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Advances in primary mitochondrial myopathies.
de Barcelos, IP, Emmanuele, V, Hirano, M
Current opinion in neurology. 2019;(5):715-721
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Abstract
PURPOSE OF REVIEW Although mitochondrial diseases impose a significant functional limitation in the lives of patients, treatment of these conditions has been limited to dietary supplements, exercise, and physical therapy. In the past few years, however, translational medicine has identified potential therapies for these patients. RECENT FINDINGS For patients with primary mitochondrial myopathies, preliminary phase I and II multicenter clinical trials of elamipretide indicate safety and suggest improvement in 6-min walk test (6MWT) performance and fatigue scales. In addition, for thymidine kinase 2-deficient (TK2d) myopathy, compassionate-use oral administration of pyrimidine deoxynucleosides have shown preliminary evidence of safety and efficacy in survival of early onset patients and motor functions relative to historical TK2d controls. SUMMARY The prospects of effective therapies that improve the quality of life for patients with mitochondrial myopathy underscore the necessity for definitive diagnoses natural history studies for better understanding of the diseases.
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Elucidating the Structures of Amyloid Oligomers with Macrocyclic β-Hairpin Peptides: Insights into Alzheimer's Disease and Other Amyloid Diseases.
Kreutzer, AG, Nowick, JS
Accounts of chemical research. 2018;(3):706-718
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Abstract
In the more than a century since its identification, Alzheimer's disease has become the archetype of amyloid diseases. The first glimpses of the chemical basis of Alzheimer's disease began with the identification of "amyloid" plaques in the brain in 1892 and extended to the identification of proteinaceous fibrils with "cross-β" structure in 1968. Further efforts led to the discovery of the β-amyloid peptide, Aβ, as a 40- or 42-amino acid peptide that is responsible for the plaques and fibrils. At this point, a three-decade-long marathon began to elucidate the structure of the fibrils and identify the molecular basis of Alzheimer's disease. Along the way, an alternative model began to emerge in which small aggregates of Aβ, called "oligomers", rather than fibrils, are the culprits that lead to neurodegeneration in Alzheimer's disease. This Account describes what is known about the structures of the fibrils and details our research group's efforts to understand the structural, biophysical, and biological properties of the oligomers in amyloid diseases. β-Sheets are the building blocks of amyloid fibrils and oligomers. Amyloid fibrils generally consist of extended networks of parallel β-sheets. Amyloid oligomers appear to be more compact enclosed structures, some of which are thought to be composed of antiparallel β-sheets comprising β-hairpins. β-Hairpins are special because their twisted shape, hydrophobic surfaces, and exposed hydrogen-bonding edges impart a unique propensity to form compact assemblies. Our laboratory has developed macrocyclic β-sheets that are designed to mimic β-hairpins formed by amyloidogenic peptides and proteins. The β-hairpin mimics contain two β-strand peptide fragments linked together at their N- and C-termini by two δ-linked ornithine turn mimics to create a macrocycle. An N-methyl group is installed on one of the β-strands to prevent uncontrolled aggregation. These design features facilitate crystallization of the β-hairpin mimics and determination of the X-ray crystallographic structures of the oligomers that they form. During the past few years, our laboratory has elucidated the X-ray crystallographic structures of oligomers formed by β-hairpin mimics derived from Aβ, α-synuclein, and β2-microglobulin. Out of these three amyloidogenic peptides and proteins, the Aβ β-hairpin mimics have provided the most insight into amyloid oligomers. Our studies have revealed a previously undiscovered mode of self-assembly, whereby three Aβ β-hairpin mimics assemble to form a triangular trimer. The triangular trimers are remarkable, because they contain two largely hydrophobic surfaces that pack together with other triangular trimers to form higher-order oligomers, such as hexamers and dodecamers. Some of the dodecamers pack in the crystal lattice to form annular porelike assemblies. Some of the β-hairpin mimics and triangular trimers assemble in solution to form oligomers that recapitulate the crystallographically observed oligomers. These oligomers exhibit toxicity toward neuronally derived cells, recapitulating the toxicity of the oligomers formed by full-length amyloidogenic peptides and proteins. These findings are significant, because they address a gap in understanding the molecular basis of amyloid diseases. We anticipate that these studies will pave the way for developing diagnostics and therapeutics to combat Alzheimer's disease, Parkinson's disease, and other amyloid diseases.
