Biomolecules

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Open AccessReview

NMR Meets Tau: Insights into Its Function and Pathology

by Guy Lippens, Isabelle Landrieu, Caroline Smet, Isabelle Huvent, Neha S. Gandhi, Benoît Gigant, Clément Despres, Haoling Qi and Juan Lopez

Biomolecules 2016, 6(2), 28; https://doi.org/10.3390/biom6020028 - 7 Jun 2016

Cited by 25 | Viewed by 8520

Abstract

In this review, we focus on what we have learned from Nuclear Magnetic Resonance (NMR) studies on the neuronal microtubule-associated protein Tau. We consider both the mechanistic details of Tau: the tubulin relationship and its aggregation process. Phosphorylation of Tau is intimately linked [...] Read more.

In this review, we focus on what we have learned from Nuclear Magnetic Resonance (NMR) studies on the neuronal microtubule-associated protein Tau. We consider both the mechanistic details of Tau: the tubulin relationship and its aggregation process. Phosphorylation of Tau is intimately linked to both aspects. NMR spectroscopy has depicted accurate phosphorylation patterns by different kinases, and its non-destructive character has allowed functional assays with the same samples. Finally, we will discuss other post-translational modifications of Tau and its interaction with other cellular factors in relationship to its (dys)function. Full article

(This article belongs to the Collection Intrinsically Disordered Proteins)

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Open AccessReview

The Diversity of Ribonuclease P: Protein and RNA Catalysts with Analogous Biological Functions

by Bradley P. Klemm, Nancy Wu, Yu Chen, Xin Liu, Kipchumba J. Kaitany, Michael J. Howard and Carol A. Fierke

Biomolecules 2016, 6(2), 27; https://doi.org/10.3390/biom6020027 - 13 May 2016

Cited by 55 | Viewed by 10010

Abstract

Ribonuclease P (RNase P) is an essential endonuclease responsible for catalyzing 5’ end maturation in precursor transfer RNAs. Since its discovery in the 1970s, RNase P enzymes have been identified and studied throughout the three domains of life. Interestingly, RNase P is either [...] Read more.

Ribonuclease P (RNase P) is an essential endonuclease responsible for catalyzing 5’ end maturation in precursor transfer RNAs. Since its discovery in the 1970s, RNase P enzymes have been identified and studied throughout the three domains of life. Interestingly, RNase P is either RNA-based, with a catalytic RNA subunit, or a protein-only (PRORP) enzyme with differential evolutionary distribution. The available structural data, including the active site data, provides insight into catalysis and substrate recognition. The hydrolytic and kinetic mechanisms of the two forms of RNase P enzymes are similar, yet features unique to the RNA-based and PRORP enzymes are consistent with different evolutionary origins. The various RNase P enzymes, in addition to their primary role in tRNA 5’ maturation, catalyze cleavage of a variety of alternative substrates, indicating a diversification of RNase P function in vivo. The review concludes with a discussion of recent advances and interesting research directions in the field. Full article

(This article belongs to the Special Issue Function and Structure of RNase P in Fungi, Bacteria and Human Cells)

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Open AccessReview

A Bitter Sweet Symphony: Immune Responses to Altered O-glycan Epitopes in Cancer

by Lenneke A.M. Cornelissen and Sandra J. Van Vliet

Biomolecules 2016, 6(2), 26; https://doi.org/10.3390/biom6020026 - 3 May 2016

Cited by 43 | Viewed by 7847

Abstract

The appearance of aberrant glycans on the tumor cell surface is one of the emerging hallmarks of cancer. Glycosylation is an important post-translation modification of proteins and lipids and is strongly affected by oncogenesis. Tumor-associated glycans have been extensively characterized regarding their composition [...] Read more.

