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Theoretical and mass spectrometric studies of damaged nucleobases and analogs toward understanding glycosylase mechanisms
Descriptive
TitleInfo
Title
Theoretical and mass spectrometric studies of damaged nucleobases and analogs toward understanding glycosylase mechanisms
Name
(type = personal)
NamePart
(type = family)
Michelson
NamePart
(type = given)
Anna
NamePart
(type = date)
1980-
DisplayForm
Anna Michelson
Role
RoleTerm
(authority = RULIB)
author
Name
(type = personal)
NamePart
(type = family)
Lee
NamePart
(type = given)
Jeehiun K.
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Jeehiun K. Lee
Affiliation
Advisory Committee
Role
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(authority = RULIB)
chair
Name
(type = personal)
NamePart
(type = family)
Romsted
NamePart
(type = given)
Laurence
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Laurence Romsted
Affiliation
Advisory Committee
Role
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(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
Krogh-Jespersen
NamePart
(type = given)
Karsten
DisplayForm
Karsten Krogh-Jespersen
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
Wood
NamePart
(type = given)
Harold B.
DisplayForm
Harold B. Wood
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
outside member
Name
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NamePart
Rutgers University
Role
RoleTerm
(authority = RULIB)
degree grantor
Name
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NamePart
Graduate School - New Brunswick
Role
RoleTerm
(authority = RULIB)
school
TypeOfResource
Text
Genre
(authority = marcgt)
theses
OriginInfo
DateCreated
(qualifier = exact)
2012
DateOther
(qualifier = exact);
(type = degree)
2012-10
Place
PlaceTerm
(type = code)
xx
Language
LanguageTerm
(authority = ISO639-2b);
(type = code)
eng
Abstract
(type = abstract)
The focus of this thesis is the examination of the thermochemical properties, primarily the gas phase acidity, proton affinity, and leaving group (LG) ability of damaged nucleobases and related species via mass spectrometry (FT-ICR, ion trap) and theoretical studies (quantum mechanical calculations). Our main hypothesis is that the study of intrinsic, gas-phase properties of the damaged nucleobases will lend insight into the mechanism of their excision from DNA. We study damaged nucleobases and analogs that are cleaved from DNA by various glycosylases: uracil-DNA glycosylase (UDG), 3-methyladenine glycosylase II (AlkA), and MutY glycosylase. The LG ability of the N1-deprotonated 3-methyluracil anion relative to the N1-deprotonated 3-methylthymine anion is examined in the context of the UDG enzymatic reaction that excises uracil but not thymine from DNA. We confirmed that despite the close acidities uracil is a much better LG in the gas phase. Another interesting disparity between the LG ability and acidity is discovered for uracil substrates: when we examined hydrochloric acid and 3-methyluracil in the gas phase we found that despite similar acidities, chloride is a better LG than N1-deprotonated 3-methyluracil. We propose that the difference in LG ability is due to the different natures of the LGs (resonance vs. inductive stabilization). To test the hypothesis, a series of pyridone substrates were designed and examined. AlkA is an enzyme that cleaves a wide range of damaged bases from DNA. Herein we examine 3- and 7-methylated AlkA purine substrates. The damaged nucleobases are found to be more acidic than the normal nucleobases. Because of this increased acidity, the damaged bases would be expected to be more easily cleaved from DNA by AlkA (their conjugate bases should be better LGs). We find that the acidity correlates to the AlkA excision rates, which lends support to an AlkA mechanism wherein the enzyme provides a nonspecific active site, and nucleobase cleavage is dependent on the intrinsic N-glycosidic bond stability. The acidities and proton affinities of adenine and six adenine analogs that were designed to test various features of the enzyme MutY are also studied to allow better understanding of the mechanism of adenine removal by MutY.
Subject
(authority = RUETD)
Topic
Chemistry and Chemical Biology
RelatedItem
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TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier
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ETD
Identifier
ETD_4238
PhysicalDescription
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electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
xx, 149 p. : ill.
Note
(type = degree)
Ph.D.
Note
(type = bibliography)
Includes bibliographical references
Note
(type = vita)
Includes vita
Note
(type = statement of responsibility)
by Anna Michelson
Subject
(authority = ETD-LCSH)
Topic
Mass spectrometry
Subject
(authority = ETD-LCSH)
Topic
Protons
Subject
(authority = ETD-LCSH)
Topic
DNA damage
Identifier
(type = hdl)
http://hdl.rutgers.edu/1782.1/rucore10001600001.ETD.000066915
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TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
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rucore19991600001
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NjNbRU
Identifier
(type = doi)
doi:10.7282/T3833QSR
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
Michelson
GivenName
Anna
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime
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(qualifier = exact);
(point = start)
2012-09-14 13:41:06
AssociatedEntity
Name
Anna Michelson
Role
Copyright holder
Affiliation
Rutgers University. Graduate School - New Brunswick
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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Technical
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