Date of Award

5-7-2016

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Chemistry

First Advisor

Dr. Aimin Liu

Second Advisor

Dr. Gregory Poon

Third Advisor

Dr. Donald Hamelberg

Abstract

3-Hydroxyanthranilate-3,4-dioxygenase (HAO) is a non-heme iron dependent enzyme that catalyzes the oxidative ring opening of 3-hydroxyanthranilate (HAA) which is an intermediate in the kynurenine pathway and its ring opening is the final enzymatic step from tryptophan to quinolinic acid (QUIN). QUIN functions as an N-methyl-D-aspartate (NMDA) receptor agonist and elevated brain levels of QUIN have been observed in neurodegenerative diseases. Reducing QUIN levels is of pharmacological importance. Kinetic and calorimetric studies were performed on human HAO using UV/Vis spectroscopy and isothermal titration calorimetry to understand its stability and behavior using its natural substrate (3-HAA) and neurological inhibitors such as acetylsalicylic acid (aspirin). This study reveals the first analysis of human HAO and facilitates understanding of its binding dynamics and enzymatic activity which will later support discovering suitable pharmacological compounds.

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