scholarly journals Biocatalysis by Transglutaminases: A Review of Biotechnological Applications

Micromachines ◽  
2018 ◽  
Vol 9 (11) ◽  
pp. 562 ◽  
Author(s):  
Maria Savoca ◽  
Elisa Tonoli ◽  
Adeola Atobatele ◽  
Elisabetta Verderio
Keyword(s):  
Nutritive Value ◽  
Large Family ◽  
Catalytic Triad ◽  
Matrix Proteins ◽  
Primary Amines ◽  
Biotechnological Applications ◽  
Post Translational Modification ◽  
The Past ◽  
Lysine Residues ◽  
Isopeptide Bonds

The biocatalytic activity of transglutaminases (TGs) leads to the synthesis of new covalent isopeptide bonds (crosslinks) between peptide-bound glutamine and lysine residues, but also the transamidation of primary amines to glutamine residues, which ultimately can result into protein polymerisation. Operating with a cysteine/histidine/aspartic acid (Cys/His/Asp) catalytic triad, TGs induce the post-translational modification of proteins at both physiological and pathological conditions (e.g., accumulation of matrices in tissue fibrosis). Because of the disparate biotechnological applications, this large family of protein-remodelling enzymes have stimulated an escalation of interest. In the past 50 years, both mammalian and microbial TGs polymerising activity has been exploited in the food industry for the improvement of aliments’ quality, texture, and nutritive value, other than to enhance the food appearance and increased marketability. At the same time, the ability of TGs to crosslink extracellular matrix proteins, like collagen, as well as synthetic biopolymers, has led to multiple applications in biomedicine, such as the production of biocompatible scaffolds and hydrogels for tissue engineering and drug delivery, or DNA-protein bio-conjugation and antibody functionalisation. Here, we summarise the most recent advances in the field, focusing on the utilisation of TGs-mediated protein multimerisation in biotechnological and bioengineering applications.

scholarly journals Transglutaminases: Nature’s biological glues

2002 ◽  
Vol 368 (2) ◽  
pp. 377-396 ◽  
Author(s):  
Martin GRIFFIN ◽  
Rita CASADIO ◽  
Carlo M. BERGAMINI
Keyword(s):  
Blood Clotting ◽  
High Molecular Mass ◽  
Primary Amines ◽  
Commercial Sector ◽  
Biotechnological Applications ◽  
Post Translational Modification ◽  
Important Group ◽  
Isopeptide Bonds ◽  
Biological Glues

Transglutaminases (Tgases) are a widely distributed group of enzymes that catalyse the post-translational modification of proteins by the formation of isopeptide bonds. This occurs either through protein cross-linking via ∊-(γ-glutamyl)lysine bonds or through incorporation of primary amines at selected peptide-bound glutamine residues. The cross-linked products, often of high molecular mass, are highly resistant to mechanical challenge and proteolytic degradation, and their accumulation is found in a number of tissues and processes where such properties are important, including skin, hair, blood clotting and wound healing. However, deregulation of enzyme activity generally associated with major disruptions in cellular homoeostatic mechanisms has resulted in these enzymes contributing to a number of human diseases, including chronic neurodegeneration, neoplastic diseases, autoimmune diseases, diseases involving progressive tissue fibrosis and diseases related to the epidermis of the skin. In the present review we detail the structural and regulatory features important in mammalian Tgases, with particular focus on the ubiquitous type 2 tissue enzyme. Physiological roles and substrates are discussed with a view to increasing and understanding the pathogenesis of the diseases associated with transglutaminases. Moreover the ability of these enzymes to modify proteins and act as biological glues has not gone unnoticed by the commercial sector. As a consequence, we have included some of the present and future biotechnological applications of this increasingly important group of enzymes.

