Date of Award

12-2010

Degree Name

Doctor of Philosophy

Department

Chemistry

First Advisor

Dr. David Huffman

Second Advisor

Dr. Susan Stapleton

Third Advisor

Dr. Ekkehard Sinn

Fourth Advisor

Dr. Thomas Thamman

Abstract

Theromin, a novel thrombin inhibitor from the leech Theromyzon tessulatum, has been shown to be the strongest inhibitor to date. There has been a lot of attention on direct thrombin inhibitors as a much more efficient drug for anticoagulation therapy. One main reason for the need of strong direct thrombin inhibitors is that the current therapy, heparin, causes alternative clotting events in some patients where antibodies are made to the heparin/thrombin complex and causes clots to occur by different methods. Recently there has been a strong inhibitor from a leech used, hirudin, that can inhibit with a Ki of 21 fM. This is the strongest inhibitor currently used as a therapy for patients suffering from clotting issues. This work investigated a leech inhibitor that has a Ki of 13 fM making it an even better candidate for therapies as it will inhibit more efficiently.

Copper is scrupulously regulated within the cell to maintain proper balance of redox activity and storage. One protein involved in this process is Wilson disease protein, which is responsible for moving copper into vesicles for either storage or removal from the cell. Previous work has shown copper is transferred to the Wilson disease protein via its metallochaperone, HAHl. The proposed mechanism for this transfer seems to involve a transient 3-coordinate copper(I) intermediate. Similar work done on Saccharomyces cerevisiae has shown that a 3-coordinate intermediate could exist between Atxl (analogue of HAHl) and its partner Ccc2. Trapping this intermediate involved selective mutation of individual cysteines involved in the copper(I) binding.

Access Setting

Dissertation-Open Access

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Chemistry Commons

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