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Different modes of activation of the four regulatory pyruvate dehydrogenase kinases by the E2 and E3 binding protein components of the human pyruvate dehydrogenase complex

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Title
Different modes of activation of the four regulatory pyruvate dehydrogenase kinases by the E2 and E3 binding protein components of the human pyruvate dehydrogenase complex
Name (type = personal)
NamePart (type = family)
Guevara
NamePart (type = given)
Elena Luisa
NamePart (type = date)
1987-
DisplayForm
Elena Luisa Guevara
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Jordan
NamePart (type = given)
Frank
DisplayForm
Frank Jordan
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
Graduate School - Newark
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (qualifier = exact)
2017
DateOther (qualifier = exact); (type = degree)
2017-05
CopyrightDate (encoding = w3cdtf); (qualifier = exact)
2017
Place
PlaceTerm (type = code)
xx
Language
LanguageTerm (authority = ISO639-2b); (type = code)
eng
Abstract (type = abstract)
The focus of this study is on the human pyruvate dehydrogenase complex (PDC) consisting of six proteins including thiamin diphosphate (ThDP)-dependent pyruvate dehydrogenase (E1p, 22-heterotetramer), the dihydrolipoamide transacetylase (E2p, with two lipoyl domains), dihydrolipoamide dehydrogenase (E3), a unique E3-binding protein (E3BP) and two regulatory enzymes, the pyruvate dehydrogenase kinases (PDK1-4) and phosphatases (PDP1-2). The flux of pyruvate through PDC is regulated via reversible phosphorylation (inactivation) at E1 by PDK1-4 and reactivation by PDP1-2. Up-regulation of gene expression of PDK isoforms is involved in several forms of cancer, and PDKs may be further activated by PDC by binding to the E2•E3BP core. Therefore, the PDK: E2•E3BP interaction provides new therapeutic targets. In this thesis functional kinetic studies were carried out to demonstrate significant differences in the activation of PDK isoforms by binding to E2•E3BP core: (i) PDK2 does not need activation by E2•E3BP for its efficient functioning, while PDK4 was the least effective of the four isoforms, and could not be further activated by E2•E3BP. Hence, development of inhibitors to the interaction of PDK2 and PDK4 with PDC core is not promising. (ii) The approach to design inhibitors, which interfere with interaction with PDC is indeed promising for PDK1 and PDK3. PDK3 needs E2•E3BP core for activation, an activation best achieved by synergistic combination of E2-derived catalytic domain and tridomain. Recently the Jordan group successfully identified the interaction loci between PDK1 or PDK2 with the E2•E3BP core. The studies described here interrogate the sites on E2•E3BP identified to interact with PDK1 or PDK2 (Glu35, Val198, Glu153, Glu209), in addition to the lipoyl-lysine sites found on L1 (Lys 46) and L2 (Lys 173). Site-directed mutagenesis was employed on the above amino acids, or ‘hot spots’, and E1 phosphorylation by PDK1, PDK2 or PDK3 in the presence of the constructed L1L2S mutants were tested to identify the resulting effects on overall PDC activity. These measurements will confirm whether the ‘hot spots’ interrogated indeed are important for the interaction of E2•E3BP with the PDKs, and will identify ‘real’ hot spots, against which rational drug design could be undertaken. Additionally, the E1o component of 2-oxoglutarate dehydrogenase complex (2-OGDHc), which belongs to the super-family of the 2 oxo acid dehydrogenase multienzyme complexes, was studied in this thesis for its potential application to chiral synthesis. Specifically, the E. coli and human E1o were used to catalyzed chiral synthesis of α-hydroxy ketones by varying both the 2-oxo acid donor and aldehyde acceptor substrates in a carboligase-type reaction.
Subject (authority = RUETD)
Topic
Chemistry
Subject (authority = ETD-LCSH)
Topic
Pyruvates
RelatedItem (type = host)
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Title
Rutgers University Electronic Theses and Dissertations
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ETD
Identifier
ETD_7896
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electronic resource
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application/pdf
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text/xml
Extent
1 online resource (xxi, 152 p. : ill.)
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Note (type = vita)
Includes vita
Note (type = statement of responsibility)
by Elena Luisa Guevara
RelatedItem (type = host)
TitleInfo
Title
Graduate School - Newark Electronic Theses and Dissertations
Identifier (type = local)
rucore10002600001
Location
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NjNbRU
Identifier (type = doi)
doi:10.7282/T3086881
Genre (authority = ExL-Esploro)
ETD doctoral
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The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Guevara
GivenName
Elena
MiddleName
Luisa
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2017-03-13 13:53:42
AssociatedEntity
Name
Elena Guevara
Role
Copyright holder
Affiliation
Rutgers University. Graduate School - Newark
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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.
RightsEvent
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2017-05-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2018-05-31
Type
Embargo
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after May 31st, 2018.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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2017-03-13T13:52:49
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2017-03-13T13:52:49
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