The appearance of aberrant glycans on the tumor cell surface is one of the emerging hallmarks of cancer. Glycosylation is an important post-translation modification of proteins and lipids and is strongly affected by oncogenesis. Tumor-associated glycans have been extensively characterized regarding their composition and tumor-type specific expression patterns. Nevertheless whether and how tumor-associated glycans contribute to the observed immunomodulatory actions by tumors has not been extensively studied. Here, we provide a detailed overview of the current knowledge on how tumor-associated O-glycans affect the anti-tumor immune response, thereby focusing on truncated O-glycans present on epithelial tumors and mucins. These tumor-associated O-glycans and mucins bind a variety of lectin receptors on immune cells to facilitate the subsequently induction of tolerogenic immune responses. We, therefore, postulate that tumor-associated glycans not only support tumor growth, but also actively contribute to immune evasion. Full article

(This article belongs to the Special Issue Cancer and Glycosylation)

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1541 KiB

Open AccessReview

Enzymes for N-Glycan Branching and Their Genetic and Nongenetic Regulation in Cancer

by Yasuhiko Kizuka and Naoyuki Taniguchi

Biomolecules 2016, 6(2), 25; https://doi.org/10.3390/biom6020025 - 28 Apr 2016

Cited by 108 | Viewed by 17275

Abstract

N-glycan, a fundamental and versatile protein modification in mammals, plays critical roles in various physiological and pathological events including cancer progression. The formation of N-glycan branches catalyzed by specific N-acetylglucosaminyltransferases [GnT-III, GnT-IVs, GnT-V, GnT-IX (Vb)] and a fucosyltransferase, Fut8, provides [...] Read more.

N-glycan, a fundamental and versatile protein modification in mammals, plays critical roles in various physiological and pathological events including cancer progression. The formation of N-glycan branches catalyzed by specific N-acetylglucosaminyltransferases [GnT-III, GnT-IVs, GnT-V, GnT-IX (Vb)] and a fucosyltransferase, Fut8, provides functionally diverse N-glycosylated proteins. Aberrations of these branches are often found in cancer cells and are profoundly involved in cancer growth, invasion and metastasis. In this review, we focus on the GlcNAc and fucose branches of N-glycans and describe how their expression is dysregulated in cancer by genetic and nongenetic mechanisms including epigenetics and nucleotide sugar metabolisms. We also survey the roles that these N-glycans play in cancer progression and therapeutics. Finally, we discuss possible applications of our knowledge on basic glycobiology to the development of medicine and biomarkers for cancer therapy. Full article

(This article belongs to the Special Issue Cancer and Glycosylation)

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Open AccessReview

Molecular Mechanisms in the Pathogenesis of Alzheimer’s disease and Tauopathies-Prion-Like Seeded Aggregation and Phosphorylation

by Masato Hasegawa

Biomolecules 2016, 6(2), 24; https://doi.org/10.3390/biom6020024 - 28 Apr 2016

Cited by 50 | Viewed by 10747

Abstract

Neurofibrillary tau pathology (tangles and threads) and extracellular amyloid-β (Aβ) pathology are defining features of Alzheimer’s disease. For 25 years, most research has focused on the amyloid hypothesis of AD pathogenesis and progression. But, because of failures in clinical trials of Aβ-targeted therapies [...] Read more.

Neurofibrillary tau pathology (tangles and threads) and extracellular amyloid-β (Aβ) pathology are defining features of Alzheimer’s disease. For 25 years, most research has focused on the amyloid hypothesis of AD pathogenesis and progression. But, because of failures in clinical trials of Aβ-targeted therapies and the new concept of prion-like propagation of intracellular abnormal proteins, tau has come back into the spotlight as a candidate therapeutic target in AD. Tau pathologies are found in a range of neurodegenerative disorders, but extensive analyses of pathological tau in diseased brains has demonstrated that the abnormal tau protein in each disease is structurally distinct, supporting the idea that progression of the diverse but characteristic tau pathologies occurs through prion-like seed-dependent aggregation. Therefore, intervention in the conversion of normal tau to abnormal forms and in cell-to-cell transmission of tau may be the key to development of disease-modifying therapies for AD and other dementing disorders. Full article

(This article belongs to the Special Issue Tau Protein and Alzheimer’s disease)

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Open AccessArticle

Taurine Bromamine: Reactivity of an Endogenous and Exogenous Anti-Inflammatory and Antimicrobial Amino Acid Derivative

by Luiza De Carvalho Bertozo, Nelson Henrique Morgon, Aguinaldo Robinson De Souza and Valdecir Farias Ximenes

Biomolecules 2016, 6(2), 23; https://doi.org/10.3390/biom6020023 - 21 Apr 2016

Cited by 14 | Viewed by 6088

Abstract

Taurine bromamine (Tau-NHBr) is produced by the reaction between hypobromous acid (HOBr) and the amino acid taurine. There are increasing number of applications of Tau-NHBr as an anti-inflammatory and microbicidal drug for topical usage. Here, we performed a comprehensive study of the chemical [...] Read more.

