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Bei Zhang, Balamurugan Shanmugaraj, Henry Daniell
After approval of the first plant-made biopharmaceutical by FDA for human use, many protein drugs are now in clinical development. Within the last decade, significant advances have been made in expression of heterologous complex/large proteins in chloroplasts of edible plants using codon optimized human or viral genes. Furthermore, advances in quantification enable determination of in-planta drug dosage. Oral delivery of plastid-made biopharmaceuticals (PMB) is affordable because it eliminates prohibitively expensive fermentation, purification processes addressing major challenges of short shelf-life after cold storage...
February 21, 2017: Current Opinion in Chemical Biology
Henry M Dewhurst, Matthew P Torres
Post-translational modifications (PTMs) provide an extensible framework for regulation of protein behavior beyond the diversity represented within the genome alone. While the rate of identification of PTMs has rapidly increased in recent years, our knowledge of PTM functionality encompasses less than 5% of this data. We previously developed SAPH-ire (Structural Analysis of PTM Hotspots) for the prioritization of eukaryotic PTMs based on function potential of discrete modified alignment positions (MAPs) in a set of 8 protein families...
2017: PloS One
Michel Degueldre, Marion Verdenaud, Garikoitz Legarda, Rebeca Minambres, Sheila Zuniga, Mathieu Leblanc, Nicolas Gilles, Frederic Ducancel, Edwin De Pauw, Loic Quinton
Venomous animals have developed a huge arsenal of reticulated peptides for defense and predation. Based on various scaffolds, they represent a colossal pharmacological diversity, making them top candidates for the development of innovative drugs. Instead of relying on the classical, low-throughput bioassay-guided approach to identify innovative bioactive peptides, this work exploits a recent paradigm to access to venom diversity. This strategy bypasses the classical approach by combining high-throughput transcriptomics, proteomics and bioinformatics cutting-edge technologies to generate reliable peptide sequences...
February 18, 2017: Toxicon: Official Journal of the International Society on Toxinology
Tobias Baumann, Jessica H Nickling, Maike Bartholomae, Andrius Buivydas, Oscar P Kuipers, Nediljko Budisa
The incorporation of non-canonical amino acids (ncAA) is an elegant way for the chemical diversification of recombinantly produced antimicrobial peptides (AMPs). Residue- and site-specific installation methods in several bacterial production hosts hold great promise for the generation of new-to-nature AMPs, and can contribute to tackle the ongoing emergence of antibiotic resistance in pathogens. Especially from a pharmacological point of view, desirable improvements span pH and protease resistance, solubility, oral availability and circulation half-life...
2017: Frontiers in Microbiology
Nori L Bradley, Sam M Wiseman
BACKGROUND: Papillary carcinomas that measure 1.0cm or less are diagnosed as papillary thyroid microcarcinomas (PTMs). The clinical significance and recommendations for management of these PTMs is still evolving. The objective of the study was to compare the characteristics of small (<5mm) to large (≥ 5mm) papillary thyroid microcarcinomas. METHODS: Amongst 1459 sequential patients undergoing thyroid surgery at a single center, 132 (9%) cases were diagnosed with PTM...
February 16, 2017: BMC Cancer
Valentina D'Atri, Szabolcs Fekete, Alain Beck, Matthew Lauber, Davy Guillarme
The development and approval processes of biosimilar mAbs depend on their comparability to originators. Therefore, analytical comparisons are required to assess structural features and post-translational modifications (PTM) and thereby minimize the risk of being clinically meaningful differences between biosimilar and originator drug products. The glycosylation pattern of mAbs is considered to be an important critical quality attribute (CQA), and several analytical approaches have been proposed that facilitate characterizing and monitoring a glycosylation profile, albeit mainly at a glycan and glycopeptide level of analysis...
February 7, 2017: Analytical Chemistry
Kjell Sergeant, Bruno Printz, Annelie Gutsch, Marc Behr, Jenny Renaut, Jean-Francois Hausman
The structure and the activity of proteins are often regulated by transient or stable post- translational modifications (PTM). Different from well-known, abundant modifications such as phosphorylation and glycosylation some modifications are limited to one or a few proteins across a broad range of related species. Although few examples of the latter type are known, the evolutionary conservation of these modifications and the enzymes responsible for their synthesis suggest an important physiological role. Here, the first observation of a new, fold-directing PTM is described...
