Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Structure-activity relationship studies of the two-component lantibiotic haloduracin.

ABSTRACT: The lantibiotic haloduracin consists of two posttranslationally processed peptides, Halalpha and Halbeta, which act in synergy to provide bactericidal activity. An in vitro haloduracin production system was used to examine the biological impact of disrupting individual thioether rings in each peptide. Surprisingly, the Halalpha B ring, which contains a highly conserved CTLTXEC motif, was expendable. This motif has been proposed to interact with haloduracin's predicted target, lipid II. Exchange of the glutamate residue in this motif for alanine or glutamine completely abolished antibacterial activity. This study also established that Halalpha-Ser26 and Halbeta-Ser22 escape dehydration, requiring revision of the Halbeta structure previously proposed. Extracellular proteases secreted by the producer strain can remove the leader peptide, and the Halalpha cystine that is dispensable for bioactivity protects Halalpha from further proteolytic degradation.

SUBMITTER: Cooper LE

PROVIDER: S-EPMC2633096 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Structure-activity relationship studies of the two-component lantibiotic haloduracin.

Cooper Lisa E LE McClerren Amanda L AL Chary Anita A van der Donk Wilfred A WA

Chemistry & biology 20081001 10

The lantibiotic haloduracin consists of two posttranslationally processed peptides, Halalpha and Halbeta, which act in synergy to provide bactericidal activity. An in vitro haloduracin production system was used to examine the biological impact of disrupting individual thioether rings in each peptide. Surprisingly, the Halalpha B ring, which contains a highly conserved CTLTXEC motif, was expendable. This motif has been proposed to interact with haloduracin's predicted target, lipid II. Exchange ...[more]

PMID: 18940665

Similar Datasets

Structure, dynamics and kinetics of two-component Lantibiotic Lichenicidin.

Project description:Two variants of the two-component Lantibiotic Lichenicidin, produced by the strains B. Licheniformis VK21 and I89 (Lch?/ Lch? and Bli?/ Bli? peptides, respectively) have been investigated by means of 2 ?s-long all-atom molecular dynamics simulations combined with Markov State Models. This rigorous statistical analysis enabled to evaluate the dynamic and kinetic properties of the aforementioned systems which are not accessible via experimental techniques. The structural flexibility characteristic of these small peptides is understood by a delicate equilibrium between random coil, ?-helices and ?-sheet structures. The undergoing secondary structure transitions from an ?-helix to a ?-sheet observed for Lch? and Lch? peptides, were not present in the Bli? component and provide new insights to understand their mechanism of action.

| S-EPMC5487065 | biostudies-literature

Thusin, a Novel Two-Component Lantibiotic with Potent Antimicrobial Activity against Several Gram-Positive Pathogens.

Project description:Due to the rapidly increasing prevalence of multidrug-resistant bacterial strains, the need for new antimicrobial drugs to treat infections has become urgent. Bacteriocins, which are antimicrobial peptides of bacterial origin, are considered potential alternatives to conventional antibiotics and have attracted widespread attention in recent years. Among these bacteriocins, lantibiotics, especially two-component lantibiotics, exhibit potent antimicrobial activity against some clinically relevant Gram-positive pathogens and have potential applications in the pharmaceutical industry. In this study, we characterized a novel two-component lantibiotic termed thusin that consists of Ths?, Ths?, and Ths?' (mutation of Ths?, A14G) and that was isolated from a B. thuringiensis strain BGSC 4BT1. Ths? and Ths? (or Ths?') exhibit optimal antimicrobial activity at a 1:1 ratio and act sequentially to affect target cells, and they are all highly thermostable (100°C for 30 min) and pH tolerant (pH 2.0 to 9.0). Thusin shows remarkable efficacy against all tested Gram-positive bacteria and greater activities than two known lantibiotics thuricin 4A-4 and ticin A4, and one antibiotic vancomycin against various bacterial pathogens (Bacillus cereus, Listeria monocytogenes, Staphylococcus aureus (MRSA), Staphylococcus sciuri, Enterococcus faecalis, and Streptococcus pneumoniae). Moreover, thusin is also able to inhibit the outgrowth of B. cereus spores. The potent antimicrobial activity of thusin against some Gram-positive pathogens indicates that it has potential for the development of new drugs.

| S-EPMC4949975 | biostudies-literature

Engineering Two-dimensional Nanomaterials to Enable Structure-Activity Relationship Studies in Nanosafety Research.