Taurine bromamine (Tau-NHBr) is produced by the reaction between hypobromous acid (HOBr) and the amino acid taurine. There are increasing number of applications of Tau-NHBr as an anti-inflammatory and microbicidal drug for topical usage. Here, we performed a comprehensive study of the chemical reactivity of Tau-NHBr with endogenous and non-endogenous compounds. Tau-NHBr reactivity was compared with HOBr, hypochlorous acid (HOCl) and taurine chloramine (Tau-NHCl). The second-order rate constants (k₂) for the reactions between Tau-NHBr and tryptophan (7.7 × 10² M⁻¹s⁻¹), melatonin (7.3 × 10³ M⁻¹s⁻¹), serotonin (2.9 × 10³ M⁻¹s⁻¹), dansylglycine (9.5 × 10¹ M⁻¹s⁻¹), tetramethylbenzidine (6.4 × 10² M⁻¹s⁻¹) and H₂O₂ (3.9 × M⁻¹s⁻¹) were obtained. Tau-NHBr demonstrated the following selectivity regarding its reactivity with free amino acids: tryptophan > cysteine ~ methionine > tyrosine. The reactivity of Tau-NHBr was strongly affected by the pH of the medium (for instance with dansylglycine: pH 5.0, 1.1 × 10⁴ M⁻¹s⁻¹, pH 7.0, 9.5 × 10 M⁻¹s⁻¹ and pH 9.0, 1.7 × 10 M⁻¹s⁻¹), a property that is related to the formation of the dibromamine form at acidic pH (Tau-NBr₂). The formation of singlet oxygen was observed in the reaction between Tau-NHBr and H₂O₂. Tau-NHBr was also able to react with linoleic acid, but with low efficiency compared with HOBr and HOCl. Compared with HOBr, Tau-NHBr was not able to react with nucleosides. In conclusion, the following reactivity sequence was established: HOBr > HOCl > Tau-NHBr > Tau-NHCl. These findings can be very helpful for researchers interested in biological applications of taurine haloamines. Full article

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Open AccessReview

Sequence Analysis and Comparative Study of the Protein Subunits of Archaeal RNase P

by Manoj P. Samanta, Stella M. Lai, Charles J. Daniels and Venkat Gopalan

Biomolecules 2016, 6(2), 22; https://doi.org/10.3390/biom6020022 - 20 Apr 2016

Cited by 10 | Viewed by 5766

Abstract

RNase P, a ribozyme-based ribonucleoprotein (RNP) complex that catalyzes tRNA 5′-maturation, is ubiquitous in all domains of life, but the evolution of its protein components (RNase P proteins, RPPs) is not well understood. Archaeal RPPs may provide clues on how the complex evolved [...] Read more.

RNase P, a ribozyme-based ribonucleoprotein (RNP) complex that catalyzes tRNA 5′-maturation, is ubiquitous in all domains of life, but the evolution of its protein components (RNase P proteins, RPPs) is not well understood. Archaeal RPPs may provide clues on how the complex evolved from an ancient ribozyme to an RNP with multiple archaeal and eukaryotic (homologous) RPPs, which are unrelated to the single bacterial RPP. Here, we analyzed the sequence and structure of archaeal RPPs from over 600 available genomes. All five RPPs are found in eight archaeal phyla, suggesting that these RPPs arose early in archaeal evolutionary history. The putative ancestral genomic loci of archaeal RPPs include genes encoding several members of ribosome, exosome, and proteasome complexes, which may indicate coevolution/coordinate regulation of RNase P with other core cellular machineries. Despite being ancient, RPPs generally lack sequence conservation compared to other universal proteins. By analyzing the relative frequency of residues at every position in the context of the high-resolution structures of each of the RPPs (either alone or as functional binary complexes), we suggest residues for mutational analysis that may help uncover structure-function relationships in RPPs. Full article

