RUcore: Rutgers University Community Repository
Synthesis and characterization of seven thiophosphate analogs of cyclic diguanosine monophosphate
Descriptive
TypeOfResource
Text
TitleInfo
(ID = T-1)
Title
Synthesis and characterization of seven thiophosphate analogs of cyclic diguanosine monophosphate
Identifier
ETD_1547
Identifier
(type = hdl)
http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000051429
Language
LanguageTerm
(authority = ISO639-2);
(type = code)
eng
Genre
(authority = marcgt)
theses
Subject
(ID = SBJ-1);
(authority = RUETD)
Topic
Chemistry and Chemical Biology
Subject
(ID = SBJ-1);
(authority = ETD-LCSH)
Topic
Cyclic nucleotides
Abstract
Cyclic diguanosine monophosphate (c-di-GMP) was first identified as an activator of bacterial cellulose synthase in 1987. Since then, it has been recognized as an important second messenger molecule in many bacterial processes, including cellulose synthesis, biofilm formation, and host-pathogen interactions. More recently, it found to stimulate innate immunity in mammals. The monothiophosphate analog was synthesized some years ago and was shown to be a highly potent activator/second messenger with a high stability to enzymatic degradation.
In the work presented here, synthetic methods have been developed to synthesize mono-, di- and trithiophosphate c-di-GMP analogs. All seven diastereomers of these analogs have been separated and purified. Stereochemistry of the two diastereomers of the monothioate analog was assigned by enzymatic digestion of the linear dimer, as well as direct enzymatic degradation of the cyclic dimers. In addition, the same linear dimer was cyclized to produce a cyclic dimer of known configuration. The correlation between stereochemistry and 31P NMR chemical shifts of the two diastereomers of the monothioate was then used to assign configurations of the di- and trithiophosphate analogs.
1D 1H and 31P NMR, as well as 2D NOSEY and DOSY were used to characterize all seven thiophosphate analogs in both Na+ and K+ forms. It was found that the [S] sulfurs, as well as the counterions, display dramatic effects on the equilibrium among five different complexes that can form. It is concluded that: 1) in all cases, the presence of an [S] sulfur promotes more extensive complex formation than [R]; 2) in both Na+ and K+ forms, two [S] sulfurs promote extensive aggregation, forming large aggregates that cannot be observed in the NMR spectra; 3) K+ promotes more extensive complex formation than Na+, with primarily octamolecular complexes in the K+ forms, but tetramolecular complexes in the Na+ forms; and 4) in all the Na+ forms, but not the K+ forms, the presence of one [S] sulfur stabilizes anti complexes and/or destabilizes syn complexes.
In the work presented here, synthetic methods have been developed to synthesize mono-, di- and trithiophosphate c-di-GMP analogs. All seven diastereomers of these analogs have been separated and purified. Stereochemistry of the two diastereomers of the monothioate analog was assigned by enzymatic digestion of the linear dimer, as well as direct enzymatic degradation of the cyclic dimers. In addition, the same linear dimer was cyclized to produce a cyclic dimer of known configuration. The correlation between stereochemistry and 31P NMR chemical shifts of the two diastereomers of the monothioate was then used to assign configurations of the di- and trithiophosphate analogs.
1D 1H and 31P NMR, as well as 2D NOSEY and DOSY were used to characterize all seven thiophosphate analogs in both Na+ and K+ forms. It was found that the [S] sulfurs, as well as the counterions, display dramatic effects on the equilibrium among five different complexes that can form. It is concluded that: 1) in all cases, the presence of an [S] sulfur promotes more extensive complex formation than [R]; 2) in both Na+ and K+ forms, two [S] sulfurs promote extensive aggregation, forming large aggregates that cannot be observed in the NMR spectra; 3) K+ promotes more extensive complex formation than Na+, with primarily octamolecular complexes in the K+ forms, but tetramolecular complexes in the Na+ forms; and 4) in all the Na+ forms, but not the K+ forms, the presence of one [S] sulfur stabilizes anti complexes and/or destabilizes syn complexes.
PhysicalDescription
Form
(authority = gmd)
electronic resource
Extent
xx, 186 p. : ill.
InternetMediaType
application/pdf
InternetMediaType
text/xml
Note
(type = degree)
Ph.D.
Note
(type = bibliography)
Includes bibliographical references
Note
(type = statement of responsibility)
by Jianwei Zhao
Name
(ID = NAME-1);
(type = personal)
NamePart
(type = family)
Zhao
NamePart
(type = given)
Jianwei
NamePart
(type = date)
1976
Role
RoleTerm
(authority = RULIB);
(type = )
author
DisplayForm
Jianwei Zhao
Name
(ID = NAME-2);
(type = personal)
NamePart
(type = family)
Jones
NamePart
(type = given)
Roger
Role
RoleTerm
(authority = RULIB);
(type = )
chair
Affiliation
Advisory Committee
DisplayForm
Roger A Jones
Name
(ID = NAME-3);
(type = personal)
NamePart
(type = family)
Lee
NamePart
(type = given)
Jeehiun
Role
RoleTerm
(authority = RULIB);
(type = )
internal member
Affiliation
Advisory Committee
DisplayForm
Jeehiun K Lee
Name
(ID = NAME-4);
(type = personal)
NamePart
(type = family)
Seidel
NamePart
(type = given)
Daniel
Role
RoleTerm
(authority = RULIB);
(type = )
internal member
Affiliation
Advisory Committee
DisplayForm
Daniel Seidel
Name
(ID = NAME-5);
(type = personal)
NamePart
(type = family)
MacCoss
NamePart
(type = given)
Malcolm
Role
RoleTerm
(authority = RULIB);
(type = )
outside member
Affiliation
Advisory Committee
DisplayForm
Malcolm MacCoss
Name
(ID = NAME-1);
(type = corporate)
NamePart
Rutgers University
Role
RoleTerm
(authority = RULIB);
(type = )
degree grantor
Name
(ID = NAME-2);
(type = corporate)
NamePart
Graduate School - New Brunswick
Role
RoleTerm
(authority = RULIB);
(type = )
school
OriginInfo
DateCreated
(point = );
(qualifier = exact)
2009
DateOther
(qualifier = exact);
(type = degree)
2009-05
Place
PlaceTerm
(type = code)
xx
RelatedItem
(type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier
(type = RULIB)
ETD
RelatedItem
(type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier
(type = local)
rucore19991600001
Location
PhysicalLocation
(authority = marcorg);
(displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier
(type = doi)
doi:10.7282/T3J38SSZ
Genre
(authority = ExL-Esploro)
ETD doctoral
Back to the top
Rights
RightsDeclaration
(AUTHORITY = GS);
(ID = rulibRdec0006)
The author owns the copyright to this work.
Copyright
Status
Copyright protected
Availability
Status
Open
RightsEvent
(AUTHORITY = rulib);
(ID = 1)
Type
Permission or license
Detail
Non-exclusive ETD license
AssociatedObject
(AUTHORITY = rulib);
(ID = 1)
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.
Back to the top
Technical
ContentModel
ETD
MimeType
(TYPE = file)
application/pdf
MimeType
(TYPE = container)
application/x-tar
FileSize
(UNIT = bytes)
4894720
Checksum
(METHOD = SHA1)
495940050dec4c64cd7dc1ff5812b54d9660389c
Back to the top
Statistical Profile