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The use of microbial genome mining for in silico discovery of novel secondary metabolite gene clusters

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TitleInfo
Title
The use of microbial genome mining for in silico discovery of novel secondary metabolite gene clusters
Name (type = personal)
NamePart (type = family)
Alawneh
NamePart (type = given)
Jafar
DisplayForm
Jafar Alawneh
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Coffman
NamePart (type = given)
Frederick
DisplayForm
Frederick Coffman
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
School of Health Professions
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (encoding = w3cdtf); (qualifier = exact)
2019
DateOther (encoding = w3cdtf); (qualifier = exact); (type = degree)
2019-05
CopyrightDate (encoding = w3cdtf); (qualifier = exact)
2019
Language
LanguageTerm (authority = ISO 639-3:2007); (type = text)
English
Abstract
Secondary metabolites (SMs) are small organic molecules that have various biological functions and produced by bacteria, fungi, archaea, and plants. Because of their diverse structures, different SMs have been shown to have antibacterial, antifungal, antiviral, and anticancer activities. Nonribosomal peptides (NRPs) and polyketides (PKs) are two diverse classes of SMs that are produced by nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS), respectively. One class of SMs, the epothilones, were discovered in the soil bacteria S. cellulosum and some epothilones have been shown to have antitumor activities similar to the taxanes. There is significant interest in expanding the available pool of structurally unique epothilones and other SMs as therapeutic candidates, however the distribution and structural variations in the microbial genomic landscape is currently poorly understood.

In this study, genome mining was used to find Epothilone-similar gene clusters (ESGCs) and other SMs gene clusters that potentially encode Epothilone-similar compounds and novel SMs. The sequences of genes (epo A-F) forming the S. cellulosum So ce90 Epothilone gene cluster were initially used to find epo A-F homologs (EAFHs) in other bacteria. These homologs were used to find gene clusters (ESGCs), and these newly discovered gene clusters were subsequently used to screen bacterial species and strains to find currently unidentified ESGCs and hybrid PKS-NRPS gene clusters that potentially encode novel SMs. The gene clusters identified in this study can be divided into three groups: 1) ESGCs highly similar to the Epothilone gene cluster and likely produce epothilone variants; 2) Gene clusters highly similar to those that encode genes which produce other secondary metabolites; 3) Gene clusters that showed relatively low similarities with secondary metabolite gene clusters. Many of these gene clusters are reported for the first time in this study. Further, a number of EAFHs identified in this study were used for in silico design of ESGCs, which resulted in new gene clusters that could produce novel Epothilone-similar compounds with predictable molecular structures. These results suggest that directed manipulation of modular EGSC components is a viable approach to producing a large number of new secondary metabolites for testing against pathogens and cancer cells.
Subject (authority = RUETD)
Topic
Biomedical Informatics
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_9913
PhysicalDescription
Form (authority = gmd)
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
1 online resource (xiii, 212 pages) : illustrations
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Subject (authority = ETD-LCSH)
Topic
Metabolites
Subject (authority = ETD-LCSH)
Topic
Data mining
Subject (authority = ETD-LCSH)
Topic
Genetics
RelatedItem (type = host)
TitleInfo
Title
School of Health Professions ETD Collection
Identifier (type = local)
rucore10007400001
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier (type = doi)
doi:10.7282/t3-sz99-qh48
Genre (authority = ExL-Esploro)
ETD doctoral
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Rights

RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Alawneh
GivenName
Jafar
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2019-04-26 12:45:57
AssociatedEntity
Name
Jafar Alawneh
Role
Copyright holder
Affiliation
Rutgers University. School of Health Professions
AssociatedObject
Type
License
Name
Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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windows xp
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2019-04-26T12:48:21
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2019-04-26T12:48:21
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