Doctor of Philosophy (Ph.D.)
Degree Granting Department
Li-June Ming, Ph.D.
Randy Larsen, Ph.D.
Jianfeng Cai, Ph.D.
Yu Chen, Ph.D.
Alzheimer’s, beets, bacitracin, oxidative stress, thiabendzole, betanin
Despite its relatively low concentration in the human body, copper is an essential transition metal ion. Under normal circumstances, it is a well-regulated trace element that is introduced via diet or environment depending on the organism. Its strong reactivity and binding to some biologically essential chemicals can be detrimental to the host organism. Herein the oxidative chemistry of copper and its possible prevention in humans and agricultural organisms is discussed, as well as the potential avenues as metal-targeting disease treatment via novel-peptide and peptoid products.
In the first study, copper is implicated in the progression and onset of Alzheimer’s disease. In this study I show a chemical that is found in beetroot, betanin, can bind to the copper-amyloid beta complex, the complex implicated in AD, using paramagnetic NMR techniques. Betanin also shows a reduction in catechol oxidase-like activity of CuAβ towards DTBC under oxidative and peroxidative conditions with a Kic and Kiu in the presence of ambient of O2 of 1.11 ± 0.03 and 2.2 ± 0.4 μM, respectively. Betanin also showed inhibition towards H2O2-mediated CuAβ oxidation with a Kic and Kiu of 0.76 ± 0.04 and 1.28 ± 0.08 μM, respectively.
Secondly, the potential activity of copper from an agricultural perspective is presented where copper-bound bacitracin from the soil bacteria Bacillus subtilus is inhibited by natural products that may occur in the environment. Natural and synthetic metal-binding oxidative inhibitors, salicylic acid and thiabendazole, respectively, were chosen based on the potential interaction with CuBc based on their place in medicine and/or the environment around plants. Paramagnetic NMR techniques show each compound can form the ternary complex with CuBc and the subsequent inhibition of redox activity. Salicylic acid of the willow tree showed inhibition constants of Kic,O2 of 5.24 ± 0.03 mM, Kiu,O2 of 21 ± 3 mM, and a Kiu,H2O2 15 ± 3 μM. Thiabendazole revealed inhibition constants of Kic,O2 of 1.1 ± 0.4 mM, Kiu,O2 of 1.5 ± mM, Kic,H2O2 6.3 ± 0.7 μM, and Kic,H2O2 of 13.2 ± 2.6 μM.
In the last chapter a novel γ-AApeptide right-handed helical “foldamer” and the structure of a similar γ-AApeptide were examined. Peptoids are a type of peptidomimetic compound that is synthesized with the α-carbon sidechain substituted onto the nitrogen on the peptide backbone. One of the key advantages in using peptoids is their increase in bioavailability given the inability to be metabolized by proteases. The first half of this study uses NMR techniques to support the structural information about a novel γ-AApeptide. The examination of incorporating metals into these novel peptides in the second half of the study would help elucidate the role of metals as they are often under-utilized in drugs or drug targets. This study shows the differences in binding resulting in a difference in metal binding as well as a difference in reactivity.
Scholar Commons Citation
Cerrato, Darrell Cole, "The Activity and Structure of Cu2+-Biomolecules in Disease and Disease Treatment" (2019). Graduate Theses and Dissertations.