Non-Ribosomal Peptide Synthesis
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Review of Oxepine-Pyrimidinone-Ketopiperazine Type Nonribosomal Peptides
H OH metabolites OH Review Review of Oxepine-Pyrimidinone-Ketopiperazine Type Nonribosomal Peptides Yaojie Guo , Jens C. Frisvad and Thomas O. Larsen * Department of Biotechnology and Biomedicine, Technical University of Denmark, Søltofts Plads, Building 221, DK-2800 Kgs. Lyngby, Denmark; [email protected] (Y.G.); [email protected] (J.C.F.) * Correspondence: [email protected]; Tel.: +45-4525-2632 Received: 12 May 2020; Accepted: 8 June 2020; Published: 15 June 2020 Abstract: Recently, a rare class of nonribosomal peptides (NRPs) bearing a unique Oxepine-Pyrimidinone-Ketopiperazine (OPK) scaffold has been exclusively isolated from fungal sources. Based on the number of rings and conjugation systems on the backbone, it can be further categorized into three types A, B, and C. These compounds have been applied to various bioassays, and some have exhibited promising bioactivities like antifungal activity against phytopathogenic fungi and transcriptional activation on liver X receptor α. This review summarizes all the research related to natural OPK NRPs, including their biological sources, chemical structures, bioassays, as well as proposed biosynthetic mechanisms from 1988 to March 2020. The taxonomy of the fungal sources and chirality-related issues of these products are also discussed. Keywords: oxepine; nonribosomal peptides; bioactivity; biosynthesis; fungi; Aspergillus 1. Introduction Nonribosomal peptides (NRPs), mostly found in bacteria and fungi, are a class of peptidyl secondary metabolites biosynthesized by large modularly organized multienzyme complexes named nonribosomal peptide synthetases (NRPSs) [1]. These products are amongst the most structurally diverse secondary metabolites in nature; they exhibit a broad range of activities, which have been exploited in treatments such as the immunosuppressant cyclosporine A and the antibiotic daptomycin [2,3]. -
Amide Bond Formation in Nonribosomal Peptide Synthesis
Amide Bond Formation in Nonribosomal Peptide Synthesis: The Formylation and Condensation Domains Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) dem Fachbereich Chemie der Philipps-Universität Marburg vorgelegt von Georg Schönafinger aus München Marburg/Lahn 2007 Vom Fachbereich Chemie der Philipps-Universität Marburg als Dissertation am _______________ angenommen. Erstgutachter : Prof. Dr. M. A. Marahiel (Philipps-Universität, Marburg) Zweitgutachter : Prof. Dr. L.-O. Essen (Philipps-Universität, Marburg) Tag der Disputation: 20. Dezember 2007 2 The majority of the work presented here has been published: Samel, S.A.†, Schoenafinger, G. †, Knappe, T.A., Marahiel, M.A., Essen, L.O. 2007. Structural and functional insights into a peptide bond-forming bidomain from a nonribosomal peptide synthetase. Structure 15(7): 781-92. † equal contribution Schoenafinger, G., Schracke, N., Linne, U., Marahiel, M.A. 2006. Formylation domain: an essential modifying enzyme for the nonribosomal biosynthesis of linear gramicidin. J Am Chem Soc. 128(23): 7406-7. Schoenafinger, G., Marahiel, M.A. accepted 2007. Nonribosomal Peptides. Wiley Encyclopaedia of Chemical Biology. In press. 3 To Anke 4 Summary Nonribosomal peptides are of outstanding pharmacological interest, since many representatives of this highly diverse class of natural products exhibit therapeutically important activities, such as antibacterial, antitumor and immunosuppressive properties. Understanding their biosynthesis performed by multimodular mega-enzymes, the nonribosomal peptide synthetases (NRPSs), is one of the key determinants in order to be able to reprogram these machineries for the production of novel therapeutics. The central structural motif of all peptides is the peptide (or amide) bond. In this work, two different amide bond forming catalytic entities from NRPSs were studied: The condensation (C) and formylation (F) domains. -
Peptide Synthesis: Chemical Or Enzymatic
