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Peptides Jun 2023Spexin, also identified as neuropeptide Q (NPQ), is a 14 amino acid peptide discovered by bioinformatic methods. It has a conserved structure in many species and is... (Review)
Review
Spexin, also identified as neuropeptide Q (NPQ), is a 14 amino acid peptide discovered by bioinformatic methods. It has a conserved structure in many species and is widely expressed in the central nervous system and peripheral tissues. It has an associated receptor, galanin receptor 2/3 (GALR2/3). Mature spexin peptides can exert various functions by activating GALR2/3, such as inhibiting food intake, inhibiting lipid absorption, reducing body weight, and improving insulin resistance. Spexin is expressed in the adrenal gland, pancreas, visceral fat, and thyroid, with the highest expression in the adrenal gland, followed by the pancreas. Physiologically, spexin and insulin interact in pancreatic islets. Spexin may be one of the regulators of endocrine function in the pancreas. Spexin is a possible indicator of insulin resistance and it has a variety of functional properties, here we review its role in energy metabolism.
Topics: Humans; Energy Metabolism; Insulin; Insulin Resistance; Islets of Langerhans; Peptide Hormones; Peptides
PubMed: 36914115
DOI: 10.1016/j.peptides.2023.170991 -
Chemical Society Reviews Apr 2020Peptide macrocyclization has traditionally relied on lactam, lactone and disulfide bond-forming reactions that aim at introducing conformational constraints into small... (Review)
Review
Peptide macrocyclization has traditionally relied on lactam, lactone and disulfide bond-forming reactions that aim at introducing conformational constraints into small peptide sequences. With the advent of ruthenium-catalyzed ring-closing metathesis and copper-catalyzed alkyne-azide cycloaddition, peptide chemists embraced transition metal catalysis as a powerful macrocyclization tool with relevant applications in chemical biological and peptide drug discovery. This article provides a comprehensive overview of the reactivity and methodological diversification of metal-catalyzed peptide macrocyclization as a special class of late-stage peptide derivatization method. We report the evolution from classic palladium-catalyzed cross-coupling approaches to more modern oxidative versions based on C-H activation, heteroatom alkylation/arylation and annulation processes, in which aspects such as chemoselectivity and diversity generation at the ring-closing moiety became dominant over the last years. The transit from early cycloadditions and alkyne couplings as ring-closing steps to very recent 3d metal-catalyzed macrocyclization methods is highlighted. Similarly, the new trends in decarboxylative radical macrocyclizations and the interplay between photoredox and transition metal catalysis are included. This review charts future perspectives in the field hoping to encourage further progress and applications, while bringing attention to the countless possibilities available by diversifying not only the metal, but also the reactivity modes and tactics to bring peptide functional groups together and produce structurally diverse macrocycles.
Topics: Catalysis; Cyclization; Molecular Structure; Oxidation-Reduction; Palladium; Peptides
PubMed: 32142086
DOI: 10.1039/c9cs00366e -
Current Opinion in Immunology Oct 2022
Topics: Humans; Protein Binding; Peptides
PubMed: 36182763
DOI: 10.1016/j.coi.2022.102244 -
Current Opinion in Structural Biology Dec 2020The amide bond with its planarity and lack of chemical reactivity is at the heart of protein structure. Chemical methylation of amides is known but was considered too... (Review)
Review
The amide bond with its planarity and lack of chemical reactivity is at the heart of protein structure. Chemical methylation of amides is known but was considered too harsh to be accessible to biology. Until last year there was no protein structure in the data bank with an enzymatically methylated amide. The discovery that the natural macrocyclic product, omphalotin is ribosomally synthesized, was not as had been assumed by non-ribosomal peptide synthesis. This was the first definitive evidence that an enzyme could methylate the amide bond. The enzyme, OphMA, iteratively self-hypermethylates its own C-terminus using SAM as cofactor. A second enzyme OphP, a prolyl oligopeptidase cleaves the core peptide from OphMA and cyclizes it into omphalotin. The molecular mechanism for OphMA was elucidated by mutagenesis, structural, biochemical and theoretical studies. This review highlights current progress in peptide N-methylating enzymes.
