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Methods in Molecular Biology (Clifton,... 2023Peptide natural products constitute a major class of secondary metabolites produced by microorganisms (mostly bacteria and fungi). In the past several decades,...
Peptide natural products constitute a major class of secondary metabolites produced by microorganisms (mostly bacteria and fungi). In the past several decades, researchers have gained extensive knowledge about nonribosomal peptides (NRPs) generated by ribosome-independent systems, namely, NRP synthetases (NRPSs). NRPSs are multifunctional enzymes consisting of semiautonomous domains that form a peptide backbone. Using a thiotemplate mechanism that employs assembly-line logic with multiple modules, NRPSs activate, tether, and modify amino acid building blocks, sequentially elongating the peptide chain before releasing the complete peptide. Adenylation, thiolation, condensation, and thioesterase domains play central roles in these reactions. This chapter focuses on the current understanding of these central domains in NRPS assembly-line enzymology.
Topics: Peptide Biosynthesis, Nucleic Acid-Independent; Peptides; Bacteria; Fungi; Amino Acids; Peptide Synthases
PubMed: 37184697
DOI: 10.1007/978-1-0716-3214-7_1 -
Current Opinion in Structural Biology Aug 2023Lanthipeptide synthetases are fascinating biosynthetic enzymes that install intramolecular thioether bridges into genetically encoded peptides, typically endowing the... (Review)
Review
Lanthipeptide synthetases are fascinating biosynthetic enzymes that install intramolecular thioether bridges into genetically encoded peptides, typically endowing the peptide with therapeutic properties. The factors that control the macrocyclic topology of lanthipeptides are numerous and remain difficult to predict and manipulate. The key challenge in this endeavor derives from the vast conformational space accessible to the disordered precursor lanthipeptide, which can be manipulated in subtle ways by interaction with the cognate synthetase. This review explores the unique strategies employed by each of the five phylogenetically divergent classes of lanthipeptide synthetase to manipulate and exploit the dynamic lanthipeptide conformational ensemble, collectively enabling these biosynthetic enzymes to guide peptide maturation along specific trajectories to products with distinct macrocyclic topology and biological activity.
Topics: Amino Acid Sequence; Peptides; Ligases; Protein Processing, Post-Translational; Biology
PubMed: 37352604
DOI: 10.1016/j.sbi.2023.102644 -
Frontiers in Endocrinology 2021More than 35 years have passed since the identification of neuromedin U (NMU). Dozens of publications have been devoted to its physiological role in the organism, which... (Review)
Review
More than 35 years have passed since the identification of neuromedin U (NMU). Dozens of publications have been devoted to its physiological role in the organism, which have provided insight into its occurrence in the body, its synthesis and mechanism of action at the cellular level. Two G protein-coupled receptors (GPCRs) have been identified, with NMUR1 distributed mainly peripherally and NMUR2 predominantly centrally. Recognition of the role of NMU in the control of energy homeostasis of the body has greatly increased interest in this neuromedin. In 2005 a second, structurally related peptide, neuromedin S (NMS) was identified. The expression of NMS is more restricted, it is predominantly found in the central nervous system. In recent years, further peptides related to NMU and NMS have been identified. These are neuromedin U precursor related peptide (NURP) and neuromedin S precursor related peptide (NSRP), which also exert biological effects without acting NMUR1, or NMUR2. This observation suggests the presence of another, as yet unrecognized receptor. Another unresolved issue within the NMU/NMS system is the differences in the effects of various NMU isoforms on diverse cell lines. It seems that development of highly specific NMUR1 and NMUR2 receptor antagonists would allow for a more detailed understanding of the mechanisms of action of NMU/NMS and related peptides in the body. They could form the basis for attempts to use such compounds in the treatment of disorders, for example, metabolic disorders, circadian rhythm, stress, etc.
Topics: Animals; Circadian Rhythm; Energy Metabolism; Homeostasis; Humans; Metabolic Diseases; Neuropeptides
PubMed: 34276571
DOI: 10.3389/fendo.2021.713961 -
Current Topics in Medicinal Chemistry 2020Several drug molecules have shown low bioavailability and pharmacokinetic profile due to metabolism by enzymes, excretion by the renal system, or due to other... (Review)
Review
Several drug molecules have shown low bioavailability and pharmacokinetic profile due to metabolism by enzymes, excretion by the renal system, or due to other physiochemical properties of drug molecules. These problems have resulted in the loss of efficacy and the gain of side effects associated with drug molecules. PEGylation is one of the strategies to overcome these pharmacokinetic issues and has been successful in the clinic. Cell-penetrating Peptides (CPPs) help to deliver molecules across biological membranes and could be used to deliver cargo selectively to the intracellular site or to the drug target. Hence CPPs could be used to improve the efficacy and selectivity of the drug. However, due to the peptidic nature of CPPs, they have a low pharmacokinetic profile. Using PEGylation and CPPs together as a component of a drug delivery system, the and efficacy of drug molecules could be improved. The other important pharmacokinetic properties such as short half-life, solubility, stability, absorption, metabolism, and elimination could be also improved. Here in this review, we summarized PEGylated CPPs or PEGylation based formulations for CPPs used in a drug delivery system for several biomedical applications until August 2019.
