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You searched for subject:(Cyanobactins). Showing records 1 – 2 of 2 total matches.

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University of St Andrews

1. Mann, Gregory. Development of a biotechnological toolkit for the synthesis of diverse cyclic peptides.

Degree: PhD, 2017, University of St Andrews

Cyclic peptides possess desirable characteristics as potential pharmaceutical scaffolds. The cyanobactin family of cyclic peptide natural products boast diverse structures and bioactivity. Exemplars are the patellamides, which have attracted attention due to their ability to reverse the effects of multi-drug resistance in human leukemia cells. In addition to their macrocyclic architecture patellamides contain azol(in)e heterocycles and d-amino acids. This structural complexity makes them challenging targets for chemical synthesis. Understanding their biosynthesis will enable the development of a biotechnological ‘toolkit' for the synthesis of new pharmaceutical compounds. Patellamides are ribosomally-synthesised and post-translationally modified peptides (RiPPs) and much of their biosynthesis has been elucidated, however there are still elements of their biosynthesis that are not yet fully understood. PatA and PatG contain C-terminal domains of unknown function (DUFs). The crystal structure of PatG-DUF has been solved and subsequent to biochemical and biophysical investigation PatG-DUF was found not to constitute an essential part of the biotechnological ‘toolkit' and can be excluded from in vitro enzyme-based synthesis of cyanobactin-like cyclic peptides. The cyanobactin heterocyclases are able to introduce heterocycles into a peptide backbone, seemingly irrespective of the neighbouring residues; however a molecular rational governing substrate recognition is unknown. Additionally the mechanism of heterocyclisaton is disputed. Analysis of crystal structures of LynD in complex with cofactor and substrate (solved by Dr Jesko Koehnke) enabled the active site and substrate recognition site to be located. A new mechanism for heterocyclisation has been proposed. Guided by the substrate recognition observed in complex structures a constituently active heterocyclase (AcLynD) has been engineered, which is able to process short, leaderless peptide substrates. Epimerisation in cyanobactin biosynthesis is believed to be spontaneous, but its precise timing is uncertain. NMR analysis of selectively labelled peptide substrates processed by the modifying enzymes, identified epimerisation to be spontaneous on the macrocycle, regardless of whether the neighbouring heterocycles have been oxidised. A one-pot in vitro synthesis of cyanobactins has been developed, and employed to create a number of patellamide D analogues to ascertain structural-activity relationships.

Subjects/Keywords: Cyanobactins; Patellamides; Biosynthesis; Macrocycles; QD431.25S93M2; Cyclic peptides – Synthesis; Macrocyclic compounds; Natural products

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Mann, G. (2017). Development of a biotechnological toolkit for the synthesis of diverse cyclic peptides. (Doctoral Dissertation). University of St Andrews. Retrieved from http://hdl.handle.net/10023/10826

Chicago Manual of Style (16th Edition):

Mann, Gregory. “Development of a biotechnological toolkit for the synthesis of diverse cyclic peptides.” 2017. Doctoral Dissertation, University of St Andrews. Accessed July 10, 2020. http://hdl.handle.net/10023/10826.

MLA Handbook (7th Edition):

Mann, Gregory. “Development of a biotechnological toolkit for the synthesis of diverse cyclic peptides.” 2017. Web. 10 Jul 2020.

Vancouver:

Mann G. Development of a biotechnological toolkit for the synthesis of diverse cyclic peptides. [Internet] [Doctoral dissertation]. University of St Andrews; 2017. [cited 2020 Jul 10]. Available from: http://hdl.handle.net/10023/10826.

Council of Science Editors:

Mann G. Development of a biotechnological toolkit for the synthesis of diverse cyclic peptides. [Doctoral Dissertation]. University of St Andrews; 2017. Available from: http://hdl.handle.net/10023/10826

2. Bent, Andrew F. Structural and biochemical studies on the biosynthetic pathways of cyanobactins.

Degree: PhD, 2016, University of St Andrews

Cyclic peptides have potential as scaffolds for novel pharmaceuticals, however their chemical synthesis can be challenging and as such natural sources are often explored. Several species of cyanobacteria produce a family of cyclic peptides, the cyanobactins, through the ribosomal synthesis of precursor peptides and post-translational tailoring. The patellamides, a member of the cyanobactin family, are cyclic octapeptides containing D-stereo centres and heterocyclised amino acids. A single gene cluster, patA - patG, contains the genes for the expression of the precursor peptide and the enzymes responsible for post-translational modifications including a heterocyclase, protease, macrocyclase and oxidase. Biochemical and structural analysis on the patellamide and related cyanobactin pathways has been carried out. The crystal structure of PatF, a proposed prenyl transferase, has been determined, highlighting that it is likely evolutionary inactive due to changes to key residues when compared to active homologues. This is in agreement with the knowledge that no naturally prenylated patellamides have been discovered to date. The crystal structure of the macrocyclase domain of PatG has been determined in complex with a substrate analogue peptide. The structure, together with biochemical analysis has allowed a mechanism of macrocyclisation to be proposed, confirming the requirement of a specific substrate conformation to enable macrocyclisation. Using isolated enzymes from the patellamide and related pathways, a small scale library of macrocycles made up of diverse sequences has been created in vitro and characterised by mass spectrometry and in certain cases NMR. In order to further enhance diversity, macrocycles containing unnatural amino acids have been created using three approaches; SeCys derived precursor peptides, intein-mediated peptide ligation and pEVOL amber codon technology. Finally, two oxidase enzymes from cyanobactin pathways have been purified, characterised and confirmed active for thiazoline oxidation. Native X-ray datasets on crystals of the oxidase CyaGox have been collected and phasing trials are on-going.

Subjects/Keywords: 572; Cyanobactins; Cyclic peptides; X-ray crystallography; QP552.P4B4; Cyclic peptides – Synthesis; Cyanobacteria

…5 Figure 1.5: Chemical Structures of Cyanobactins… …RiPPs and Cyanobactins 1.1.1 Cyclic Peptides Cyclic peptides have long been of interest to… …x28;LAPs) [20], amatoxins and phallotoxins [21], cyanobactins [… …x28;e.g. cyanobactins [22] and cyclotides [23]). Figure 1.3… …1. Introduction 1.1.3 Cyanobactins The cyanobactins, a member of the RiPPs, are a… 

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Bent, A. F. (2016). Structural and biochemical studies on the biosynthetic pathways of cyanobactins. (Doctoral Dissertation). University of St Andrews. Retrieved from http://hdl.handle.net/10023/10404

Chicago Manual of Style (16th Edition):

Bent, Andrew F. “Structural and biochemical studies on the biosynthetic pathways of cyanobactins.” 2016. Doctoral Dissertation, University of St Andrews. Accessed July 10, 2020. http://hdl.handle.net/10023/10404.

MLA Handbook (7th Edition):

Bent, Andrew F. “Structural and biochemical studies on the biosynthetic pathways of cyanobactins.” 2016. Web. 10 Jul 2020.

Vancouver:

Bent AF. Structural and biochemical studies on the biosynthetic pathways of cyanobactins. [Internet] [Doctoral dissertation]. University of St Andrews; 2016. [cited 2020 Jul 10]. Available from: http://hdl.handle.net/10023/10404.

Council of Science Editors:

Bent AF. Structural and biochemical studies on the biosynthetic pathways of cyanobactins. [Doctoral Dissertation]. University of St Andrews; 2016. Available from: http://hdl.handle.net/10023/10404

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