Date of Award:
5-2022
Document Type:
Dissertation
Degree Name:
Doctor of Philosophy (PhD)
Department:
Chemistry and Biochemistry
Committee Chair(s)
Alvan C. Hengge
Committee
Alvan C. Hengge
Committee
Lance C. Seefeldt
Committee
Sean J. Johnson
Committee
Brett Adams
Committee
Nicholas E. Dickenson
Abstract
As Westheimer elucidated in the Science article “Why Nature Chose Phosphates” in 1987, phosphates serve many biological roles, such as linkers in nucleic acids, in energy molecules such as ATP, and intermediary metabolites due to their unique properties. The hydrolysis of a phosphate ester is thermodynamically favorable yet extraordinarily slow: the half-time for the uncatalyzed hydrolysis of alkyl phosphate dianions exceeds a billion years at 25 °C. As essential biological catalysts, phosphatases are among the most efficient enzymes that provide enormous rate accelerations to the hydrolysis reaction by significantly lowering the activation barrier.
Protein tyrosine phosphatases (PTPs) are lifeguards for crucial physiological processes, such as cell signaling, growth, and division. Over 100 PTP genes have been identified within the human genome, and mutations or inactivation of expression of these genes are associated with hereditary human diseases or disease susceptibilities. Throughout the last several decades, mechanistic studies on PTP-catalyzed phosphoryl transfer have been blooming to enable the development of therapeutic targets to overcome a variety of human diseases. Explicitly, insights into PTP structure-function relationships are gradually elucidated with the combination of experimental and computational approaches. Among all the studies and findings, the utmost important concept to describe PTP-catalyzed phosphoryl transfer and the foundation of this work is: conformational dynamics are correlated to catalysis. In this work, we investigate three modern PTPs and a simulation-predicted ancestral PTP. Our results reveal properties related to enzyme evolvability that apply to the PTP family as a whole.
Checksum
043896a16d8d663d5c9d27388007b0d6
Recommended Citation
Shen, Ruidan, "Correlation Between Loop Motions and Catalysis in Protein Tyrosine Phosphatases" (2022). All Graduate Theses and Dissertations, Spring 1920 to Summer 2023. 8490.
https://digitalcommons.usu.edu/etd/8490
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