Topics: Amides; Cyclosporine; Methylation; Peptides, Cyclic; Protein Processing, Post-Translational; Proteins
PubMed: 32653730
DOI: 10.1016/j.sbi.2020.06.004 -
Chemical Biology & Drug Design May 2019Retroinverso analog of a natural polypeptide can sometimes mimic the structure and function of the natural peptide. The additional advantage of using retroinverso analog... (Review)
Review
Retroinverso analog of a natural polypeptide can sometimes mimic the structure and function of the natural peptide. The additional advantage of using retroinverso analog is that it is resistant to proteolysis. The retroinverso analogs have peptide sequence in reverse direction with respect to natural peptide and also have chirality of amino acid inverted from L to D. The D amino acids cannot be recognized by common proteases of the body; therefore, these peptides will not be degraded easily and have a longer-lasting effect as vaccine and inhibitor drugs. There have been many contested propositions about the geometric relationship between a peptide and its retro, inverso, or retroinverso analog. A retroinverso analog sometimes fails to adopt the structure that can mimic the function of the natural peptide. In such cases, partial retroinverso analog and other modifications can help in achieving the desired structure and function. Here, we review the theory, major experimental attempts, prediction methods, and alternative strategies related to retroinverso peptidomimetics.
Topics: Amino Acids; Peptides; Peptidomimetics; Protein Binding; Proteins; Stereoisomerism
PubMed: 30582286
DOI: 10.1111/cbdd.13472 -
Current Protein & Peptide Science 2020Ghrelin is a 28-amino acid octanoylated peptide hormone that is implicated in many physiological and pathophysiological processes. Specific visualization of ghrelin and... (Review)
Review
Ghrelin is a 28-amino acid octanoylated peptide hormone that is implicated in many physiological and pathophysiological processes. Specific visualization of ghrelin and its cognate receptor using traceable ligands is crucial in elucidating the localization, functions, and expression pattern of the peptide's signaling pathway. Here 12 representative radio- and fluorescently-labeled peptide-based ligands are reviewed for in vitro and in vivo imaging studies. In particular, the focus is on their structural features, pharmacological properties, and applications in further biochemical research.
Topics: Amino Acid Sequence; Animals; Fluorescent Dyes; Gene Expression Regulation; Ghrelin; Humans; Ligands; Microscopy, Fluorescence; Molecular Structure; Peptides; Receptors, Ghrelin; Signal Transduction; Staining and Labeling
PubMed: 32614744
DOI: 10.2174/1389203721666200702131457 -
Peptides Aug 2021Plant protein-derived peptides, focusing especially on soybean protein-derived peptides have considerable effects on metabolic regulation and modulation such as... (Review)
Review
Plant protein-derived peptides, focusing especially on soybean protein-derived peptides have considerable effects on metabolic regulation and modulation such as cholesterol lowering, triglyceride lowering, anti-obesity, inhibition of fatty acid synthase, and antidiabetic effects. The molecules targeted to study the metabolic regulatory functions of the peptides included the following: intestinal cholesterol micelle, cholesterol metabolism-related genes for cholesterol lowering, triglyceride metabolism-related genes for triglyceride lowering and anti-obesity, dipeptidyl peptidase-IV (DPP-IV), α-amylase, α-glucosidase, or glucose metabolism-related genes for lowering blood glucose levels. This review article outlines the physiological functions of plant protein-derived peptides for the improvement of lipid and glucose metabolism in vitro or in vivo.