Project description:Emerging, two-dimensional engineered nanomaterials (2DNMs) possess unique and diverse physical and chemical properties, such as extreme aspect ratios, adjustable electronic properties as well as functional lattice defects and surface chemistry which underpin their interactions with biological systems. This perspective highlights the need for structure activity relationship (SAR) studies for key properties of emerging grapheme-related and inorganic 2DNMs upon prioritization based on their potential impact and trajectory for large-scale production and applications. Further, it is discussed how a synthesis platform of microbiologically sterile, size-sorted, "model" 2DNMs with precise structure would enable SAR toxicological studies and allow for the sustainable and safe translation of 2D nanotechnology to real-world applications.

| S-EPMC7331938 | biostudies-literature

4-Thiazolidinone coumarin derivatives as two-component NS2B/NS3 DENV flavivirus serine protease inhibitors: synthesis, molecular docking, biological evaluation and structure-activity relationship studies.

Project description:A series of novel 4-thiazolidinone inhibitors SKYa-SKYg, containing coumarin as a core structure were synthesized via facile and efficient method. The structures of the synthesized compounds were established by extensive spectroscopic studies (FT IR, 1D NMR, 2D NMR, LC-MS) and elemental analysis. All the synthesized hybrids were further evaluated for their potential as anti-tubercular agents against Mycobacterium tuberculosis H37Rv ATCC 25618, and anti-bacterial agents against Escherichia coli, Enterobacter aerogenes, Salmonella typhi, Streptococcus pneumoniae and Staphylococcus aureus. Interestingly, the hybrids displayed potent bioactivity. However, compounds SKYc, SKYd, and SKYe appeared to be more effective against the tested bacterial strains, among which compound SKYb showed the highest inhibition against all the bacterial strains ranging from 41 to 165 ?g/mL, as compared to the standards, streptomycin, kanamycin and vancomycin. Moreover, derivative SKYa was found to be the strongest against M. tuberculosis (83 ?g/mL). Additionally, the anti-dengue potential of the coumarin hybrids as two-component NS2B/NS3 DENV flavivirus serine protease inhibitors was calculated using computational molecular docking approach, with reference to the standards 4-hydroxypanduratin, panduratin and ethyl 3-(4-(hydroxymethyl)-2-methoxy-5-nitrophenoxy)propanoate with DS of -?3.379, -?3.189 and -?3.381, respectively. The docking results revealed that the synthesized hybrids exhibited potent anti-dengue activity among which compounds SKYf, SKYd, SKYc and SKYe were found to be the best ones with docking scores of -?4.014, -?3.964, -?3.905 and -?3.889. In summary, we discovered 4-thiazolidinone coumarin derivatives as a new scaffold that may eventually yield useful compounds in the treatment of bacterial and viral infections.

| S-EPMC5997609 | biostudies-literature

Structure-activity relationship studies of SETD8 inhibitors.

Project description:SETD8 (also known as SET8, PR-SET7, or KMT5A (lysine methyltransferase 5A)) is the only known lysine methyltransferase that catalyzes monomethylation of histone H4 lysine 20 (H4K20). In addition to H4K20, SETD8 monomethylates non-histone substrates such as the tumor suppressor p53 and proliferating cell nuclear antigen (PCNA). Because of its role in regulating diverse biological processes, SETD8 has been pursued as a potential therapeutic target. We recently reported the first substrate-competitive SETD8 inhibitor, UNC0379 (1), which is selective for SETD8 over 15 other methyltransferases. We characterized this inhibitor in a battery of biochemical and biophysical assays. Here we describe our comprehensive structure-activity relationship (SAR) studies of this chemical series. In addition to 2- and 4-substituents, we extensively explored 6- and 7-substituents of the quinazoline scaffold. These SAR studies led to the discovery of several new compounds, which displayed similar potencies as compound 1, and interesting SAR trends.

| S-EPMC4278651 | biostudies-literature

Relaxin family peptides: structure-activity relationship studies.

Project description:The human relaxin peptide family consists of seven cystine-rich peptides, four of which are known to signal through relaxin family peptide receptors, RXFP1-4. As these peptides play a vital role physiologically and in various diseases, they are of considerable importance for drug discovery and development. Detailed structure-activity relationship (SAR) studies towards understanding the role of important residues in each of these peptides have been reported over the years and utilized for the design of antagonists and minimized agonist variants. This review summarizes the current knowledge of the SAR of human relaxin 2 (H2 relaxin), human relaxin 3 (H3 relaxin), human insulin-like peptide 3 (INSL3) and human insulin-like peptide 5 (INSL5). LINKED ARTICLES:This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc.

| S-EPMC5406294 | biostudies-literature

Truncated Orexin Peptides: Structure-Activity Relationship Studies.