Electronic Journal of Biotechnology ISSN: 0717-3458 Vol.10 No.2, Issue of April 15, 2007 © 2007 by Pontificia Universidad Católica de Valparaíso -- Chile Received June 6, 2006 / Accepted November 28, 2006 DOI: 10.2225/vol10-issue2-fulltext-13 REVIEW ARTICLE Peptide synthesis: chemical or enzymatic Fanny Guzmán Instituto de Biología Pontificia Universidad Católica de Valparaíso Avenida Brasil 2950 Valparaíso, Chile Fax: 56 32 212746 E-mail: [email protected] Sonia Barberis Facultad de Química, Bioquímica y Farmacia Universidad Nacional de San Luis Ejército de los Andes 950 (5700) San Luis, Argentina E-mail: [email protected] Andrés Illanes* Escuela de Ingeniería Bioquímica Pontificia Universidad Católica de Valparaíso Avenida Brasil 2147 Fax: 56 32 2273803 E-mail: [email protected] Financial support: This work was done within the framework of Project CYTED IV.22 Industrial Application of Proteolytic Enzymes from Higher Plants. Keywords: enzymatic synthesis, peptides, proteases, solid-phase synthesis. Abbreviations: CD: circular dichroism CLEC: cross linked enzyme crystals DDC: double dimer constructs ESI: electrospray ionization HOBT: hydroxybenzotriazole HPLC: high performance liquid hromatography KCS: kinetically controlled synthesis MALDI: matrix-assisted laser desorption ionization MAP: multiple antigen peptide system MS: mass spectrometry NMR: nuclear magnetic resonance SPS: solution phase synthesis SPPS: solid-phase peptide synthesis t-Boc: tert-butoxycarbonyl TCS: thermodynamically controlled synthesis TFA: trifluoroacetic acid Peptides are molecules of paramount importance in the medium, biocatalyst and substrate engineering, and fields of health care and nutrition. Several technologies recent advances and challenges in the field are analyzed. for their production are now available, among which Even though chemical synthesis is the most mature chemical and enzymatic synthesis are especially technology for peptide synthesis, lack of specificity and relevant. -
Peptide Services090320.Ai
FlexPeptideTM Ensures Delivery & Quality! cGMP Peptide: Up to kilograms can be synthesized Mirror-Image Peptide Drug Discovery Services (Cat.No. SC1211) GenScript constructs libraries with natural L-peptides, which are easily amendable. These libraries are then screened with synthetic mirror-image D-forms of the target proteins to identify potent leads that can guide the synthesis of their mirror-image D-peptides. Competitive Advantages Services Include Delivery Specifications Synthesis and purification of D-enantiomers of target protein Chemically synthesized and purified D-enantiomers of the target protein Synthesis and screening of L-peptide libraries Libraries of chemically synthesized L-peptides Construction and screening of L-peptide phage display libraries Libraries of L-peptide phage display Synthesis of D-enantiomers of isolated peptide leads D-enantiomers of the isolated L-peptide leads Functional characterization data of the leads (if applicable) QC reports Custom Recombinant Peptide Services (Cat.No. SC1082) Due to the fact that long peptides (> 150 residues) or complicated peptides (multiple disulfide bonds) are prohibitively expensive to synthesize chemically. GenScript has developed a proprietary recombinant peptide system that complements our standard chemical peptide synthesis service. The powerful combination of these two-protocol allows GenScript to provide our customers with any peptide of any length on any scale. Competitive Advantages Services Include Key Features • Any length • Superior precision • Any sequence • Outstanding procedure • Any scale • Scalable system Custom Peptide Services • Low cost • Batch-to-Batch consistency FlexPeptideTM Ensures Delivery & Quality! Recommended Purity Levels Standard Peptide Synthesis GenScript proposes a range of different purity levels to help you make the right choice for your application. -
Synthesis of Proteins by Automated Flow Chemistry
Synthesis of Proteins by Automated Flow Chemistry Authors: N. Hartrampf1, A. Saebi1†, M. Poskus1†, Z. P. Gates1, A. J. Callahan1, A. E. Cowfer1, S. Hanna1, S. Antilla1, C. K. Schissel1, A. J. Quartararo1, X. Ye1, A. J. Mijalis1,2, M. D. Simon1, A. Loas1, S. Liu1,3, C. Jessen4, T. E. Nielsen4 and B. L. Pentelute1* 5 Affiliations: 1 Massachusetts Institute of Technology, Department of Chemistry, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. 2 Current address: Harvard Medical School, Department of Genetics, 77 Avenue Louis Pasteur, Boston, 10 MA 02115, USA. 3 Current address: Department of Chemistry, East China Normal University, 3663 North Zhongshan Rd., Shanghai, 200062, China. 4 Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark. *Correspondence to: [email protected] 15 † authors contributed equally. Abstract: Ribosomes produce most proteins of living cells in seconds. Here we report highly efficient 20 chemistry matched with an automated fast-flow instrument for the direct manufacturing of peptide chains up to 164 amino acids over 328 consecutive reactions. The machine is rapid - the peptide chain elongation is complete in hours. We demonstrate the utility of this approach by the chemical synthesis of nine different protein chains that represent enzymes, structural units, and regulatory factors. After purification and folding, the synthetic materials display biophysical and enzymatic 25 properties comparable to the biologically expressed proteins. High-fidelity automated flow chemistry is an alternative for producing single-domain proteins without the ribosome. One Sentence Summary: A benchtop automated machine synthesizes protein chains in hours. 30 Main Text: Mechanical pumps, valves, solid supports and computers have transformed the way we perform chemical reactions. -
