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Title: Solid phase peptide synthesis of substrates for the chemoenzymatic generation of cyanobactins analogues
Author: Umeobika, Ugochukwu Christian
ISNI:       0000 0004 6423 2935
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2017
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Ribosomal synthesized and post translational modified peptide natural products have attracted a lot of interest in the past decade. Backbone cyclization of the translated linear peptides is generally catalysed by specific enzymes giving them peptidase resistance, thermodynamic stability and various other physiological activities. These features have made backbone cyclic peptide to become an attractive resource for drug discovery. Here, we described the synthesis of linear peptides containing natural and unnatural residues and its biosynthetic mechanism to generate man-made cyclic peptides. In this thesis we used SPPS to make short and medium linear peptide chains, we purified them using HPLC, and analysed them using MS. We incorporated unnatural residues such as homocysteine, homoserine, aminoalanine, propargyl glycine and the substrates were subjected to different enzymatic reaction such as prenylation, heterocyclization and macrocyclization modification reactions to generate small macrocycles (4-6 residues), prenylated linear peptides, and patellamime analogues. The final products were analysed using LC-MS. In our results, we verified that kawaguchipeptin (kgp) gene cluster is responsible for the production of kawaguchipeptins through heterologous expression of the kgp gene cluster in Escherichia coli. The KgpF prenyltransferase was overexpressed and was shown to prenylate C-3 of Trp residues in both linear and cyclic peptides in vitro. We also found out that PatGmac can macrocyclise short peptides (4-6 residues) to generate small macrocyclic peptides. We also tested the flexibility of OscGmac using unnatural amino acid residues such as pseudoprolines and pipecolic acid that can mimic the heterocyle incorporated as the final residue in the natural product. Our results show that OscGmac recognises pseudoprolines before AYD(G) to process a linear peptide.
Supervisor: Not available Sponsor: Tertiary Education Trust Fund (TETFUND) ; Nigeria
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Cyclic peptides ; Peptides