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N-Terminal Cu-Binding Motifs (Xxx-Zzz-His, Xxx-His) and Their Derivatives: Chemistry, Biology and Medicinal Applications.
Gonzalez, P, Bossak, K, Stefaniak, E, Hureau, C, Raibaut, L, Bal, W, Faller, P
Chemistry (Weinheim an der Bergstrasse, Germany). 2018;(32):8029-8041
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Abstract
Peptides and proteins with N-terminal amino acid sequences NH2 -Xxx-His (XH) and NH2 -Xxx-Zzz-His (XZH) form well-established high-affinity CuII -complexes. Key examples are Asp-Ala-His (in serum albumin) and Gly-His-Lys, the wound healing factor. This opens a straightforward way to add a high-affinity CuII -binding site to almost any peptide or protein, by chemical or recombinant approaches. Thus, these motifs, NH2 -Xxx-Zzz-His in particular, have been used to equip peptides and proteins with a multitude of functions based on the redox activity of Cu, including nuclease, protease, glycosidase, or oxygen activation properties, useful in anticancer or antimicrobial drugs. More recent research suggests novel biological functions, mainly based on the redox inertness of CuII in XZH, like PET imaging (with 64 Cu), chelation therapies (for instance in Alzheimer's disease and other types of neurodegeneration), antioxidant units, Cu transporters and activation of biological functions by strong CuII binding. This Review gives an overview of the chemical properties of Cu-XH and -XZH motifs and discusses the pros and cons of the vastly different biological applications, and how they could be improved depending on the application.
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Methanobactins: Maintaining copper homeostasis in methanotrophs and beyond.
Kenney, GE, Rosenzweig, AC
The Journal of biological chemistry. 2018;(13):4606-4615
Abstract
Methanobactins (Mbns) are ribosomally produced, post-translationally modified natural products that bind copper with high affinity and specificity. Originally identified in methanotrophic bacteria, which have a high need for copper, operons encoding these compounds have also been found in many non-methanotrophic bacteria. The proteins responsible for Mbn biosynthesis include several novel enzymes. Mbn transport involves export through a multidrug efflux pump and re-internalization via a TonB-dependent transporter. Release of copper from Mbn and the molecular basis for copper regulation of Mbn production remain to be elucidated. Future work is likely to result in the identification of new enzymatic chemistry, opportunities for bioengineering and drug targeting of copper metabolism, and an expanded understanding of microbial metal homeostasis.
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Methanobactins: from genome to function.
Dassama, LM, Kenney, GE, Rosenzweig, AC
Metallomics : integrated biometal science. 2017;(1):7-20
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Abstract
Methanobactins (Mbns) are ribosomally produced, post-translationally modified peptide (RiPP) natural products that bind copper with high affinity using nitrogen-containing heterocycles and thioamide groups. In some methanotrophic bacteria, Mbns are secreted under conditions of copper starvation and then re-internalized as a copper source for the enzyme particulate methane monooxygenase (pMMO). Genome mining studies have led to the identification and classification of operons encoding the Mbn precursor peptide (MbnA) as well as a number of putative transport, regulatory, and biosynthetic proteins. These Mbn operons are present in non-methanotrophic bacteria as well, suggesting a broader role in and perhaps beyond copper acquisition. Genetic and biochemical studies indicate that specific operon-encoded proteins are involved in Mbn transport and provide insight into copper-responsive gene regulation in methanotrophs. Mbn biosynthesis is not yet understood, but combined analysis of Mbn structures, MbnA sequences, and operon content represents a powerful approach to elucidating the roles of specific biosynthetic enzymes. Future work will likely lead to the discovery of unique pathways for natural product biosynthesis and new mechanisms of microbial metal homeostasis.
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What is next after anamorelin?