Construction of Hybrid Peptide Synthetases for the Production of A-L-Aspartyl-L-Phenylalanine, a Precursor for the High-Intensity Sweetener Aspartame
Eur. J. Biochem. 270, 4555–4563 (2003) Ó FEBS 2003 doi:10.1046/j.1432-1033.2003.03858.x Construction of hybrid peptide synthetases for the production of a-L-aspartyl-L-phenylalanine, a precursor for the high-intensity sweetener aspartame Thomas Duerfahrt1, Sascha Doekel1,*, Theo Sonke2, Peter J. L. M. Quaedflieg2 and Mohamed A. Marahiel1 1Philipps-Universita¨t Marburg, Fachbereich Chemie/Biochemie, Marburg, Germany; 2DSM Research, Life Sciences – Advanced Synthesis, Catalysis and Development, Geleen, the Netherlands Microorganisms produce a large number of pharmaco- Product release was ensured by a C-terminally fused logically and biotechnologically important peptides by thioesterase domains and quantified by HPLC/MS ana- using nonribosomal peptide synthetases (NRPSs). Due to lysis. Significant differences of enzyme activity caused by their modular arrangement and their domain organization the fusion strategies were observed. Two forms of the NRPSs are particularly suitable for engineering recom- Asp-Phe dipeptide were detected, the expected a-Asp-Phe binant proteins for the production of novel peptides with and the by-product b-Asp-Phe. Dependent on the turn- interesting properties. In order to compare different over rates ranging from 0.01–0.7 min)1, the amount of strategies of domain assembling and module fusions we a-Asp-Phe was between 75 and 100% of overall product, focused on the selective construction of a set of peptide indicating a direct correlation between the turnover synthetases that catalyze the formation of the dipeptide numbers and the ratios of a-Asp-Phe to b-Asp-Phe. a-L-aspartyl-L-phenylalanine (Asp-Phe), the precursor of Taken together these results provide useful guidelines for the high-intensity sweetener a-L-aspartyl-L-phenylalanine the rational construction of hybrid peptide synthetases. -
Nonribosomal Peptides Synthetases and Their Applications in Industry Mario Alberto Martínez‑Núñez1,2* and Víctor Eric López Y López3
Martínez‑Núñez and López Sustain Chem Process (2016) 4:13 DOI 10.1186/s40508-016-0057-6 REVIEW Open Access Nonribosomal peptides synthetases and their applications in industry Mario Alberto Martínez‑Núñez1,2* and Víctor Eric López y López3 Abstract Nonribosomal peptides are products that fall into the class of secondary metabolites with a diverse properties as toxins, siderophores, pigments, or antibiotics, among others. Unlike other proteins, its biosynthesis is independent of ribosomal machinery. Nonribosomal peptides are synthesized on large nonribosomal peptide synthetase (NRPS) enzyme complexes. NRPSs are defined as multimodular enzymes, consisting of repeated modules. The NRPS enzymes are at operons and their regulation can be positive or negative at transcriptional or post-translational level. The pres‑ ence of NRPS enzymes has been reported in the three domains of life, being prevalent in bacteria. Nonribosomal pep‑ tides are use in human medicine, crop protection, or environment restoration; and their use as commercial products has been approved by the U. S Food and Drug Administration (FDA) and the U. S. Environmental Protection Agency (EPA). The key features of nonribosomal peptides and NRPS enzymes, and some of their applications in industry are summarized. Keywords: Nonribosomal peptides, Nonribosomal peptides synthetases, Environmental restoration, Human healt Background half of the NRPS enzymes found in a genome-mining Nonribosomal peptides is a diverse family of natural study of 2699 genomes by Wang et al. [1] are nonmodular products fall into the class of secondary metabolites with NRPS enzymes. Nonmodular NRPS enzymes are found a diverse properties as toxins, siderophores, pigments, in siderophore biosynthetic pathways like EntE and antibiotics, cytostatics, immunosuppressants or antican- VibH in enterobactin, and VibE in vibriobactin [5] or as cer agents [1, 2]; and have a particularity: their synthesis a stand-alone peptidyl carrier protein such as BlmI from is independent of ribosomal machinery. -
