has been considered a target for anticancer therapy. However, the relationship between distinct tumor-initiating lesions and anomalies of tumor metabolism in vivo has not been addressed. We report that MYC-induced mouse liver tumors significantly increase both glucose and glutamine catabolism, whereas MET-induced li...
The chapters in this book are arranged within a thematic structure as indicated in the sections below. The first part pursues the theme of amino acid metabolism through the driving actions of the principal enzymes, emphasizing recent developments particularly with reference to localization, molecular genetics, biophysical characterization and regul...
The prevention of oxidation is an essential process in all cells, as decreased antioxidant protection may lead to cytotoxicity, mutagenicity and carcinogenicity. The mechanisms by which oxidative stress contributes to carcinogenesis include modulation of gene expression and induction of genetic modifications. Cellular methylation and antioxidant me...
A key role for phosphate-activated glutaminasehas been proposed for the synthesis of neurotransmitterglutamate and g - aminobutyric acid(GABA) in the brain. This synthesis must beexquisitely regulated because of its potentialharmful effects giving rise to excitotoxic damage.It is noteworthy that two glutaminaseisozymes coded by different genes are...
Lysophosphatidic acid is a phospholipid mediator that modulates neurodevelopment and neurogenesis in the hippocampus through its actions on LPA1 receptors. Emerging evidences support LPA(1) as a mediator of learning and emotional behaviour. There are no studies addressing its role on behaviours associated to drug abuse.
We examined whether genetic...
Plant foods are not only a main source of nutrients, but they are also rich in physiologically bioactive bionutrients or phytochemicals. Consumption of fruit and vegetables is associated with a decreased risk of pathological status, including cancer. Reactive oxygen species play a key role in the genesis and development of cancer. Therefore, antiox...
Oxidants have critical functions inside healthy and unhealthy cells. Deregulated cell cycle and apoptosis, both regulated by oxidative stress, have been described as hallmarks of mitotic (cancer) and postmitotic (neuronal) cells. This review provides an updated revision of the oxidant effects of some environmental contaminants such as dioxins and t...
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Glutaminase is considered as the main glutamate producer enzyme in brain. Consequently, the enzyme is essential for both glutamatergic and gabaergic transmissions. Glutamine-derived glutamate and ammonia, the products of glutaminase reaction, fulfill crucial roles in energy metabolism and in the biosynthesis of basic metabolites, such as GABA, prot...
Glutamine is a multifaceted amino acid that plays key roles in many metabolic pathways and also fulfils essential signaling functions. Although classified as non-essential, recent evidence suggests that glutamine is a conditionally essential amino acid in several physiological situations. Glutamine homeostasis must therefore be exquisitely regulate...
An all out war is continuously occurring between oxidants and antioxidants inside the cells. This mini-review will provide an updated revision of the function of some natural compounds having main roles in antioxidant function. We will point on some phytochemicals working at two outstanding targets, tumour cells and neurons.
Liver-type glutaminase (LGA) is a glutaminase isoform that has been implicated in transcription modulation. LGA mRNA is absent from postoperative samples of primary gliomas and is low in cultured astrocytes. In this study, stable transfection of T98G cells with a vector carrying human LGA sequence increased the expression of LGA mRNA and protein, a...
The synthesis of glutamate in brain must be exquisitely regulated because of its harmful potential giving rise to excitotoxic damage. In this sense, a stringent control based on multiple regulatory mechanisms should be expected to be exhibited by the biosynthetic enzymes responsible of glutamate generation, to assure that glutamate is only synthesi...
The synthesis of neurotransmitter glutamate in brain is mainly carried out by glutaminase enzymes. This synthesis must be exquisitely regulated because of its harmful potential giving rise to excitotoxic damage. It is noteworthy that two glutaminase isozymes coded by different genes are expressed in the brain of mammals. The need for two genes and...