Garcia, JM
Current opinion in supportive and palliative care. 2017;(4):266-271
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PURPOSE OF REVIEW In spite of its relevance, treatments for the cancer anorexia and cachexia syndrome (CACS) are not available. One of the agents that recently reached phase III clinical trials is anamorelin. Its development, along with that of other agents for this indication, will be reviewed here, with a focus on the gaps in the current knowledge and future directions. RECENT FINDINGS In spite of several targets showing promising results in early development, their difficulties obtaining regulatory approval underscore the need to reconsider the current strategies in drug development and the challenges in the field of CACS. SUMMARY Further research is needed in order to meet the challenges of developing treatments for CACS. Preclinical studies should expand our understanding about key regulators of appetite, muscle, and energy metabolism in this setting using models that can be translated reliably to humans. Clinical research efforts should focus on validating the entry criteria, endpoints, outcomes, and the potential synergistic effects and interaction between different targets, nutrition, and exercise interventions. Clinical meaningfulness and significance should be taken into account in the design of clinical trials. It is essential that all key stakeholders are included in the design of future strategies.
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A brief history of the TDIF-PXY signalling module: balancing meristem identity and differentiation during vascular development.
Etchells, JP, Smit, ME, Gaudinier, A, Williams, CJ, Brady, SM
The New phytologist. 2016;(2):474-84
Abstract
474 I. 474 II. 475 III. 475 IV. 477 V. 477 VI. 477 VII. 479 VIII. 481 482 References 482 SUMMARY A significant proportion of terrestrial biomass is constituted of xylem cells that make up woody plant tissue. Xylem is required for water transport, and is present in the vascular tissue with a second conductive tissue, phloem, required primarily for nutrient transport. Both xylem and phloem are derived from cell divisions in vascular meristems known as the cambium and procambium. One major component that influences several aspects of plant vascular development, including cell division in the vascular meristem, vascular organization and differentiation of vascular cell types, is a signalling module characterized by a peptide ligand called TRACHEARY ELEMENT DIFFERENTIATION INHIBITORY FACTOR (TDIF) and its cognate receptor, PHLOEM INTERCALATED WITH XYLEM (PXY). In this review, we explore the literature that describes signalling components, phytohormones and transcription factors that interact with these two central factors, to control the varying outputs required in vascular tissues for normal organization and elaboration of plant vascular tissue.
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Gibberellin signaling: a theme and variations on DELLA repression.
Hauvermale, AL, Ariizumi, T, Steber, CM
Plant physiology. 2012;(1):83-92
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The oligopeptide transporters: a small gene family with a diverse group of substrates and functions?
Lubkowitz, M
Molecular plant. 2011;(3):407-15
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Abstract
Genes in the Oligopeptide Transport family encode integral membrane proteins that are believed to translocate their substrates from either the extracellular environment or an organelle into the cytosol. Phylogenetic analyses of plant transporters have revealed two distant clades: the Yellow Stripe-Like (YSL) proteins and the so-called Oligopeptide Transporters (OPTs), for which the family was named. Three categories of substrates have been identified for this family: small peptides, secondary amino acids bound to metals, and glutathione. Notably, the YSL transporters are involved in metal homeostasis through the translocation of metal-chelates, indicating a level of conservation both in biological function as well as substrates. In contrast, the functions of OPT proteins seem to be less defined and, in this review, I will examine the supporting and contradictory evidence for the proposed roles of OPTs in such diverse functions as long-distance sulfur distribution, nitrogen mobilization, metal homeostasis, and heavy metal sequestration through the transport of glutathione, metal-chelates, and peptides.
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Click chemistry for the synthesis of RGD-containing integrin ligands.
Colombo, M, Bianchi, A
Molecules (Basel, Switzerland). 2010;(1):178-97
Abstract
In the last few years click chemistry reactions, and in particular copper-catalyzed cycloadditions, have been used intensively for the preparation of new bioconjugate molecules and materials applicable to biomedical and pharmaceutical areas. This review will be focused on conjugates of the tripeptide Arg-Gly-Asp formed by means of click chemistry reactions. This sequence is a well known binding motif for specific transmembrane proteins and is involved in cellular adhesion to the extracellular matrix, allowing the selective recognition of the biomolecule or polymer in which it is incorporated.