General rules of fragmentation evidencing lasso structures in CID and ETD

The Analyst ◽  
2018 ◽  
Vol 143 (5) ◽  
pp. 1157-1170 ◽  
Author(s):  
K. Jeanne Dit Fouque ◽  
H. Lavanant ◽  
S. Zirah ◽  
J. D. Hegemann ◽  
C. D. Fage ◽  
...  
Keyword(s):  
Lasso Peptides ◽  
General Rules ◽  
Modified Peptides

Lasso peptides are ribosomally synthesized and post-translationally modified peptides (RiPPs) characterized by a mechanically interlocked structure in which the C-terminal tail of the peptide is threaded and trapped within an N-terminal macrolactam ring.

scholarly journals Put a Bow on It: Knotted Antibiotics Take Center Stage

Antibiotics ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 117 ◽  
Author(s):  
Stephanie Tan ◽  
Gaelen Moore ◽  
Justin Nodwell
Keyword(s):  
Current Knowledge ◽  
Chemical Diversity ◽  
Peptide Antibiotics ◽  
Linear Peptide ◽  
Peptidoglycan Biosynthesis ◽  
Lasso Peptides ◽  
Lipid Ii ◽  
Modified Peptides ◽  
Domains Of Life ◽  
Peptide Biosynthesis

Ribosomally-synthesized and post-translationally modified peptides (RiPPs) are a large class of natural products produced across all domains of life. The lasso peptides, a subclass of RiPPs with a lasso-like structure, are structurally and functionally unique compared to other known peptide antibiotics in that the linear peptide is literally “tied in a knot” during its post-translational maturation. This underexplored class of peptides brings chemical diversity and unique modes of action to the antibiotic space. To date, eight different lasso peptides have been shown to target three known molecular machines: RNA polymerase, the lipid II precursor in peptidoglycan biosynthesis, and the ClpC1 subunit of the Clp protease involved in protein homeostasis. Here, we discuss the current knowledge on lasso peptide biosynthesis as well as their antibiotic activity, molecular targets, and mechanisms of action.

scholarly journals Cellulonodin-2 and Lihuanodin: Lasso Peptides with an Aspartimide Post-Translational Modification

2021 ◽  
Author(s):  
Li Cao ◽  
Moshe Beiser ◽  
Joseph D Koos ◽  
Margarita Orlova ◽  
Hader E Elashal ◽  
...  
Keyword(s):  
Heterologous Expression ◽  
Genome Mining ◽  
Gene Clusters ◽  
Post Translational Modification ◽  
Protein Repair ◽  
Lasso Peptide ◽  
Lasso Peptides ◽  
Modified Peptides ◽  
Asparagine Deamidation

Lasso peptides are a family of ribosomally synthesized and post-translationally modified peptides (RiPPs) defined by their threaded structure. Besides the class-defining isopeptide bond, other post-translational modifications (PTMs) that further tailor lasso peptides have been previously reported. Using genome mining tools, we identified a subset of lasso peptide biosynthetic gene clusters (BGCs) that are colocalized with protein L-isoaspartyl methyltransferase (PIMT) homologs. PIMTs have an important role in protein repair, restoring isoaspartate residues formed from asparagine deamidation to aspartate. Here we report a new function for PIMT enzymes in the post-translational modification of lasso peptides. The PIMTs associated with lasso peptide BGCs first methylate an L-aspartate sidechain found within the ring of the lasso peptide. The methyl ester is then converted into a stable aspartimide moiety, endowing the lasso peptide ring with rigidity relative to its unmodified counterpart. We describe the heterologous expression and structural characterization of two examples of aspartimide-modified lasso peptides from thermophilic Gram-positive bacteria. The lasso peptide cellulonodin-2 is encoded in the genome of actinobacterium Thermobifida cellulosilytica, while lihuanodin is encoded in the genome of firmicute Lihuaxuella thermophila. Additional genome mining revealed PIMT-containing lasso peptide BGCs in 48 organisms. In addition to heterologous expression, we have reconstituted PIMT-mediated aspartimide formation in vitro, showing that lasso peptide-associated PIMTs transfer methyl groups very rapidly as compared to canonical PIMTs. Furthermore, in stark contrast to other characterized lasso peptide PTMs, the methyltransferase functions only on lassoed substrates.

scholarly journals Reactivity-based screening for citrulline-containing natural products reveals a family of bacterial peptidyl arginine deiminases