The synthesis of glutamate in brain must be exquisitely regulated because of its harmful potential giving rise to excitotoxic damage. In this sense, a stringent control based on multiple regulatory mechanisms should be expected to be exhibited by the biosynthetic enzymes responsible of glutamate generation, to assure that glutamate is only synthesi...
The synthesis of neurotransmitter glutamate in brain is mainly carried out by glutaminase enzymes. This synthesis must be exquisitely regulated because of its harmful potential giving rise to excitotoxic damage. It is noteworthy that two glutaminase isozymes coded by different genes are expressed in the brain of mammals. The need for two genes and...
Oxidative stress can be defined as the imbalance between cellular oxidant species production and antioxidant capability. Reactive oxygen species (ROS) are involved in a variety of different cellular processes ranging from apoptosis and necrosis to cell proliferation and carcinogenesis. In fact, molecular events, such as induction of cell proliferat...
A human brain cDNA clone coding for a novel PDZ-domain protein of 124 amino acids was previously isolated in our laboratory. The protein was termed glutaminase-interacting protein (GIP), because it interacts with the C-terminal region of the human L-type glutaminase (LGA). The pattern of expression and functions of GIP in brain are completely unkno...
A human brain cDNA clone coding for a novel PDZ-domain protein of 124 amino acids was previously isolated in our laboratory. The protein was termed glutaminase-interacting protein (GIP), because it interacts with the C-terminal region of the human L-type glutaminase (LGA). The pattern of expression and functions of GIP in brain are completely unkno...
A human brain cDNA clone coding for a novel PDZ-domain protein of 124 amino acids was previously isolated in our laboratory. The protein was termed glutaminase-interacting protein (GIP), because it interacts with the C-terminal region of the human L-type glutaminase (LGA). The pattern of expression and functions of GIP in brain are completely unkno...
Glutaminase catalyzes the hydrolysis of glutamine yielding stoichiometric amounts of glutamate plus ammonium ions. In mammals, there are two different genes encoding for glutaminase, known as liver (L) and kidney (K) types. The human L-type isoform expressed in baculovirus yielded functional recombinant enzyme in Sf9 insect cells. A novel affinity...
The protein glutaminase has been traditionally considered as a mitochondrial enzyme, playing a key role in the energy and nitrogen metabolism of mammalian cells. However, new experimental evidence in the last few years has challenged this simplified view. The recent discovery of novel extramitochondrial localizations, the identification of potentia...
It is fascinating that a relatively simple amino acid like glutamine is involved in such large variety of cellular reactions. Glutamine is required for nitrogen-stimulated proliferation in many cells, but glutamine stimulates not only the growth of cells but also the expression of surface antigens, the formation of cytokines, the synthesis of heat...
Ehrlich ascites tumor cells (EATC) is a highly proliferative malignant cell line derived from mouse mammary epithelia, whereas their derivative, 0.28AS-2 cells, expressing antisense glutaminase mRNA, show a less transformed phenotype and loss of their tumorigenic capacity in vivo correlated with an inhibition of glutaminase expression. The mRNA dif...
Glutaminase activity is correlated with cancer proliferation and with growth rate in normal cells. Ehrlich ascites tumour cells (EATC) and their derivative 0.28AS-2 cells, which express antisense glutaminase mRNA, show differences in both morphology and tumorigenic capacity.
Cell viability was determined with the microtetrazolium cytotoxicity test...
The pattern of expression of glutaminase isoenzymes in tumour cells has been investigated to clarify its role in the malignant transformation and the prospect of its use as a clinically relevant factor. Using leukaemia cells from medullar blood of human patients and several established human cancer cell lines, we have developed a competitive RT (re...
Tumor cells expressing antisense glutaminase RNA show a drastic inhibition of glutaminase activity and they acquire a more differentiated phenotype. We have studied the expression of Sp1 and Sp3 transcription factors in both Ehrlich tumor cells and their derivative 0.28AS-2 antisense glutaminase expressing cells. The expression of phosphorylated Sp...
