The Structural and Biochemical Studies of the Thioesterase Domains of Them1 Público
Adhiyaman, Akshitha (Spring 2020)
Published
Abstract
Obesity is an overwhelmingly large health issue across the world and we desperately need new ways to battle this epidemic. Brown adipose tissue can potentially be utilized to treat obesity due to its high capacity to burn fat to drive non-shivering thermogenesis. Thioesterase superfamily member 1 (Them1) is highly expressed in brown adipose tissue and suppresses thermogenesis through hydrolyzing acyl-CoA, antagonizing lipid metabolism. Mice lacking Them1 are protected against diet-induced obesity and metabolic disorders; therefore, inhibitors of Them1 are highly desired. There is currently no structure of the thioesterase domains of Them1 and the enzymatic mechanism of the enzyme remains unknown. In this study, we elucidated the mechanism by which Them1 hydrolyzes acyl-CoA using mutagenesis, and made progress in determining the structure of Them1’s thioesterase domains. Collectively, this work advances us one step closer to pharmacologically targeting Them1 to counter obesity and its related disorders.
Table of Contents
Chapter 1: Introduction 1
Chapter 2: Creating the Them1 Construct 7
Chapter 3: Purifying the Them1 Thioesterase Domains 10
Chapter 4: Thioesterase Activity Assays 15
Chapter 5: Purifying the MBP Tagged Them1 Thioesterase Domains 19
Chapter 6: Crystallography Screens with Them1 Thioesterase Domains 24
Chapter 7: Future Directions and Conclusion 26
References 28
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