University of Illinois Urbana-Champaign

Expanding the structural diversity of the RiPP class of natural products

Kakkar, Nidhi

Content Files
KAKKAR-DISSERTATION-2018.pdf

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https://hdl.handle.net/2142/101115

Description

Title
Expanding the structural diversity of the RiPP class of natural products
Author(s)
Kakkar, Nidhi
Issue Date
2018-02-23
Director of Research (if dissertation) or Advisor (if thesis)
van der Donk, Wilfred A.
Doctoral Committee Chair(s)
van der Donk, Wilfred A.
Committee Member(s)
  • Mitchell, Douglas A.
  • Lu, Yi
  • Gerlt, John A.
Department of Study
Chemistry
Discipline
Chemistry
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Date of Ingest
2018-09-04T20:33:48Z
Keyword(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.
Graduation Semester
2018-05
Type of Resource
text
Permalink
http://hdl.handle.net/2142/101115
Copyright and License Information
Copyright 2018 Nidhi Kakkar

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