Degree Type

Dissertation

Date of Award

2013

Degree Name

Doctor of Philosophy

Department

Biochemistry, Biophysics and Molecular Biology

Major

Bioinformatics and Computational Biology

First Advisor

Robert L. Jernigan

Second Advisor

Drena Dobbs

Abstract

Glycolysis is a central metabolic pathway, present in almost all organisms, that produces energy. The pathway has been extensively investigated by biochemists. There is a significant body of structural and biochemical information about this pathway. The complete pathway is a ten step process. At each step, a specific chemical reaction is catalyzed by a specific enzyme. Fructose bisphosphate aldolase (FBA) and triosephosphate isomerase (TIM) catalyze the fourth and the fifth steps on the pathway.

This thesis investigates the possible substrate transfer mechanism between FBA and TIM. FBA cleaves its substrate, the six-carbon fructose-1,6-bisphosphate (FBP), into two three-carbon products - glyceraldehydes 3-phosphate (GAP) and dihydroxy acetone phosphate (DHAP). One component of these two products, DHAP, is the substrate for TIM and the other component GAP goes directly to GAPDH, the subsequent enzyme on the pathway. TIM converts DHAP to GAP and delivers the product to GAPDH. I employ Elastic Network Models (ENM) to investigate the mechanistic and dynamic aspects of the functionality of FBA and TIM enzymes - (1) the effects of the oligomerization of these two enzymes on their functional dynamics and the coordination of the individual protein's structural components along the functional region; and (2) the mechanistic synchrony of these two protein machines that may enable them to operate in a coordinated fashion as a conjugate machine - transferring the product from FBA as substrate to TIM.

A macromolecular machine comprised of FBA and TIM will facilitate the substrate catalysis mechanism and the product flow between FBA and TIM. Such a machine could be used as a functional unit in building a larger a machine for the structural modeling of the whole glycolysis pathway. Building such machines for the glycolysis pathway may reveal the interplay of the enzymes as a complete machine. Also the methods and insights developed from the efforts to build such large machines could be applied to build macromolecular structures for other biologically important clusters of interacting enzymes centered around individual metabolic pathways.

DOI

https://doi.org/10.31274/etd-180810-4303

Copyright Owner

Ataur Rahim Katebi

Language

en

File Format

application/pdf

File Size

223 pages

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