Review of Progress in Predicting Protein Methylation Sites

2019 ◽  
Vol 23 (15) ◽  
pp. 1663-1670 ◽  
Author(s):  
Chunyan Ao ◽  
Shunshan Jin ◽  
Yuan Lin ◽  
Quan Zou
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Transcriptional Activity ◽  
Regulation Of Gene Expression ◽  
Protein Methylation ◽  
Biological Processes ◽  
Post Translational Modification ◽  
Regulatory Enzymes ◽  
Lysine Residues ◽  
Arginine Residues

Protein methylation is an important and reversible post-translational modification that regulates many biological processes in cells. It occurs mainly on lysine and arginine residues and involves many important biological processes, including transcriptional activity, signal transduction, and the regulation of gene expression. Protein methylation and its regulatory enzymes are related to a variety of human diseases, so improved identification of methylation sites is useful for designing drugs for a variety of related diseases. In this review, we systematically summarize and analyze the tools used for the prediction of protein methylation sites on arginine and lysine residues over the last decade.

scholarly journals Advances in the Development Ubiquitin-Specific Peptidase (USP) Inhibitors

2021 ◽  
Vol 22 (9) ◽  
pp. 4546
Author(s):  
Shiyao Chen ◽  
Yunqi Liu ◽  
Huchen Zhou
Keyword(s):  
Signaling Pathways ◽  
Transforming Growth Factor ◽  
Regulatory System ◽  
Transforming Growth Factor Β ◽  
Molecular Signaling ◽  
Post Translational Modification ◽  
The Past ◽  
Damage Repair ◽  
Wide Range ◽  
Cancer And Inflammation

Ubiquitylation and deubiquitylation are reversible protein post-translational modification (PTM) processes involving the regulation of protein degradation under physiological conditions. Loss of balance in this regulatory system can lead to a wide range of diseases, such as cancer and inflammation. As the main members of the deubiquitinases (DUBs) family, ubiquitin-specific peptidases (USPs) are closely related to biological processes through a variety of molecular signaling pathways, including DNA damage repair, p53 and transforming growth factor-β (TGF-β) pathways. Over the past decade, increasing attention has been drawn to USPs as potential targets for the development of therapeutics across diverse therapeutic areas. In this review, we summarize the crucial roles of USPs in different signaling pathways and focus on advances in the development of USP inhibitors, as well as the methods of screening and identifying USP inhibitors.

scholarly journals Duality and hidden equilibrium in transport models

2020 ◽  
Vol 9 (4) ◽  
Author(s):  
Rouven Frassek ◽  
Cristian Giardina ◽  
Jorge Kurchan
Keyword(s):  
Free Energy ◽  
Time Reversal ◽  
Large Family ◽  
Equilibrium States ◽  
Transport Models ◽  
Good Opportunity ◽  
The Past ◽  
Non Equilibrium

A large family of diffusive models of transport that have been considered in the past years admit a transformation into the same model in contact with an equilibrium bath. This mapping holds at the full dynamical level, and is independent of dimension or topology. It provides a good opportunity to discuss questions of time reversal in out of equilibrium contexts. In particular, thanks to the mapping one may define the free energy in the non-equilibrium states very naturally as the (usual) free energy of the mapped system.

scholarly journals Development of a yeast model to study the contribution of vacuolar polyphosphate metabolism to lysine polyphosphorylation

2019 ◽  
Vol 295 (6) ◽  
pp. 1439-1451 ◽  
Author(s):  
Cristina Azevedo ◽  
Yann Desfougères ◽  
Yannasittha Jiramongkol ◽  
Hamish Partington ◽  
Sasanan Trakansuebkul ◽  
...  
Keyword(s):  
Cell Lysis ◽  
Covalent Attachment ◽  
Amino Acid Residues ◽  
Post Translational Modification ◽  
Target Domain ◽  
Inorganic Polyphosphate ◽  
Topoisomerase 1 ◽  
Lysine Residues ◽  
Polyphosphate Metabolism ◽  
Nuclear Targets

A recently-discovered protein post-translational modification, lysine polyphosphorylation (K-PPn), consists of the covalent attachment of inorganic polyphosphate (polyP) to lysine residues. The nonenzymatic nature of K-PPn means that the degree of this modification depends on both polyP abundance and the amino acids surrounding the modified lysine. K-PPn was originally discovered in budding yeast (Saccharomyces cerevisiae), in which polyP anabolism and catabolism are well-characterized. However, yeast vacuoles accumulate large amounts of polyP, and upon cell lysis, the release of the vacuolar polyP could nonphysiologically cause K-PPn of nuclear and cytosolic targets. Moreover, yeast vacuoles possess two very active endopolyphosphatases, Ppn1 and Ppn2, that could have opposing effects on the extent of K-PPn. Here, we characterized the contribution of vacuolar polyP metabolism to K-PPn of two yeast proteins, Top1 (DNA topoisomerase 1) and Nsr1 (nuclear signal recognition 1). We discovered that whereas Top1-targeting K-PPn is only marginally affected by vacuolar polyP metabolism, Nsr1-targeting K-PPn is highly sensitive to the release of polyP and of endopolyphosphatases from the vacuole. Therefore, to better study K-PPn of cytosolic and nuclear targets, we constructed a yeast strain devoid of vacuolar polyP by targeting the exopolyphosphatase Ppx1 to the vacuole and concomitantly depleting the two endopolyphosphatases (ppn1Δppn2Δ, vt-Ppx1). This strain enabled us to study K-PPn of cytosolic and nuclear targets without the interfering effects of cell lysis on vacuole polyP and of endopolyphosphatases. Furthermore, we also define the fundamental nature of the acidic amino acid residues to the K-PPn target domain.