Topics: Glucose; Lipid Metabolism; Peptide Fragments; Plant Proteins
PubMed: 34033874
DOI: 10.1016/j.peptides.2021.170577 -
Chemical Reviews Sep 2019Cyclization is an important post-translational modification of peptides and proteins that confers key advantages such as protection from proteolytic degradation, altered... (Review)
Review
Cyclization is an important post-translational modification of peptides and proteins that confers key advantages such as protection from proteolytic degradation, altered solubility, membrane permeability, bioavailability, and especially restricted conformational freedom in water that allows the peptide backbone to adopt the major secondary structure elements found in proteins. Non-ribosomal synthesis in bacteria, fungi, and plants or synthetic chemistry can introduce unnatural amino acids and non-peptidic constraints that modify peptide backbones and side chains to fine-tune cyclic peptide structure. Structures can be potentially altered further upon binding to a protein in biological environments. Here we analyze three-dimensional crystal structures for 211 bioactive cyclic peptides bound to 65 different proteins. The protein-bound cyclic peptides were examined for similarities and differences in bonding modes, for main-chain and side-chain structure, and for the importance of polarity, hydrogen bonds, hydrophobic effects, and water molecules in interactions with proteins. Many protein-bound cyclic peptides show backbone structures like those (strands, sheets, turns, helices, loops, or distorted variations) found at protein-protein binding interfaces. However, the notion of macrocycles simply as privileged scaffolds that primarily project side-chain substituents for complementary interactions with proteins is dispelled here. Unlike small-molecule drugs, the cyclic peptides do not rely mainly upon hydrophobic and van der Waals interactions for protein binding; they also use their main chain and side chains to form polar contacts and hydrogen bonds with proteins. Compared to small-molecule ligands, cyclic peptides can bind across larger, polar, and water-exposed protein surface areas, making many more contacts that can increase affinity, selectivity, biological activity, and ligand-receptor residence time. Cyclic peptides have a greater capacity than small-molecule drugs to modulate protein-protein interfaces that involve large, shallow, dynamic, polar, and water-exposed protein surfaces.
Topics: Animals; Bacteria; Catalytic Domain; Crystallography, X-Ray; Humans; Hydrogen Bonding; Peptides, Cyclic; Protein Binding; Proteins; Static Electricity
PubMed: 31046237
DOI: 10.1021/acs.chemrev.8b00807 -
Current Opinion in Structural Biology Apr 2018Nonribosomal peptide synthetases (NRPSs) produce peptide products with wide-ranging biological activities. NRPSs are macromolecular machines with modular assembly-line... (Review)
Review
Nonribosomal peptide synthetases (NRPSs) produce peptide products with wide-ranging biological activities. NRPSs are macromolecular machines with modular assembly-line logic, a complex catalytic cycle, moving parts and multiple active sites. They are organized into repeating sets of domains, called modules. Each module contains all functionality to introduce a building block into the growing peptide, many also perform cosynthetic tailoring. Structures of individual domains have provided insights into their catalytic mechanisms, but with one exception, larger NRPS proteins were refractory to structure determination. Recently, structure determination succeeded for four multi-domain NRPS proteins: an alternative formylating initiation and two termination modules as well as a large cross-module construct. This review highlights how these data, together with novel didomain structures, contribute to a holistic view of the architecture, domain-domain interactions and conformational changes in NRPS megaenzymes.
Topics: Catalytic Domain; Models, Molecular; Molecular Conformation; Peptide Biosynthesis, Nucleic Acid-Independent; Peptide Synthases; Peptides; Protein Binding; Structure-Activity Relationship
PubMed: 29444491
DOI: 10.1016/j.sbi.2018.01.011 -
Chemical Society Reviews Feb 2015In this review, we discuss the factors that influence electron transfer in peptides. We summarize experimental results from solution and surface studies and highlight... (Review)
Review
In this review, we discuss the factors that influence electron transfer in peptides. We summarize experimental results from solution and surface studies and highlight the ongoing debate on the mechanistic aspects of this fundamental reaction. Here, we provide a balanced approach that remains unbiased and does not favor one mechanistic view over another. Support for a putative hopping mechanism in which an electron transfers in a stepwise manner is contrasted with experimental results that support electron tunneling or even some form of ballistic transfer or a pathway transfer for an electron between donor and acceptor sites. In some cases, experimental evidence suggests that a change in the electron transfer mechanism occurs as a result of donor-acceptor separation. However, this common understanding of the switch between tunneling and hopping as a function of chain length is not sufficient for explaining electron transfer in peptides. Apart from chain length, several other factors such as the extent of the secondary structure, backbone conformation, dipole orientation, the presence of special amino acids, hydrogen bonding, and the dynamic properties of a peptide also influence the rate and mode of electron transfer in peptides. Electron transfer plays a key role in physical, chemical and biological systems, so its control is a fundamental task in bioelectrochemical systems, the design of peptide based sensors and molecular junctions. Therefore, this topic is at the heart of a number of biological and technological processes and thus remains of vital interest.
Topics: Electron Transport; Electrons; Hydrogen Bonding; Kinetics; Peptides; Protein Structure, Secondary
PubMed: 25619931
DOI: 10.1039/c4cs00297k