2020 ◽  
Author(s):  
Lonnie A. Harris ◽  
Patricia M. B. Saint-Vincent ◽  
Xiaorui Guo ◽  
Graham A. Hudson ◽  
Douglas A. Mitchell
Keyword(s):  
Natural Products ◽  
Arginine Deiminase ◽  
Post Translational Modification ◽  
Genomic Context ◽  
Lasso Peptide ◽  
Lasso Peptides ◽  
C Terminus ◽  
A Genome ◽  
Modified Peptides ◽  
Phylogenetic Profiling

ABSTRACTRibosomally synthesized and post-translationally modified peptides (RiPPs) are a family of natural products defined by a genetically encoded precursor peptide that is tailored by associated biosynthetic enzymes to form the mature product. Lasso peptides are a class of RiPP defined by an isopeptide linkage between the N-terminal amine and an internal Asp/Glu residue with the C-terminus threaded through the macrocycle. This unique lariat topology, which provides considerable stability towards heat and proteases, has stimulated interest in lasso peptides as potential therapeutics. Post-translational modifications beyond the class-defining, threaded macrolactam have been reported, including one example of arginine deimination to yield citrulline. Although a citrulline-containing lasso peptide (i.e., citrulassin) was serendipitously discovered during a genome-guided campaign, the gene(s) responsible for arginine deimination has remained unknown. Herein we describe the use of reactivity-based screening to discriminate bacteria that produce arginine-versus citrulline-bearing citrulassins, culminating in the discovery and characterization of 11 new lasso peptide variants. Phylogenetic profiling identified a distally encoded peptidyl arginine deiminase (PAD) gene ubiquitous to the citrulline-containing variants. Absence of this gene correlated strongly with citrulassin variants only containing arginine (des-citrulassin). Heterologous expression of the PAD in a non-citrulassin producer resulted in the production of the deiminated analog, confirming PAD involvement in arginine deimination. The family of PADs were then bioinformatically surveyed for a deeper understanding of its genomic context and potential role in post-translational modification of RiPPs.

scholarly journals Recent Advances and Perspectives on Expanding the Chemical Diversity of Lasso Peptides

2021 ◽  
Vol 9 ◽  
Author(s):  
Mengjiao Wang ◽  
Christopher D. Fage ◽  
Yile He ◽  
Jinhui Mi ◽  
Yang Yang ◽  
...  
Keyword(s):  
Functional Groups ◽  
Catalyst Design ◽  
Chemical Diversity ◽  
Dependent Manner ◽  
Processing Enzymes ◽  
Lasso Peptides ◽  
Precursor Peptide ◽  
Potential Applications ◽  
Modified Peptides ◽  
Tailoring Enzymes

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a growing family of natural products that exhibit a range of structures and bioactivities. Initially assembled from the twenty proteinogenic amino acids in a ribosome-dependent manner, RiPPs assume their peculiar bioactive structures through various post-translational modifications. The essential modifications representative of each subfamily of RiPP are performed on a precursor peptide by the so-called processing enzymes; however, various tailoring enzymes can also embellish the precursor peptide or processed peptide with additional functional groups. Lasso peptides are an interesting subfamily of RiPPs characterized by their unique lariat knot-like structure, wherein the C-terminal tail is inserted through a macrolactam ring fused by an isopeptide bond between the N-terminal amino group and an acidic side chain. Until recently, relatively few lasso peptides were found to be tailored with extra functional groups. Nevertheless, the development of new routes to diversify lasso peptides and thus introduce novel or enhanced biological, medicinally relevant, or catalytic properties is appealing. In this review, we highlight several strategies through which lasso peptides have been successfully modified and provide a brief overview of the latest findings on the tailoring of these peptides. We also propose future directions for lasso peptide tailoring as well as potential applications for these peptides in hybrid catalyst design.

scholarly journals Transcription-factor centric genome mining strategy for discovery of diverse unprecedented RiPP gene clusters

2018 ◽  
Author(s):  
Shaozhou Zhu ◽  
Guojun Zheng
Keyword(s):  
Transcription Factor ◽  
Natural Products ◽  
Biological Activity ◽  
Genome Mining ◽  
Gene Clusters ◽  
Biosynthetic Pathways ◽  
Lasso Peptides ◽  
Modified Peptides ◽  
Diverse Biological Activity

ABSTRACTRibosomally synthesized and post-translationally modified peptides (RiPPs) are a rapidly emerging group of natural products with diverse biological activity. Most of their biosynthetic mechanisms are well studied and the “genome mining” strategy based on homology has led to the unearthing of many new ribosomal natural products, including lantipeptides, lasso peptides, cyanobactins. These precursor-centric or biosynthetic protein-centric genome mining strategies have encouraged the discovery of RiPPs natural products. However, a limitation of these strategies is that the newly identified natural products are similar to the known products and novel families of RiPP pathways were overlooked by these strategies. In this work, we applied a transcription-factor centric genome mining strategy and diverse unique crosslinked RiPP gene clusters were predicted in several sequenced microorganisms. Our research could significantly expand the category of biosynthetic pathways of RiPP natural products and predict new resources for novel RiPPs.

