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THE STUDY OF THE ASPERGILLUS NIDULANS METABOLOME
IN THE POST-GENOMIC ERA
by
James Sanchez
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PHARMACEUTICAL SCIENCES)
August 2011
Copyright 2011 James Sanchez
Object Description
| Title | The study of the Aspergillus nidulans metabolome in the post-genomic era |
| Author | Sanchez, James F. |
| Author email | jfsanche@usc.edu;jfsanchezusc@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Pharmaceutical Sciences |
| School | School of Pharmacy |
| Date defended/completed | 2011-06-17 |
| Date submitted | 2011-07-18 |
| Date approved | 2011-07-18 |
| Restricted until | 2011-07-18 |
| Date published | 2011-07-18 |
| Advisor (committee chair) | Wang, Clay C. C. |
| Advisor (committee member) |
Shen, Wei-Chiang Roberts, Richard W. |
| Abstract | Filamentous fungi have long been recognized to be a rich source of bioactive secondary metabolites. The genomic sequencing of several species of Aspergillus, however, has revealed that the number of secondary metabolite genes indicated in the genome far exceeds the number of products that have already been obtained in the laboratory, suggesting that many more metabolites await discovery. The challenge is to develop methods to uncover these hidden natural products. The work herein describes the discovery of several metabolites not previously observed from Aspergillus nidulans and the study of their biosynthesis in a post-genomic context. First, a group of polyketide-nonribosomal peptides known as the emericellamides were identified by using state-of-the-art detection techniques. Through efficient gene deletion analysis, a biosynthesis was proposed. Next, the same gene deletion technology was used to delete a gene involved in modulating chromatin architecture, with the idea that previously inaccessible sections of the genome would be available to the transcriptional machinery. Indeed, two groups of related compounds, monodictyphenone/emodins and F9775 A/B, were revealed. The polyketides F9775 A and B were also generated when the culture conditions were altered, indicating that the problem of unlocking a secondary metabolite can have multiple solutions. Gene deletions showed that a cluster of three genes were responsible for the formation of F9775 A/B, implying that other genes for these complex molecules exist elsewhere in the genome. Finally, the two major prenylated xanthones of A. nidulans, shamixanthone and emericellin, were previously identified, but two more were discovered, and genome-based deletion analysis uncovered much information about the four compounds’ biosynthesis. Unprecedented, the genes for these metabolites were proven to be located in at least three distinct loci in the genome. Moreover, the two responsible prenyltransferase genes belong to a family known as fungal indole prenyltransferases, when the data here suggests that these enzymes in general may also catalyze the prenylation of polyketides. Overall, the results suggest that, contrary to the current paradigm, fungal secondary metabolite genes may not be wholly clustered in some instances, accenting the utility of genomics combined with rapid, powerful methods of targeting these dispersed genes. |
| Keyword | Aspergillus nidulans; secondary metabolites; genetic deletion analysis; F9775; xanthones; prenylations |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Rights | Sanchez, James F. |
| Access conditions | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@usc.edu |
| Archival file | uscthesesreloadpub_Volume71/etd-SanchezJam-112.pdf |
Description
| Title | Page 1 |
| Full text | THE STUDY OF THE ASPERGILLUS NIDULANS METABOLOME IN THE POST-GENOMIC ERA by James Sanchez A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (PHARMACEUTICAL SCIENCES) August 2011 Copyright 2011 James Sanchez |
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