(This article belongs to the Special Issue Function and Structure of RNase P in Fungi, Bacteria and Human Cells)

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Open AccessReview

New Features about Tau Function and Dysfunction

by Miguel Medina, Félix Hernández and Jesús Avila

Biomolecules 2016, 6(2), 21; https://doi.org/10.3390/biom6020021 - 19 Apr 2016

Cited by 68 | Viewed by 8027

Abstract

Tau is a brain microtubule-associated protein that directly binds to a microtubule and dynamically regulates its structure and function. Under pathological conditions, tau self-assembles into filamentous structures that end up forming neurofibrillary tangles. Prominent tau neurofibrillary pathology is a common feature in a [...] Read more.

Tau is a brain microtubule-associated protein that directly binds to a microtubule and dynamically regulates its structure and function. Under pathological conditions, tau self-assembles into filamentous structures that end up forming neurofibrillary tangles. Prominent tau neurofibrillary pathology is a common feature in a number of neurodegenerative disorders, collectively referred to as tauopathies, the most common of which is Alzheimer’s disease (AD). Beyond its classical role as a microtubule-associated protein, recent advances in our understanding of tau cellular functions have revealed novel insights into their important role during pathogenesis and provided potential novel therapeutic targets. Regulation of tau behavior and function under physiological and pathological conditions is mainly achieved through post-translational modifications, including phosphorylation, glycosylation, acetylation, and truncation, among others, indicating the complexity and variability of factors influencing regulation of tau toxicity, all of which have significant implications for the development of novel therapeutic approaches in various neurodegenerative disorders. A more comprehensive understanding of the molecular mechanisms regulating tau function and dysfunction will provide us with a better outline of tau cellular networking and, hopefully, offer new clues for designing more efficient approaches to tackle tauopathies in the near future. Full article

(This article belongs to the Special Issue Tau Protein and Alzheimer’s disease)

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Open AccessEditorial

Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment

by Natalia A. Osna and Kusum K. Kharbanda

Biomolecules 2016, 6(2), 20; https://doi.org/10.3390/biom6020020 - 15 Apr 2016

Cited by 23 | Viewed by 6024

Abstract

Alcohol consumption causes damage to various organs and systems.[...] Full article

(This article belongs to the Special Issue Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)

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Open AccessArticle

Absence of a Role for Phosphorylation in the Tau Pathology of Alzheimer’s Disease

by Robert Y. K. Lai, Charles R. Harrington and Claude M. Wischik

Biomolecules 2016, 6(2), 19; https://doi.org/10.3390/biom6020019 - 8 Apr 2016

Cited by 19 | Viewed by 7247

Abstract

Alzheimer’s disease is characterized by redistribution of the tau protein pool from soluble to aggregated states. Aggregation forms proteolytically stable core polymers restricted to the repeat domain, and this binding interaction has prion-like properties. We have compared the binding properties of tau and [...] Read more.

Alzheimer’s disease is characterized by redistribution of the tau protein pool from soluble to aggregated states. Aggregation forms proteolytically stable core polymers restricted to the repeat domain, and this binding interaction has prion-like properties. We have compared the binding properties of tau and tubulin in vitro using a system in which we can measure binding affinities for proteins alternated between solid and aqueous phases. The study reveals that a phase-shifted repeat domain fragment from the Paired Helical Filament core contains all that is required for high affinity tau-tau binding. Unlike tau-tubulin binding, tau-tau binding shows concentration-dependent enhancement in both phase directions due to an avidity effect which permits one molecule to bind to many as the concentration in the opposite phase increases. Phosphorylation of tau inhibits tau-tau binding and tau-tubulin binding to equivalent extents. Tau-tau binding is favoured over tau-tubulin binding by factors in the range 19–41-fold, irrespective of phosphorylation status. A critical requirement for tau to become aggregation-competent is prior binding to a solid-phase substrate, which induces a conformational change in the repeat domain permitting high-affinity binding to occur even if tau is phosphorylated. The endogenous species enabling this nucleation event to occur in vivo remains to be identified. The findings of the study suggest that development of disease-modifying drugs for tauopathies should not target phosphorylation, but rather should target inhibitors of tau-tau binding or inhibitors of the binding interaction with as yet unidentified endogenous polyanionic substrates required to nucleate tau assembly. Full article