Peptide Synthesis and Modification As a Versatile Strategy for Probes Construction
University of Pennsylvania ScholarlyCommons Master of Chemical Sciences Capstone Projects Department of Chemistry 8-11-2017 Peptide Synthesis and Modification as a ersatileV Strategy for Probes Construction Jieliang Wang University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/mcs_capstones Part of the Chemistry Commons Wang, Jieliang, "Peptide Synthesis and Modification as a ersatileV Strategy for Probes Construction" (2017). Master of Chemical Sciences Capstone Projects. 7. https://repository.upenn.edu/mcs_capstones/7 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/mcs_capstones/7 For more information, please contact [email protected]. Peptide Synthesis and Modification as a ersatileV Strategy for Probes Construction Abstract Peptide synthesis and modification is a ersatilev chemical biology strategy to construct probes and sensors of a variety of types of biological activity, including protein/protein interactions, protein localization, and proteolysis. In my thesis work, I have made probes for three distinct biological applications. To do so, I have used a combination of solid phase peptide synthesis (SPPS), native chemical ligation (NCL), protein expression, and S-alkylation to construct probes with desired functional groups, while minimizing the perturbation to the native structure. In the first project, I constructed photo- crosslinking probes to study the difference in protein-protein interactions of N-terminal acetylated (N-ac) histone H4 peptide versus non-acetylated histone H4 peptide. One protein was identified yb Western blot with binding preference to N-Ace histone H4 peptide. In the second separate project, I constructed probes to study the toxicity mechanism of proline/arginine dipeptide PRx from amyotrophic lateral sclerosis (ALS) associated gene C9ORF72. -
Custom Peptide Services
Innovative Peptide Solutions Custom Peptide Services Custom & Specialty Peptides Clinical Peptides Peptide Libraries Peptide Pools Peptide Arrays Peptidomimetic & Organic Synthesis Innovative Peptide Solutions JPT’s key technologies are: Custom & Specialty Peptides We are peptide experts with a track record of more than 20 years and offer the largest variety of peptide History chemistries, formats and modifications. JPT Peptide Technologies is a service provider located in Berlin, Germany that has achieved worldwide credi- PepMix™ bility for its commitment to rigorous quality standards Defined antigen spanning peptide pools to and a reputation for developing and implementing stimulate CD4+ and CD8+ T-cells. innovative peptide-based services and research tools for various applications. PepTrack™ Together with its US-subsidiary JPT serves its clientele Peptide libraries of individual peptides offering in the pharmaceutical and biotechnology industries as various specifications and optimization for different well as researchers in universities, governmental and types of assays. non-profit organizations. Clinical Peptides Custom peptides produced for the stringent require- ments of cellular therapy as well as vaccine and Technology & drug development. Application PepStar™ Over the past decade JPT has developed a portfolio of Peptide microarray platform for antibody epitope propietary technologies as well as innovative products dis covery, monitoring of humoral immune responses, and services that have helped to advance the develop- protein-protein interactions and enzyme profiling. ment of new immunotherapies, proteomics and drug discovery. SPOT High-throughput peptide synthesis for T-cell epitope discovery , neo epitope qualification and peptide lead Quality Assurance discovery. JPT is DIN EN ISO 9001:2015 certified and GCLP audited. SpikeTides™ Light and stable isotope-labeled or quantified peptides for mass spectrometry based proteomics assays. -
Biosynthesis and Engineering of Cyclomarin and Cyclomarazine: Prenylated, Non-Ribosomal Cyclic Peptides of Marine Actinobacterial Origin