scholarly journals The role of chemical synthesis in developing RiPP antibiotics

2021 ◽  
Vol 50 (7) ◽  
pp. 4245-4258
Author(s):  
Sam M. Rowe ◽  
David R. Spring
Keyword(s):  
Chemical Synthesis ◽  
Lasso Peptides ◽  
Modified Peptides

This tutorial review discusses the potential of ribosomally synthesised and post-translationally modified peptides (RiPPs) as antimicrobials and looks at the chemical synthesis of three classes of RiPP: lasso peptides, cyclotides, and lanthipeptides.

Introduction of a quality management system compliant with DIN EN ISO 9001:2000 into a university department of nuclear medicine

2001 ◽  
Vol 40 (06) ◽  
pp. 228-238 ◽  
Author(s):  
U. Paschen ◽  
S. Kröger ◽  
K. H. Bohuslavizki ◽  
M. Clausen ◽  
V. Jansen-Schmidt
Keyword(s):  
Nuclear Medicine ◽  
Quality Management System ◽  
Iso 9001 ◽  
Total Quality ◽  
System A ◽  
General Rules ◽  
Therapeutic Procedures ◽  
University Department ◽  
Referring Physicians ◽  
The University

SummaryIn 1995, the management of the University Clinic Hamburg-Eppendorf proposed to establish a total quality assurance (QA) system. A revised QA-system has been introduced stepwise in the department of nuclear medicine since 1997, and certification was achieved in accordance with DIN EN ISO 9001:2000 on February 14,2001.The QA-handbook is devided into two parts. The first part contains operational (diagnostic and therapeutic) procedures in so-called standard operating procedures (SOP). They describe the indication of procedures as well as the competences and time necessary in a standardized manner. Up to now, more than 70 SOPs have been written as a collaborative approach between technicians and physicians during daily clinical routine after analysing and discussing the procedures. Thus, the results were more clearly defined processes and more satisfied employees.The second part consists of general rules and directions concerning the security of work and equipment as well as radialion protection tasks, hygiene etc. as it is required by the law. This part was written predominantly by the management of the department of nuclear-medicine and the QA-coordinator. Detailed information for the patients, documentation of the work-flows as well as the medical report was adapted to the QM-system. Although in the introduction phase of a QA-system a vast amount of time is necessary, some months later a surplus for the clinical workday will become available. The well defined relations of competences and procedures will result in a gain of time, a reduction of costs and a help to ensure the legal demands. Last but not least, the QA-system simply helps to build up confidence and acceptance both by the patients and the referring physicians.

Eurasian Economic Union: A sober look

2016 ◽  
pp. 43-60 ◽  
Author(s):  
E. Vinokurov
Keyword(s):  
The State ◽  
Customs Union ◽  
Macroeconomic Policies ◽  
Member States ◽  
Goods And Services ◽  
Eurasian Economic Union ◽  
Ongoing Work ◽  
General Rules ◽  
Economic Union ◽  
Trade And Investment

The paper appraises current progress in establishing the Customs Union and the Eurasian Economic Union (EAEU). Although the progress has slowed down after the initial rapid advancement, the Union is better viewed not as an exception from the general rules of regional economic integration but rather as one of the functioning customs unions with its successes and stumbling blocs. The paper reviews the state of Eurasian institutions, the establishment of the single market of goods and services, the situation with mutual trade and investment flows among the member states, the ongoing work on the liquidation/unification of non-tariff barriers, the problems of the efficient coordination of macroeconomic policies, progress towards establishing an EAEU network of free trade areas with partners around the world, the state of the common labor market, and the dynamics of public opinion on Eurasian integration in the five member states.

PERJANJIAN PERKAWINAN; ASAS KESEIMBANGAN DALAM PERKAWINAN

2020 ◽  
Vol 6 (1) ◽  
pp. 125-137
Author(s):  
Puji Kurniawan
Keyword(s):  
Public Order ◽  
General Rules ◽  
Husband And Wife

A marriage agreement is an agreement between a prospective husband and wife to regulate matters that are mutually agreed upon especially regarding assets in their marriage, provided that they do not conflict with law, decency and public order, and pay attention to general rules relating to the prohibition of the contents of the marriage agreement. This is in accordance with the principle of balance that we can find in the legislation.

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