Presentation Title

Brevotoxin Adduct Mechanism and Effect on Thioredoxin Reductase Activity

Abstract

Thioredoxin reductase (TrxR) is an enzyme that is ubiquitous to all known life because of its important role in maintaining the reducing environment of cells. The mammalian version of TrxR has selenium in place of a sulfur at the C-terminal redox center in the form of a selenocysteine (Sec) residue. The nucleophilic nature of Sec allows for the C-terminal redox center of TrxR to undergo a Michael addition reaction and the resulting adduct changes the activity of the enzyme and what substrates it can reduce. The dinoflagellate Karenia brevis, the cause of Florida’s “red tide”, produces brevotoxin-2 which has a Michael acceptor that can become adducted to TrxR. We hypothesis that this interaction with brevotoxin-2 will inhibit the reduction of canonical TrxR substrates while greatly increasing the NADPH oxidase activity of TrxR. Whilst typically an antioxidant enzyme, the NADPH oxidase activity of TrxR results in the production of reactive and damaging oxidants in the cell. We believe this is one way in which brevotoxin is toxic to humans.

Primary Faculty Mentor Name

Robert Hondal, PhD

Graduate Student Mentors

Emma Ste Marie

Status

Undergraduate

Student College

College of Arts and Sciences

Program/Major

Biochemistry

Primary Research Category

Biological Sciences

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Brevotoxin Adduct Mechanism and Effect on Thioredoxin Reductase Activity

Thioredoxin reductase (TrxR) is an enzyme that is ubiquitous to all known life because of its important role in maintaining the reducing environment of cells. The mammalian version of TrxR has selenium in place of a sulfur at the C-terminal redox center in the form of a selenocysteine (Sec) residue. The nucleophilic nature of Sec allows for the C-terminal redox center of TrxR to undergo a Michael addition reaction and the resulting adduct changes the activity of the enzyme and what substrates it can reduce. The dinoflagellate Karenia brevis, the cause of Florida’s “red tide”, produces brevotoxin-2 which has a Michael acceptor that can become adducted to TrxR. We hypothesis that this interaction with brevotoxin-2 will inhibit the reduction of canonical TrxR substrates while greatly increasing the NADPH oxidase activity of TrxR. Whilst typically an antioxidant enzyme, the NADPH oxidase activity of TrxR results in the production of reactive and damaging oxidants in the cell. We believe this is one way in which brevotoxin is toxic to humans.