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Studies on superoxide dismutase inhibition and application of methods to study metal ion participation in complication of diabetes

WCU Author/Contributor (non-WCU co-authors, if there are any, appear on document)
Benjamin Hickman (Creator)
Institution
Western Carolina University (WCU )
Web Site: http://www.wcu.edu/404.asp
Advisor
Jack Summers

Abstract: Studies on Superoxide Dismutase Inhibition We used NMR relaxation rates to study reactions of the enzyme superoxide dismutase (SOD) with low molecular weight polyphenolic compounds. While the compounds appeared to inhibit SOD, we discovered evidence that the reaction proceeds with electron transfer from the polyphenols to the enzyme, giving a form of the SOD that was inactive in the assay but retained enzymatic activity. The reaction was highly dependent on the aggregation and protonation states of the compounds. Application of Methods to Study Metal Ion Participation in Complication of Diabetes Diabetics display increases in chemical modification of proteins and also increased levels of oxidative stress. Alderson et al. reports one of these modifications involves reaction of the sulfhydryl group of cysteine residues with the Krebs Cycle intermediate fumarate. It has been proposed that the product, S-(2-Succinyl)cysteine (2SC), can bind metals, and may catalyze reactions such as the Haber-Weiss cycle. It is possible that 2SC will catalyze the disproportionation of superoxide. To study the possible link between 2SC and oxidative stress we synthesized two model compounds and studied their reactions. One of these is S-(2-succinyl)-Nacetlycysteine (2SAC). We have shown the 2SAC will bind copper with a stability constant of log(K)= 3.59 ± 0.05. Also we have shown that the compound 2SAC-Cu will catalyze the Haber- Weiss reaction but not the disproportination of superoxide. Furthermore, since glutathione concentrations in vivo can reach up to 10 mM it seems likely that reduced glutathione will react with fumerate to give S-(2-succinyl)-glutathione (2SGT). To study its possible role in vivo, we synthesized 2SGT. For the 2SGT compound, the binding constant of Cu-2SGT was determined to be log(K)=10.9 ± 0.2. Likewise, we have found that 2SGT binds to copper in such a way as to prevent catalysis of further reactions. Our attempts to study the iron complexes for these compounds have been unsuccessful due to their low solubility.

Additional Information

Publication
Thesis
Language: English
Date: 2012
Keywords
diabetes, flavonols, oxidative stress, superoxide dismutase
Subjects
Superoxide dismutase -- Inhibitors
Diabetes