Author ORCID Identifier

0000-002-1566-4972

Date of Award

8-10-2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Aimin Liu

Abstract

Tryptophan is an essential amino acid that is used as a building block to construct proteins, the biosynthetic precursor for several essential molecules, and is modified to serve as a cofactor in some enzymes. This dissertation focuses on two enzymes involved in tryptophan oxidation, AMSDH and MauG. AMSDH is a dehydrogenase in the kynurenine pathway, which is the main metabolic route for tryptophan catabolism. In addition to breaking down tryptophan, the kynurenine pathway is also involved in regulating the innate immune response, NAD biosynthesis, and some neurodegenerative. As such, enzymes of the kynurenine pathway are of fundamental interest for study. This work leveraged a bacterial homologue of human AMSDH to solve its crystal structure in various forms, including several catalytic intermediates. The knowledge gained from the bacterial enzyme was then used to identify and verify human ALDH8A1 as the human AMSDH. MauG is the enzyme responsible for catalyzing the formation of the tryptophan-derived cofactor of methylamine dehydrogenase. It is a diheme enzyme that utilizes hydrogen peroxide perform long-range oxidations on its protein substrate. MauG possesses the remarkable ability to store two oxidizing equivalents as a bis-Fe(IV) species that is stabilized through a type III charge resonance phenomenon. The nature of the charge resonance phenomenon was investigated with exogenous small molecules, radical traps, and temperature dependent studies. Finally, a cryogenic method for generating radicals was developed to study the electronic structure of model compounds similar to the substrate of MauG.

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