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Title:Expanding the structural diversity of the RiPP class of natural products
Author(s):Kakkar, Nidhi
Director of Research:van der Donk, Wilfred A.
Doctoral Committee Chair(s):van der Donk, Wilfred A.
Doctoral Committee Member(s):Mitchell, Douglas A.; Lu, Yi; Gerlt, John A.
Department / Program:Chemistry
Discipline:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):RiPP, structural analogs, hybrid peptides, non-canonical amino acids
Abstract:Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a diverse and rapidly expanding class of natural products. Despite starting out as linear chains of amino acids, RiPP natural products acquire structural diversity ranging from small molecules like microcin C7 to 48-mer polytheonamides with varying post-translational modifications installed by biosynthetic enzymes. These conformational restrictions allow these natural products to exhibit a wide range of therapeutic activities like antifungal, antibacterial, allelopathic, and antiviral. Despite the structural and functional disparities, they all share a common feature: the presence of amino acid sequence in the precursor peptide called the 'leader peptide' that helps guide the biosynthetic enzymes towards the remaining precursor peptide termed the 'core peptide' to act on specific residues and install different PTMs. This leader-peptide guided biosynthetic route provides tremendous opportunity to bioengineer libraries of analogues of RiPPs. Exploiting this feature, in Chapter 2, I report my investigations on a strategy wherein by swapping the leader peptides from unrelated RiPP biosynthetic pathways and modifying the core peptide sequences, different biosynthetic enzymes can perform their characteristic chemistries on the core peptide residues. In Chapter 3, I report the design and usage of chimeric leader peptides that can be bound by multiple enzymes from unrelated RiPP pathways to create new-to-nature hybrid RiPPs. This strategy involves the combination of a cyclodehydratase with modification enzymes from different lanthipeptide RiPP classes. These hybrids provide insight into enzyme promiscuity and compatibility, and the biosynthetic order of events, and establish a general platform for the engineering additional hybrid RiPPs. In Chapter 4, I develop two different strategies for non-proteinogenic amino acid incorporation in the class I lantibiotic nisin and the class II lantibiotic lacticin 481 using amber stop codon technology.
Issue Date:2018-02-23
Type:Text
URI:http://hdl.handle.net/2142/101115
Rights Information:Copyright 2018 Nidhi Kakkar
Date Available in IDEALS:2018-09-04
2020-09-05
Date Deposited:2018-05


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