scholarly journals Cellular functions and molecular mechanisms of non-lysine ubiquitination

Open Biology ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 190147 ◽  
Author(s):  
Amie J. McClellan ◽  
Sophie Heiden Laugesen ◽  
Lars Ellgaard
Keyword(s):  
Dna Repair ◽  
Molecular Mechanisms ◽  
Future Perspectives ◽  
Cellular Functions ◽  
The Past ◽  
Protein Ubiquitination ◽  
Open Questions ◽  
Lysine Residues ◽  
Molecular Machinery ◽  
Mechanistic Basis

Protein ubiquitination is of great cellular importance through its central role in processes such as degradation, DNA repair, endocytosis and inflammation. Canonical ubiquitination takes place on lysine residues, but in the past 15 years non-lysine ubiquitination on serine, threonine and cysteine has been firmly established. With the emerging importance of non-lysine ubiquitination, it is crucial to identify the responsible molecular machinery and understand the mechanistic basis for non-lysine ubiquitination. Here, we first provide an overview of the literature that has documented non-lysine ubiquitination. Informed by these examples, we then discuss the molecular mechanisms and cellular implications of non-lysine ubiquitination, and conclude by outlining open questions and future perspectives in the field.

scholarly journals Small but Smart: On the Diverse Role of Small Proteins in the Regulation of Cyanobacterial Metabolism

Life ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 322
Author(s):  
Fabian Brandenburg ◽  
Stephan Klähn
Keyword(s):  
Metabolic Pathways ◽  
Chemical Compounds ◽  
Industrial Processes ◽  
Biotechnological Applications ◽  
Major Focus ◽  
The Past ◽  
Metabolic Fluxes ◽  
Reactor Technology ◽  
Small Proteins

Over the past few decades, bioengineered cyanobacteria have become a major focus of research for the production of energy carriers and high value chemical compounds. Besides improvements in cultivation routines and reactor technology, the integral understanding of the regulation of metabolic fluxes is the key to designing production strains that are able to compete with established industrial processes. In cyanobacteria, many enzymes and metabolic pathways are regulated differently compared to other bacteria. For instance, while glutamine synthetase in proteobacteria is mainly regulated by covalent enzyme modifications, the same enzyme in cyanobacteria is controlled by the interaction with unique small proteins. Other prominent examples, such as the small protein CP12 which controls the Calvin–Benson cycle, indicate that the regulation of enzymes and/or pathways via the attachment of small proteins might be a widespread mechanism in cyanobacteria. Accordingly, this review highlights the diverse role of small proteins in the control of cyanobacterial metabolism, focusing on well-studied examples as well as those most recently described. Moreover, it will discuss their potential to implement metabolic engineering strategies in order to make cyanobacteria more definable for biotechnological applications.

scholarly journals Bromodomains as therapeutic targets

2011 ◽  
Vol 13 ◽  
Author(s):  
Susanne Muller ◽  
Panagis Filippakopoulos ◽  
Stefan Knapp
Keyword(s):  
Squamous Cell Carcinoma ◽  
Drug Development ◽  
Cell Carcinoma ◽  
Protein Interaction ◽  
Histone Deacetylases ◽  
Histone Acetyltransferases ◽  
Reading Process ◽  
Post Translational Modification ◽  
Disease Biology ◽  
Lysine Residues