Glutamine is an essential amino acid in cancer cells and is required for the growth of many other cell types. Glutaminase activity is positively correlated with malignancy in tumours and with growth rate in normal cells. In the present work, Ehrlich ascites tumour cells, and their derivative, 0.28AS-2 cells, expressing antisense glutaminase mRNA, w...
The first complete sequence of human L-glutaminase was deduced from breast cancer glutaminase cDNA cloned in our laboratory. This cDNA clone has now been engineered to synthesize both precursor and mature forms of the protein in Escherichia coli. Among several different plasmid constructions, the expression system based on phage T7 promoter (vector...
In mammals, glutaminase (GA) is expressed in most tissues, but the regulation of organ-specific expression is largely unknown. Therefore, as an essential step towards studying the regulation of GA expression, the human liver-type GA (hLGA) gene has been characterized. LGA genomic sequences were isolated using the genome walking technique. Analysis...
In mammals, there are two different genes encoding for glutaminase isoforms, named liver (LGA) and kidney (KGA) types. LGA has long been believed to be present only in liver mitochondria from adult animals. However, we have recently reported the presence of LGA mRNA in human brain. We now describe the expression of LGA mRNA in the brain of other ma...
Glutaminase (EC 3.5.1.2) is a key enzyme in rapidly proliferating cells. Using anti-sense technology, an Ehrlich ascites tumor cell line (0.28AS-2) with reduced glutaminase activity has been obtained. We investigated the in vivo growth characteristics of the 0.28AS-2 cells. When injected i.p. into normal Swiss albino mice, the 0.28AS-2 cells were u...
Glutaminase (EC 3.5.1.2) is a key enzyme in rapidly proliferating cells. Using anti-sense technology, an Ehrlich ascites tumor cell line (0.28AS-2) with reduced glutaminase activity has been obtained. We investigated the in vivo growth characteristics of the 0.28AS-2 cells. When injected i.p. into normal Swiss albino mice, the 0.28AS-2 cells were u...
Glutaminase (EC 3.5.1.2) is a key enzyme in rapidly proliferating cells. Using anti‐sense technology, an Ehrlich ascites tumor cell line (0.28AS‐2) with reduced glutaminase activity has been obtained. We investigated the in vivo growth characteristics of the 0.28AS‐2 cells. When injected i.p. into normal Swiss albino mice, the 0.28AS‐2 cells were u...
Phosphate-activated glutaminase has a critical role in tumours and rapidly dividing cells and its activity is correlated with malignancy. Ehrlich ascites tumour cells transfected with the pcDNA3 vector containing an antisense segment (0.28 kb) of rat kidney glutaminase showed impairment in the growth rate and plating efficiency, as well as a shorta...
The last step in the synthesis of lignin and suberin has been proposed to be catalyzed by peroxidases, although other proteins may also be involved. To determine which peroxidases are involved in the synthesis of lignin and suberin, five peroxidases from tomato (Lycopersicon esculentum) roots, representing the majority of the peroxidase activity in...
Phosphate-activated glutaminase (GA) is overexpressed in certain types of tumour but its exact role in tumour cell growth and proliferation is unknown. Here we describe the isolation of a full-length cDNA clone of human breast cancer ZR75 cells, by a combination of lambdagt10 cDNA library screening and the rapid amplification of cDNA ends ('RACE')...
Didemnins are cytotoxic agents belonging to a depsipeptide family isolated from marine tunicates. In the present study, a new member, dehydrodidemnin B (DDB), isolated from the mediterranean tunicate Aplidium albicans, was used. The effect of the drug on human colon cultured cell lines was tested using multiple approaches: proliferation studies, lo...
The subcommissural organ secretes N-linked complex-type glycoproteins into the cerebrospinal fluid. These glycoproteins condense to form Reissner's fiber (RF), which extends along the fourth ventricle and central canal of the spinal cord. A set of three monoclonal antibodies (Mabs 3E6, 3B1, and 2A5) has been obtained using these glycoproteins as im...