Project description:Orexin receptors are involved in many processes including energy homeostasis, wake/sleep cycle, metabolism and reward. Development of potent and selective ligands is an essential step for defining the mechanism(s) underlying such critical processes. The goal of this study was to further investigate the structure-activity relationships of these peptides and to identify truncated form of the orexin peptides active at OX1. Truncation studies have led to OXA (17-33) as the shortest active peptide known to date with a 23-fold selectivity for OX1 over OX2. Alanine, D-amino acid and proline scans have highlighted the particular importance of Tyr17, Leu20, Asn25 and His26 for agonist properties of OXA(17-33). The conformation of the C-terminus might also be a defining factor in agonist activity and selectivity of the orexin peptides for the OX1 receptor.

| S-EPMC3975045 | biostudies-literature

Discovery and in vitro biosynthesis of haloduracin, a two-component lantibiotic.

Project description:Lantibiotics are ribosomally synthesized peptides that undergo posttranslational modifications to their mature, antimicrobial form. They are characterized by the unique amino acids lanthionine and methyllanthionine, introduced by means of dehydration of Ser/Thr residues followed by reaction of the resulting dehydro amino acids with cysteines to form thioether linkages. Two-component lantibiotics use two peptides that are each posttranslationally modified to yield two functionally distinct products that act in synergy to provide bactericidal activity. By using genetic data instead of isolation, a two-component lantibiotic, haloduracin, was identified in the genome of the Gram-positive alkaliphilic bacterium Bacillus halodurans C-125. We show that heterologously expressed and purified precursor peptides HalA1 and HalA2 are processed by the purified modification enzymes HalM1 and HalM2 in an in vitro reconstitution of the biosynthesis of a two-component lantibiotic. The activity of each HalM enzyme is substrate-specific, and the assay products exhibit antimicrobial activity after removal of their leader sequences at an engineered Factor Xa cleavage site, indicating that correct thioether formation has occurred. Haloduracin's biological activity depends on the presence of both modified peptides. The structures of the two mature haloduracin peptides Halalpha and Halbeta were investigated, indicating that they have similarities as well as some distinct differences compared with other two-component lantibiotics.

| S-EPMC1859917 | biostudies-literature

Structure-activity relationship studies of pyrrolone antimalarial agents.

Project description:Previously reported pyrrolones, such as TDR32570, exhibited potential as antimalarial agents; however, while these compounds have potent antimalarial activity, they suffer from poor aqueous solubility and metabolic instability. Here, further structure-activity relationship studies are described that aimed to solve the developability issues associated with this series of compounds. In particular, further modifications to the lead pyrrolone, involving replacement of a phenyl ring with a piperidine and removal of a potentially metabolically labile ester by a scaffold hop, gave rise to derivatives with improved in vitro antimalarial activities against Plasmodium falciparum K1, a chloroquine- and pyrimethamine-resistant parasite strain, with some derivatives exhibiting good selectivity for parasite over mammalian (L6) cells. Three representative compounds were selected for evaluation in a rodent model of malaria infection, and the best compound showed improved ability to decrease parasitaemia and a slight increase in survival.

| S-EPMC3963473 | biostudies-literature

Stereochemical Structure Activity Relationship Studies (S-SAR) of Tetrahydrolipstatin.

Project description:Tetrahydrolipstatin (THL), its enantiomer, and an additional six diastereomers were evaluated as inhibitors of the hydrolysis of p-nitrophenyl butyrate by porcine pancreatic lipase. IC50s were found for all eight stereoisomers ranging from a low of 4.0 nM for THL to a high of 930 nM for the diastereomer with the inverted stereocenters at the 2,3,2'-positions. While the enantiomer of THL was also significantly less active (77 nM) the remaining five stereoisomers retained significant inhibitory activities (IC50s = 8.0 to 20 nM). All eight compounds were also evaluated against three human cancer cell lines (human breast cancers MCF-7 and MDA-MB-231, human large-cell lung carcinoma H460). No appreciable cytotoxicity was observed for THL and its seven diastereomers, as their IC50s in a MTT cytotoxicity assay were all greater than 3 orders of magnitude of camptothecin.

| S-EPMC5846039 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data