(This article belongs to the Special Issue Tau Protein and Alzheimer’s disease)

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2126 KiB

Open AccessReview

Trying on tRNA for Size: RNase P and the T-box Riboswitch as Molecular Rulers

by Jinwei Zhang and Adrian R. Ferré-DAmaré

Biomolecules 2016, 6(2), 18; https://doi.org/10.3390/biom6020018 - 1 Apr 2016

Cited by 22 | Viewed by 7786

Abstract

Length determination is a fundamental problem in biology and chemistry. Numerous proteins measure distances on linear biopolymers to exert effects with remarkable spatial precision. Recently, ruler-like devices made of noncoding RNAs have been structurally and biochemically characterized. Two prominent examples are the RNase [...] Read more.

Length determination is a fundamental problem in biology and chemistry. Numerous proteins measure distances on linear biopolymers to exert effects with remarkable spatial precision. Recently, ruler-like devices made of noncoding RNAs have been structurally and biochemically characterized. Two prominent examples are the RNase P ribozyme and the T-box riboswitch. Both act as molecular calipers. The two RNAs clamp onto the elbow of tRNA (or pre-tRNA) and make distance measurements orthogonal to each other. Here, we compare and contrast the molecular ruler characteristics of these RNAs. RNase P appears pre-configured to measure a fixed distance on pre-tRNA to ensure the fidelity of its maturation. RNase P is a multiple-turnover ribozyme, and its rigid structure efficiently selects pre-tRNAs, cleaves, and releases them. In contrast, the T-box is flexible and segmented, an architecture that adapts to the intrinsically flexible tRNA. The tripartite T-box inspects the overall shape, anticodon sequence, and aminoacylation status of an incoming tRNA while it folds co-transcriptionally, leading to a singular, conditional genetic switching event. The elucidation of the structures and mechanisms of action of these two RNA molecular rulers may augur the discovery of new RNA measuring devices in noncoding and viral transcriptomes, and inform the design of artificial RNA rulers. Full article

(This article belongs to the Special Issue Function and Structure of RNase P in Fungi, Bacteria and Human Cells)

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Open AccessArticle

The Involvement of Acetaldehyde in Ethanol-Induced Cell Cycle Impairment

by Marc A. Scheer, Katrina J. Schneider, Rochelle L. Finnigan, Eamon P. Maloney, Mark A. Wells and Dahn L. Clemens

Biomolecules 2016, 6(2), 17; https://doi.org/10.3390/biom6020017 - 31 Mar 2016

Cited by 9 | Viewed by 6907

Abstract

Background: Hepatocytes metabolize the vast majority of ingested ethanol. This metabolic activity results in hepatic toxicity and impairs the ability of hepatocytes to replicate. Previous work by our group has shown that ethanol metabolism results in a G2/M cell cycle arrest. The intent [...] Read more.

Background: Hepatocytes metabolize the vast majority of ingested ethanol. This metabolic activity results in hepatic toxicity and impairs the ability of hepatocytes to replicate. Previous work by our group has shown that ethanol metabolism results in a G2/M cell cycle arrest. The intent of these studies was to discern the roles of acetaldehyde and reactive oxygen, two of the major by-products of ethanol metabolism, in the G2/M cell cycle arrest. Methods: To investigate the role of ethanol metabolites in the cell cycle arrest, VA-13 and VL-17A cells were used. These are recombinant Hep G2 cells that express alcohol dehydrogenase or alcohol dehydrogenase and cytochrome P450 2E1, respectively. Cells were cultured with or without ethanol, lacking or containing the antioxidants N-acetylcysteine (NAC) or trolox, for three days. Cellular accumulation was monitored by the DNA content of the cultures. The accumulation of the cyclin-dependent kinase, Cdc2 in the inactive phosphorylated form (p-Cdc2) and the cyclin-dependent kinase inhibitor p21 were determined by immunoblot analysis. Results: Cultures maintained in the presence of ethanol demonstrated a G2/M cell cycle arrest that was associated with a reduction in DNA content and increased levels of p-Cdc2 and p21, compared with cells cultured in its absence. Inclusion of antioxidants in the ethanol containing media was unable to rescue the cells from the cell cycle arrest or these ethanol metabolism-mediated effects. Additionally, culturing the cells in the presence of acetaldehyde alone resulted in increased levels of p-Cdc2 and p21. Conclusions: Acetaldehyde produced during ethanol oxidation has a major role in the ethanol metabolism-mediated G2/M cell cycle arrest, and the concurrent accumulation of p21 and p-Cdc2. Although reactive oxygen species are thought to have a significant role in ethanol-induced hepatocellular damage, they may have a less important role in the inability of hepatocytes to replace dead or damaged cells. Full article