Acetylation of lysine residues is a post-translational modification with broad relevance to cellular signalling and disease biology. Enzymes that ‘write’ (histone acetyltransferases, HATs) and ‘erase’ (histone deacetylases, HDACs) acetylation sites are an area of extensive research in current drug development, but very few potent inhibitors that modulate the ‘reading process’ mediated by acetyl lysines have been described. The principal readers of ɛ-N-acetyl lysine (Kac) marks are bromodomains (BRDs), which are a diverse family of evolutionary conserved protein-interaction modules. The conserved BRD fold contains a deep, largely hydrophobic acetyl lysine binding site, which represents an attractive pocket for the development of small, pharmaceutically active molecules. Proteins that contain BRDs have been implicated in the development of a large variety of diseases. Recently, two highly potent and selective inhibitors that target BRDs of the BET (bromodomains and extra-terminal) family provided compelling data supporting targeting of these BRDs in inflammation and in an aggressive type of squamous cell carcinoma. It is likely that BRDs will emerge alongside HATs and HDACs as interesting targets for drug development for the large number of diseases that are caused by aberrant acetylation of lysine residues.

The molecular basis of homocysteine thiolactone-mediated vascular disease

2007 ◽  
Vol 45 (12) ◽  
Author(s):  
Hieronim Jakubowski
Keyword(s):  
Vascular Disease ◽  
Vascular System ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Autoimmune Response ◽  
Protein Targets ◽  
Homocysteine Thiolactone ◽  
Lysine Residues ◽  
Isopeptide Bonds ◽  
Chronic Activation

AbstractAccumulating evidence suggests that a metabolite of homocysteine (Hcy), the thioester Hcy-thiolactone, plays an important role in atherogenesis and thrombosis. Hcy-thiolactone levels are elevated in hyperhomocysteinemic humans and mice. The thioester chemistry of Hcy-thiolactone underlies its ability to form isopeptide bonds with protein lysine residues, which impairs or alters the protein's function. Protein targets for the modification by Hcy-thiolactone in human blood include fibrinogen, low-density lipoprotein, and high-density lipoprotein. Protein N-homocysteinylation leads to pathophysiological responses, including increased susceptibility to thrombogenesis caused by N-Hcy-fibrinogen, and an autoimmune response elicited by N-Hcy-proteins. Chronic activation of these responses in hyperhomocysteinemia over many years could lead to vascular disease. This article reviews recent evidence supporting the hypothesis that Hcy-thiolactone contributes to pathophysiological effects of Hcy on the vascular system.Clin Chem Lab Med 2007;45:1704–16.

scholarly journals Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis

2020 ◽  
Vol 21 (23) ◽  
pp. 9043
Author(s):  
Maria Mercado-Gómez ◽  
Fernando Lopitz-Otsoa ◽  
Mikel Azkargorta ◽  
Marina Serrano-Maciá ◽  
Sofia Lachiondo-Ortega ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Cell Function ◽  
Gene Array ◽  
Matrix Proteins ◽  
Nuclear Antigen ◽  
Post Translational Modification ◽  
Physiological Processes ◽  
Ubiquitin System ◽  
Proliferating Cell

Liver fibrosis is the excessive accumulation of extracellular matrix proteins that occurs in chronic liver disease. Ubiquitination is a post-translational modification that is crucial for a plethora of physiological processes. Even though the ubiquitin system has been implicated in several human diseases, the role of ubiquitination in liver fibrosis remains poorly understood. Here, multi-omics approaches were used to address this. Untargeted metabolomics showed that carbon tetrachloride (CCl4)-induced liver fibrosis promotes changes in the hepatic metabolome, specifically in glycerophospholipids and sphingolipids. Gene ontology analysis of public deposited gene array-based data and validation in our mouse model showed that the biological process “protein polyubiquitination” is enriched after CCl4-induced liver fibrosis. Finally, by using transgenic mice expressing biotinylated ubiquitin (bioUb mice), the ubiquitinated proteome was isolated and characterized by mass spectrometry in order to unravel the hepatic ubiquitinated proteome fingerprint in CCl4-induced liver fibrosis. Under these conditions, ubiquitination appears to be involved in the regulation of cell death and survival, cell function, lipid metabolism, and DNA repair. Finally, ubiquitination of proliferating cell nuclear antigen (PCNA) is induced during CCl4-induced liver fibrosis and associated with the DNA damage response (DDR). Overall, hepatic ubiquitome profiling can highlight new therapeutic targets for the clinical management of liver fibrosis.

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