Topics: Animals; Biological Transport; Cell-Penetrating Peptides; Drug Compounding; Drug Delivery Systems; Humans; Polyethylene Glycols
PubMed: 31994461
DOI: 10.2174/1568026620666200128142603 -
Bioinformatics (Oxford, England) Sep 2022Cyclization is a common strategy to enhance the therapeutic potential of peptides. Many cyclic peptide drugs have been approved for clinical use, in which the...
MOTIVATION
Cyclization is a common strategy to enhance the therapeutic potential of peptides. Many cyclic peptide drugs have been approved for clinical use, in which the disulfide-driven cyclic peptide is one of the most prevalent categories. Molecular docking is a powerful computational method to predict the binding modes of molecules. For protein-cyclic peptide docking, a big challenge is considering the flexibility of peptides with conformers constrained by cyclization.
RESULTS
Integrating our efficient peptide 3D conformation sampling algorithm MODPEP2.0 and knowledge-based scoring function ITScorePP, we have proposed an extended version of our hierarchical peptide docking algorithm, named HPEPDOCK2.0, to predict the binding modes of the peptide cyclized through a disulfide against a protein. Our HPEPDOCK2.0 approach was extensively evaluated on diverse test sets and compared with the state-of-the-art cyclic peptide docking program AutoDock CrankPep (ADCP). On a benchmark dataset of 18 cyclic peptide-protein complexes, HPEPDOCK2.0 obtained a native contact fraction of above 0.5 for 61% of the cases when the top prediction was considered, compared with 39% for ADCP. On a larger test set of 25 cyclic peptide-protein complexes, HPEPDOCK2.0 yielded a success rate of 44% for the top prediction, compared with 20% for ADCP. In addition, HPEPDOCK2.0 was also validated on two other test sets of 10 and 11 complexes with apo and predicted receptor structures, respectively. HPEPDOCK2.0 is computationally efficient and the average running time for docking a cyclic peptide is about 34 min on a single CPU core, compared with 496 min for ADCP. HPEPDOCK2.0 will facilitate the study of the interaction between cyclic peptides and proteins and the development of therapeutic cyclic peptide drugs.
AVAILABILITY AND IMPLEMENTATION
http://huanglab.phys.hust.edu.cn/hpepdock/.
SUPPLEMENTARY INFORMATION
Supplementary data are available at Bioinformatics online.
Topics: Molecular Docking Simulation; Peptides, Cyclic; Software; Proteins; Peptides; Disulfides; Protein Binding
PubMed: 35801933
DOI: 10.1093/bioinformatics/btac486 -
Microbial Biotechnology Nov 2021Small peptides are a group of natural products with low molecular weights and complex structures. The diverse structures of small peptides endow them with broad... (Review)
Review
Small peptides are a group of natural products with low molecular weights and complex structures. The diverse structures of small peptides endow them with broad bioactivities and suggest their potential therapeutic use in the medical field. The remaining challenge is methods to address the main limitations, namely (i) the low amount of available small peptides from natural sources, and (ii) complex processes required for traditional chemical synthesis. Therefore, harnessing microbial cells as workhorse appears to be a promising approach to synthesize these bioactive peptides. As an emerging engineering technology, synthetic biology aims to create standard, well-characterized and controllable synthetic systems for the biosynthesis of natural products. In this review, we describe the recent developments in the microbial production of small peptides. More importantly, synthetic biology approaches are considered for the production of small peptides, with an emphasis on chassis cells, the evolution of biosynthetic pathways, strain improvements and fermentation.
Topics: Biological Products; Biosynthetic Pathways; Metabolic Engineering; Peptides; Synthetic Biology
PubMed: 33459516
DOI: 10.1111/1751-7915.13743 -
Journal of Proteome Research Aug 2022Virtual screening of protein-protein and protein-peptide interactions is a challenging task that directly impacts the processes of hit identification and hit-to-lead...
Virtual screening of protein-protein and protein-peptide interactions is a challenging task that directly impacts the processes of hit identification and hit-to-lead optimization in drug design projects involving peptide-based pharmaceuticals. Although several screening tools designed to predict the binding affinity of protein-protein complexes have been proposed, methods specifically developed to predict protein-peptide binding affinity are comparatively scarce. Frequently, predictors trained to score the affinity of small molecules are used for peptides indistinctively, despite the larger complexity and heterogeneity of interactions rendered by peptide binders. To address this issue, we introduce PPI-Affinity, a tool that leverages support vector machine (SVM) predictors of binding affinity to screen datasets of protein-protein and protein-peptide complexes, as well as to generate and rank mutants of a given structure. The performance of the SVM models was assessed on four benchmark datasets, which include protein-protein and protein-peptide binding affinity data. In addition, we evaluated our model on a set of mutants of EPI-X4, an endogenous peptide inhibitor of the chemokine receptor CXCR4, and on complexes of the serine proteases HTRA1 and HTRA3 with peptides. PPI-Affinity is freely accessible at https://protdcal.zmb.uni-due.de/PPIAffinity.
