Part I. Fitting protein aggregation kinetic data relevant to neurodegenerative diseases with an "Ockham's Razor" model en route to meaningful rate constants and mechanistic insights. Part II. Dioxygenases: the development of new, and the reinvestigation of prior, precatalysts
| dc.contributor.author | Morris, Aimee M., author | |
| dc.contributor.author | Finke, Richard G., advisor | |
| dc.date.accessioned | 2024-03-13T20:12:27Z | |
| dc.date.available | 2024-03-13T20:12:27Z | |
| dc.date.issued | 2009 | |
| dc.description.abstract | This dissertation is presented in two parts. Part I starts with a review of models that have been used to curve-fit or obtain rate constants for protein aggregation kinetic data. Following the review, the research presented in Part I is primarily focused on fitting protein aggregation literature relevant to neurodegenerative diseases using the Finke-Watzky (hereafter F-W) 2-step model of nucleation and autocatalytic growth. Part I includes: (i) the fits to the F-W model and resultant nucleation and growth rate constants of 14 representative data sets of amyloid-β, α-synuclein, and polyglutamine aggregation relevant to Alzheimer's, Parkinson's, and Huntington's diseases, respectively; (ii) the fits of 27 data sets of yeast and mammalian prion aggregation, along with the resultant rate constants and interpretation of factors that contribute to nucleation and growth of prion aggregates; and (iii) a re-examination of variable temperature and variable pH α-synuclein aggregation data in which the insights are elucidated that: (a) the processes of nucleation and growth are energetically similar, (b) the net charge of the protein affects nucleation, and (c) the lag-time does not, as previously thought, correspond to the rate of nucleation. Part II begins with a brief review of the importance of dioxygenases followed by an introduction to two important synthetic dioxygenases, the catechol dioxygenase [VO(3,5-DTBC)(3,5-DBSQ)]2 (where 3,5-DTBC = 3,5-di- tert-butylcatechol and 3,5-DBSQ = 3,5-di-tert-butylsemiquinone) and the claimed polyoxometalate dioxygenase, [WZnRu2(OH)(H 2O)(ZnW9O34)2]11-. The synthesis and characterization of a new dioxygenase, V(3,6-DBSQ)(3,6-DTBC) 2, along with the initial catalytic results with the H2(3,6-DTBC), substrate are given. Next is a full report of the dioxygenase activity with H2(3,5-DTBC) and H2(3,6-DTBC) substrates of three d 0 metal precatalysts: [VO(3,5-DTBC)(3,5-DBSQ)]2, V(3,6-DTBC) 2(3,6-DBSQ), and [MoO(3,5-DTBC)2]2. The d 0 vanadium bound to a semiquinone ligand in both V-precatalysts appears to be an important component for obtaining dioxygenase products from the H 2(3,5-DTBC) and H2(3,6-DTBC) substrates. Finally, Part II concludes with a reinvestigation a claimed dioxygenase, [WZnRu2(OH)(H 2O)(ZnW9O34)2]12- (1). Three independent samples of 1 from two different laboratories, samples that also give the same catalysis results as previously reported, are all consistent with the composition of the parent, Ru-free polyoxometalate, [WZn3(H2O)2(ZnW9O34) 2]12- (2). Also, simple mixtures of 2 plus [Ru(DMSO)4Cl2] is a ca. 2-fold more efficient catalyst than "1", placing in serious doubt a prior Nature paper detailing the claim that "1" is a Ru-based, all-inorganic dioxygenase. | |
| dc.format.medium | born digital | |
| dc.format.medium | doctoral dissertations | |
| dc.identifier | ETDF_Morris_2009_3385122.pdf | |
| dc.identifier.uri | https://hdl.handle.net/10217/237881 | |
| dc.language | English | |
| dc.language.iso | eng | |
| dc.publisher | Colorado State University. Libraries | |
| dc.relation.ispartof | 2000-2019 | |
| dc.rights | Copyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright. | |
| dc.rights.license | Per the terms of a contractual agreement, all use of this item is limited to the non-commercial use of Colorado State University and its authorized users. | |
| dc.subject | dioxygenases | |
| dc.subject | neurodegenerative diseases | |
| dc.subject | precatalysts | |
| dc.subject | protein aggregation | |
| dc.subject | biochemistry | |
| dc.subject | inorganic chemistry | |
| dc.title | Part I. Fitting protein aggregation kinetic data relevant to neurodegenerative diseases with an "Ockham's Razor" model en route to meaningful rate constants and mechanistic insights. Part II. Dioxygenases: the development of new, and the reinvestigation of prior, precatalysts | |
| dc.type | Text | |
| dcterms.rights.dpla | This Item is protected by copyright and/or related rights (https://rightsstatements.org/vocab/InC/1.0/). You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). | |
| thesis.degree.discipline | Chemistry | |
| thesis.degree.grantor | Colorado State University | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Doctor of Philosophy (Ph.D.) |
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