UC San Diego Research Theses and Dissertations Title Biosynthesis and Engineering of Cyclomarin and Cyclomarazine: Prenylated, Non-Ribosomal Cyclic Peptides of Marine Actinobacterial Origin Permalink https://escholarship.org/uc/item/21b965z8 Author Schultz, Andrew W. Publication Date 2010 Peer reviewed eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA, SAN DIEGO Biosynthesis and Engineering of Cyclomarin and Cyclomarazine: Prenylated, Non-Ribosomal Cyclic Peptides of Marine Actinobacterial Origin A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Oceanography by Andrew William Schultz Committee in charge: Professor Bradley Moore, Chair Professor Eric Allen Professor Pieter Dorrestein Professor William Fenical Professor William Gerwick 2010 Copyright Andrew William Schultz, 2010 All rights reserved. The Dissertation of Andrew William Schultz is approved, and it is acceptable in quality and form for publication on microfilm and electronically: ________________________________________________________________ ________________________________________________________________ ________________________________________________________________ Chair University of California, San Diego 2010 iii DEDICATION To my wife Elizabeth and our son Orion and To my parents Dale and Mary Thank you for your never ending love and support iv TABLE OF CONTENTS Signature Page .................................................................................................... -
Synthesis, Characterization and Evaluation of Peptide Nanostructures for Biomedical Applications
molecules Review Synthesis, Characterization and Evaluation of Peptide Nanostructures for Biomedical Applications Fanny d’Orlyé, Laura Trapiella-Alfonso , Camille Lescot, Marie Pinvidic, Bich-Thuy Doan and Anne Varenne * Chimie ParisTech PSL, CNRS 8060, Institute of Chemistry for Life and Health (i-CLeHS), 75005 Paris, France; [email protected] (F.d.); [email protected] (L.T.-A.); [email protected] (C.L.); [email protected] (M.P.); [email protected] (B.-T.D.) * Correspondence: [email protected]; Tel.: +33-1-8578-4252 Abstract: There is a challenging need for the development of new alternative nanostructures that can allow the coupling and/or encapsulation of therapeutic/diagnostic molecules while reducing their toxicity and improving their circulation and in-vivo targeting. Among the new materials using natural building blocks, peptides have attracted significant interest because of their simple structure, relative chemical and physical stability, diversity of sequences and forms, their easy functionalization with (bio)molecules and the possibility of synthesizing them in large quantities. A number of them have the ability to self-assemble into nanotubes, -spheres, -vesicles or -rods under mild conditions, which opens up new applications in biology and nanomedicine due to their intrinsic biocompatibility and biodegradability as well as their surface chemical reactivity via amino- and carboxyl groups. In order to obtain nanostructures suitable for biomedical applications, the structure, size, shape and surface chemistry of these nanoplatforms must be optimized. These properties depend directly on Citation: d’Orlyé, F.; the nature and sequence of the amino acids that constitute them. -
And Light-Directed Peptide Microarray Synthesis
Development of Chip-Based Electrochemically- and Light-Directed Peptide Microarray Synthesis by Pallav Kumar A Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy Approved October 2013 by the Graduate Supervisory Committee: Neal Woodbury, Chair James Allen Stephen Johnston ARIZONA STATE UNIVERSITY December 2013 ABSTRACT Peptide microarrays may prove to be a powerful tool for proteomics research and clinical diagnosis applications. Fodor et al. and Maurer et al. have shown proof-of- concept methods of light- and electrochemically-directed peptide microarray fabrication on glass and semiconductor microchips respectively. In this work, peptide microarray fabrication based on the abovementioned techniques were optimized. In addition, MALDI mass spectrometry based peptide synthesis characterization on semiconductor microchips was developed and novel applications of a CombiMatrix (CBMX) platform for electrochemically controlled synthesis were explored. We have investigated performance of 2-(2-nitrophenyl)propoxycarbonyl (NPPOC) derivatives as photo-labile protecting group. Specifically, influence of substituents on 4 and 5 positions of phenyl ring of NPPOC group on the rate of photolysis and the yield of the amine was investigated. The results indicated that substituents capable of forming a π-network with the nitro group enhanced the rate of photolysis and yield. Once such properly substituted NPPOC groups were used, the rate of photolysis/yield depended on the nature of protected amino group indicating that a different chemical step during the photocleavage process became the rate limiting step. We also focused on electrochemically-directed parallel synthesis of high-density peptide microarrays using the CBMX technology referred to above which uses electrochemically generated acids to perform patterned chemistry.