(This article belongs to the Special Issue Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)

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Open AccessReview

Central Role of Glutamate Metabolism in the Maintenance of Nitrogen Homeostasis in Normal and Hyperammonemic Brain

by Arthur J. L. Cooper and Thomas M. Jeitner

Biomolecules 2016, 6(2), 16; https://doi.org/10.3390/biom6020016 - 26 Mar 2016

Cited by 145 | Viewed by 25513

Abstract

Glutamate is present in the brain at an average concentration—typically 10–12 mM—far in excess of those of other amino acids. In glutamate-containing vesicles in the brain, the concentration of glutamate may even exceed 100 mM. Yet because glutamate is a major excitatory neurotransmitter, [...] Read more.

Glutamate is present in the brain at an average concentration—typically 10–12 mM—far in excess of those of other amino acids. In glutamate-containing vesicles in the brain, the concentration of glutamate may even exceed 100 mM. Yet because glutamate is a major excitatory neurotransmitter, the concentration of this amino acid in the cerebral extracellular fluid must be kept low—typically µM. The remarkable gradient of glutamate in the different cerebral compartments: vesicles > cytosol/mitochondria > extracellular fluid attests to the extraordinary effectiveness of glutamate transporters and the strict control of enzymes of glutamate catabolism and synthesis in well-defined cellular and subcellular compartments in the brain. A major route for glutamate and ammonia removal is via the glutamine synthetase (glutamate ammonia ligase) reaction. Glutamate is also removed by conversion to the inhibitory neurotransmitter γ-aminobutyrate (GABA) via the action of glutamate decarboxylase. On the other hand, cerebral glutamate levels are maintained by the action of glutaminase and by various α-ketoglutarate-linked aminotransferases (especially aspartate aminotransferase and the mitochondrial and cytosolic forms of the branched-chain aminotransferases). Although the glutamate dehydrogenase reaction is freely reversible, owing to rapid removal of ammonia as glutamine amide, the direction of the glutamate dehydrogenase reaction in the brain in vivo is mainly toward glutamate catabolism rather than toward the net synthesis of glutamate, even under hyperammonemia conditions. During hyperammonemia, there is a large increase in cerebral glutamine content, but only small changes in the levels of glutamate and α-ketoglutarate. Thus, the channeling of glutamate toward glutamine during hyperammonemia results in the net synthesis of 5-carbon units. This increase in 5-carbon units is accomplished in part by the ammonia-induced stimulation of the anaplerotic enzyme pyruvate carboxylase. Here, we suggest that glutamate may constitute a buffer or bulwark against changes in cerebral amine and ammonia nitrogen. Although the glutamate transporters are briefly discussed, the major emphasis of the present review is on the enzymology contributing to the maintenance of glutamate levels under normal and hyperammonemic conditions. Emphasis will also be placed on the central role of glutamate in the glutamine-glutamate and glutamine-GABA neurotransmitter cycles between neurons and astrocytes. Finally, we provide a brief and selective discussion of neuropathology associated with altered cerebral glutamate levels. Full article

(This article belongs to the Special Issue Role and Regulation of Glutamate Metabolism)

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Biomolecules, Volume 6, Issue 2 (June 2016) – 13 articles

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