2017: PloS One
Thung-S Lai, Cheng-Jui Lin, Yu-Ting Wu, Chih-Jen Wu
Mitochondria are the cell's power plant to satisfy the energy demands. However, dysfunctional mitochondria can cause overproduction of reactive oxygen species (ROS), oxidative stress, and alteration of calcium homeostasis, which are the hallmarks of mitochondrial diseases. Under prolong oxidative stress, repeated cytosolic calcium elevations even only transiently, can lead to activation of some enzymes. One calcium-activated enzyme with demonstrated pathophysiological important in mitochondrial disease is tissue transglutaminase (TG2)...
March 1, 2017: Frontiers in Bioscience (Landmark Edition)
Yi Fan, Qijun Zhang, Hua Li, Zijie Cheng, Xing Li, Yumei Chen, Yahui Shen, Guixian Song, Lingmei Qian
Neonatal mouse hearts have completely regenerative capability after birth, but the ability to regenerate rapidly lost after 7 days, the mechanism has not been clarified. Previous studies have shown that mRNA profile of adult mouse changed greatly compared to neonatal mouse. So far, there is no research of peptidomics related to heart regeneration. In order to explore the changes of proteins, enzymes and peptides related to the transient regeneration, we used comparative petidomics technique to compare the endogenous peptides in the mouse heart of postnatal 1 and 7 days...
February 15, 2017: Journal of Cellular Biochemistry
Peter E Feist, Simone Sidoli, Xin Liu, Monica M Schroll, Sharif Rahmy, Rina Fujiwara, Benjamin A Garcia, Amanda B Hummon
Multicellular tumor spheroids (MCTS) are valuable in vitro tumor models frequently used to evaluate the penetration and efficacy of therapeutics. In this study, we evaluated potential differences in epigenetic markers, i.e., histone post-translational modifications (PTMs), in the layers of the HCT116 colon carcinoma MCTS. Cells were grown in agarose-coated 96 well plates, forming reproducible 1-mm-diameter MCTS. The MCTS were fractionated into three radially concentric portions, generating samples containing cells from the core, the mid and the external layers...
February 21, 2017: Analytical Chemistry
Yang Pan, Cheng Yan, Yu Hu, Yu Fan, Qing Pan, Quan Wan, John Torcivia-Rodriguez, Raja Mazumder
Single nucleotide variations (SNVs) can result in loss or gain of protein functional sites. We analyzed the effects of SNVs on enzyme active sites, ligand binding sites, and various types of post translational modification (PTM) sites. We found that, for most types of protein functional sites, the SNV pattern differs between germline and somatic mutations as well as between synonymous and non-synonymous mutations. From a total of 51,138 protein functional site affecting SNVs (pfsSNVs), a pan-cancer analysis revealed 142 somatic pfsSNVs in five or more cancer types...
February 8, 2017: Scientific Reports
Sander Willems, Maarten Dhaenens, Elisabeth Govaert, Laura De Clerck, Paulien Meert, Christophe Van Neste, Filip Van Nieuwerburgh, Dieter Deforce
Epigenetic changes can be studied with an untargeted characterization of histone post-translational modifications (PTMs) by liquid chromatography-mass spectrometry (LC-MS). While prior information about more than 20 types of histone PTMs exists, little is known about histone PTM combinations (PTMCs). Because of the combinatorial explosion it is intrinsically impossible to consider all potential PTMCs in a database search. Consequentially, high-scoring false positives with unconsidered but correct alternative isobaric PTMCs can occur...
February 3, 2017: Journal of Proteome Research
K Ilker Sen, Robert Hepler, Hirsh Nanda
Methionine oxidation is a prevalent modification found in proteins both in biological settings and in the manufacturing of biotherapeutic molecules. In cells, the oxidation of specific methionine sites can modulate protein function or promote interactions that trigger signaling pathways. In biotherapeutic development, the formation of oxidative species could be detrimental to the efficacy or safety of the drug product. Thus, methionine oxidation is a critical quality attribute that needs to be monitored throughout development...
