Advisor(s)
Gayan Wijeratne
Committee Member(s)
Anna Sorace
Pengfei Wang
Sadanandan Velu
Wenli Bi
School
College of Arts and Sciences
Document Type
Dissertation
Department (new version)
Chemistry
Date of Award
1-6-2025
Abstract
Tryptophan catabolizing human heme-dioxyganase enzymes have been linked to a multitude of disease conditions; therefore, understanding the mechanistic details of their function is of great interest to facilitate the design of effective inhibitors for therapeutic applications. Synthetic model systems have demonstrated dioxygenation of indole moieties, elucidating key mechanistic details of the overall reaction. However, the contrastingly low reactivity of the synthetic heme-superoxide intermediates compared to those of dioxygenase enzymes necessitates the revaluation of these models with direct relevance to their biological mode of action. Herein, we report detailed mechanistic studies on the reactivity of model porphyrin systems with installed non-covalent interactions to mimic those found crucial for the efficient function of the inspiring enzymatic systems. This biomimetic approach is amenable to precise modulation of the secondary coordination sphere in a way that is not possible in biological systems. In that, variation of exogenously added Lewis acid species and/or the substitution of select groups to modulate proton affinity of hydrogen bond donors/acceptors enable direct control over the extent, type(s), and position(s) of non-covalent interactions surrounding the distal face of the porphyrin. Vigorous spectroscopic and theoretical kinetic studies of these models reveal crucial insights into fundamental reactivity properties, including kinetic rates, kinetic isotope effects (KIEs), activation parameters, reaction coordinate diagrams, reaction intermediate and transitions state structures, mechanistic details such as electrophilic, nucleophilic and/or radical nature of the reaction progression, bond dissociation free energies (BDFEs) and linear free energy relationships. Ultimately, this work contributes to i) establishing a complete understanding of parameters that govern the bio-relevant reactivity landscape of mid-valent synthetic heme-oxygen intermediates, ii) aiding the design of inhibitor moieties for dioxygenase targeting therapeutics, iii) producing insights into the role of the distal coordination environment in modulating proton-coupled electron transfer (PCET) reactivity with direct relevance to O2 reduction catalysts for alternative energy applications such as fuel cells, and iv) elucidation of the role of secondary sphere coordination in other biologically relevant reaction intermediates including they ferryl intermediate invoked in the proposed heme-dioxygenase mechanism.
ProQuest ID
Recommended Citation
Tolbert, Garrett B., "Elucidating The Role Of The Secondary Coordination Sphere In Tuning Reactivity Of Synthetic Heme Superoxide Complexes And Other Biologically Relevant Intermediates" (2025). All ETDs from UAB. 7283.
https://digitalcommons.library.uab.edu/etd-collection/7283