Topics: Drug Design; Peptides; Protein Binding; Proteins; Support Vector Machine
PubMed: 35654412
DOI: 10.1021/acs.jproteome.2c00020 -
Chemical Communications (Cambridge,... Jan 2022We here describe the synthesis and biological evaluation of glycan shields for cell penetrating peptides. A new benzyl alkoxyamine connector was employed for the...
We here describe the synthesis and biological evaluation of glycan shields for cell penetrating peptides. A new benzyl alkoxyamine connector was employed for the coupling of two saccharides units in the lateral side chain of individual amino acids in a peptide sequence. The oxyme bond formation with the corresponding glycan aldehydes allowed the preparation of highly glycosylated penetrating peptides with a minimal synthetic effort. Surprisingly, it was found that a four to six saccharide substitution did not decrease uptake efficiency in cells, whereas it significantly improved the toxicity profile of the penetrating peptide. In particular, glucose substitution was confirmed as an optimal glycan shield that showed an excellent uptake and intracellular localization as well as a superior biodistribution.
Topics: Amino Acid Sequence; Animals; Cell Membrane Permeability; Cell-Penetrating Peptides; Glycosylation; HeLa Cells; Heart; Humans; Kidney; Liver; Lung; Mice; Polysaccharides; Spleen; Structure-Activity Relationship; Tissue Distribution
PubMed: 34994362
DOI: 10.1039/d1cc06252b -
International Journal of Molecular... Aug 2022Arrestins were first discovered as suppressors of G protein-mediated signaling by G protein-coupled receptors. It was later demonstrated that arrestins also initiate...
Arrestins were first discovered as suppressors of G protein-mediated signaling by G protein-coupled receptors. It was later demonstrated that arrestins also initiate several signaling branches, including mitogen-activated protein kinase cascades. Arrestin-3-dependent activation of the JNK family can be recapitulated with peptide fragments, which are monofunctional elements distilled from this multi-functional arrestin protein. Here, we use maltose-binding protein fusions of arrestin-3-derived peptides to identify arrestin elements that bind kinases of the ASK1-MKK4/7-JNK3 cascade and the shortest peptide facilitating JNK signaling. We identified a 16-residue arrestin-3-derived peptide expressed as a Venus fusion that leads to activation of JNK3α2 in cells. The strength of the binding to the kinases does not correlate with peptide activity. The ASK1-MKK4/7-JNK3 cascade has been implicated in neuronal apoptosis. While inhibitors of MAP kinases exist, short peptides are the first small molecule tools that can activate MAP kinases.
Topics: Arrestin; Arrestins; Mitogen-Activated Protein Kinase 10; Peptides; Phosphorylation; Protein Binding; beta-Arrestin 2; beta-Arrestins
PubMed: 35955810
DOI: 10.3390/ijms23158679 -
Journal of Experimental Botany Nov 2019The endosymbiotic origin of the mitochondrion and the subsequent transfer of its genome to the host nucleus has resulted in intricate mechanisms of regulating... (Review)
Review
The endosymbiotic origin of the mitochondrion and the subsequent transfer of its genome to the host nucleus has resulted in intricate mechanisms of regulating mitochondrial biogenesis and protein content. The majority of mitochondrial proteins are nuclear encoded and synthesized in the cytosol, thus requiring specialized and dedicated machinery for the correct targeting import and sorting of its proteome. Most proteins targeted to the mitochondria utilize N-terminal targeting signals called presequences that are cleaved upon import. This cleavage is carried out by a variety of peptidases, generating free peptides that can be detrimental to organellar and cellular activity. Research over the last few decades has elucidated a range of mitochondrial peptidases that are involved in the initial removal of the targeting signal and its sequential degradation, allowing for the recovery of single amino acids. The significance of these processing pathways goes beyond presequence degradation after protein import, whereby the deletion of processing peptidases induces plant stress responses, compromises mitochondrial respiratory capability, and alters overall plant growth and development. Here, we review the multitude of plant mitochondrial peptidases that are known to be involved in protein import and processing of targeting signals to detail how their activities can affect organellar protein homeostasis and overall plant growth.
Topics: Amino Acid Sequence; Amino Acids; Mitochondrial Proteins; Peptide Hydrolases; Peptides; Plants; Protein Transport
PubMed: 31738432
DOI: 10.1093/jxb/erz365