February 2, 2017: Current Protocols in Protein Science
Rima Chaudhuri, Jean Yee Hwa Yang
Protein post-translational modifications (PTMs) are crucial for signal transduction in cells. In order to understand key cell signaling events, identification of functionally important PTMs, which are more likely to be evolutionarily conserved, is necessary. In recent times, high-throughput mass spectrometry (MS) has made quantitative datasets in diverse species readily available, which has led to a growing need for tools to facilitate cross-species comparison of PTM data. Cross-species comparison of PTM sites is difficult since they often lie in structurally disordered protein domains...
2017: Methods in Molecular Biology
Veit Schwämmle, Marc Vaudel
Cell signaling and functions heavily rely on post-translational modifications (PTMs) of proteins. Their high-throughput characterization is thus of utmost interest for multiple biological and medical investigations. In combination with efficient enrichment methods, peptide mass spectrometry analysis allows the quantitative comparison of thousands of modified peptides over different conditions. However, the large and complex datasets produced pose multiple data interpretation challenges, ranging from spectral interpretation to statistical and multivariate analyses...
2017: Methods in Molecular Biology
Karen E Ross, Hongzhan Huang, Jia Ren, Cecilia N Arighi, Gang Li, Catalina O Tudor, Mengxi Lv, Jung-Youn Lee, Sheng-Chih Chen, K Vijay-Shanker, Cathy H Wu
Protein post-translational modification (PTM) is an essential cellular regulatory mechanism, and disruptions in PTM have been implicated in disease. PTMs are an active area of study in many fields, leading to a wealth of PTM information in the scientific literature. There is a need for user-friendly bioinformatics resources that capture PTM information from the literature and support analyses of PTMs and their functional consequences. This chapter describes the use of iPTMnet ( http://proteininformationresource...
2017: Methods in Molecular Biology
Jonathan Woodsmith, Ulrich Stelzl, Arunachalam Vinayagam
Normal cellular functioning is maintained by macromolecular machines that control both core and specialized molecular tasks. These machines are in large part multi-subunit protein complexes that undergo regulation at multiple levels, from expression of requisite components to a vast array of post-translational modifications (PTMs). PTMs such as phosphorylation, ubiquitination, and acetylation currently number more than 200,000 in the human proteome and function within all molecular pathways. Here we provide a framework for systematically studying these PTMs in the context of global protein-protein interaction networks...
2017: Methods in Molecular Biology
Revati Wani, Brion W Murray
Reversible cysteine oxidation is an emerging class of protein post-translational modification (PTM) that regulates catalytic activity, modulates conformation, impacts protein-protein interactions, and affects subcellular trafficking of numerous proteins. Redox PTMs encompass a broad array of cysteine oxidation reactions with different half-lives, topographies, and reactivities such as S-glutathionylation and sulfoxidation. Recent studies from our group underscore the lesser known effect of redox protein modifications on drug binding...
2017: Methods in Molecular Biology
Naila Gulzar, Hayley Dingerdissen, Cheng Yan, Raja Mazumder
Post-translational modifications (PTMs) are covalent modifications that proteins might undergo following or sometimes during the process of translation. Together with gene diversity, PTMs contribute to the overall variety of possible protein function for a given organism. Single-nucleotide polymorphisms (SNPs) are the most common form of variations found in the human genome, and have been found to be associated with diseases like Alzheimer's disease (AD) and Parkinson's disease (PD), among many others. Studies have also shown that non-synonymous single-nucleotide variation (nsSNV) at the PTM site, which alters the corresponding encoded amino acid in the translated protein sequence, can lead to abnormal activity of a protein and can contribute to a disease phenotype...
2017: Methods in Molecular Biology
Agnes Grallert, Iain M Hagan
We outline immunoprecipitation (IP) procedures to isolate the large quantities of a molecule of interest that are required to identify posttranslational modifications (PTMs) in subsequent targeted mass spectrometry analysis. In situ denaturation by trichloroacetic acid precipitation inhibits the activities of modifying enzymes that could alter the PTM profile to preserve the PTMs on a target of interest throughout the precipitation step. In contrast, isolation of the same molecule with the nondenaturing variation on this IP procedure can maintain associations with partner molecules whose PTMs can also be mapped, albeit with the caveat that modifications could have occurred during the extended IP period...
February 1, 2017: Cold Spring Harbor Protocols
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