Chemistry and Chemical Biology ETDs

Publication Date

Spring 4-15-2018

Abstract

Type II polyketides (PK-II) has made up a class of natural products that are structurally diverse and are clinically useful due to their wide-range of bioactivity. The work described in this dissertation focuses on developing approaches to facilitate our understanding of sequence-function relationships of PK-II biosynthetic gene clusters (BGCs). We have systematically summarized the previous characterizations of enzymes involved in the core structure biosynthesis, which have set a foundation for our developments of approaches to discover organisms harboring novel enzymes responsible for novel PK-II molecules. We have successfully developed bioinformatics tools to globally mine the PK-II BGCs in the NCBI databank. From there, we have developed predictive models to predict the outcomes of PK-II BGCs at each stage of biosynthesis: priming-extension (KSα/β product prediction), cyclization (core structure prediction), and tailoring (whole structure prediction). We have applied the predictive models for more than 500 clusters identified from NCBI databank and have elected strains and clusters that have a high level of novelty in biosynthesis for further characterizations. Through phylogenetic analysis, we were able to identify uncharacterized proteins and protein families. The results from phylogenetic analysis could also work as a roadmap for synthetic biology approaches such as pathway engineering. Furthermore, the results of the co-evolutional analysis have suggested the existence of multienzyme complexes of PK-II biosynthetic genes. Lastly, we have developed and optimized a new approach to assess the availability and diversity of PK-II biosynthetic genes in environment soil bacteria. The method was applied to two bacterial collections to identify and elect strains for compound discovery and characterization.

Language

English

Document Type

Dissertation

Degree Name

Chemistry

Level of Degree

Doctoral

Department Name

Department of Chemistry and Chemical Biology

First Committee Member (Chair)

Dr. Jeremy Edwards

Second Committee Member

Dr. Charles Melancon

Third Committee Member

Dr. Fu-Sen Liang

Fourth Committee Member

Dr. Diana Northup

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