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The Role of Oxygen and Oxygen-Dependent Enzymes in Protein Folding, Metabolism, and Redox Homeostasis
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The Role of Oxygen and Oxygen-Dependent Enzymes in Protein Folding, Metabolism, and Redox Homeostasis
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Dissertation
The Role of Oxygen and Oxygen-Dependent Enzymes in Protein Folding, Metabolism, and Redox Homeostasis
2023
Overview
Low levels of oxygen (hypoxia) in solid tumors contributes to therapy resistance and poor patient prognosis. How the cells in the tumor microenvironment (TME) adapt to hypoxia at a transcriptional, epigenetic, and translational level has been extensively explored. Here, we provide a comprehensive review on how molecular signaling in hypoxia represents an intricate, coordinated response triggered by oxygen dependent enzymes. Our work also highlights the lack of understanding of the requirement for oxygen in protein folding and the biological roles of an oxygen dependent enzyme, 2-aminoethanethiol dioxygenase (ADO).Secreted proteins contribute to aggressive cancer phenotypes in the TME. These secreted proteins are thought to utilize an oxygen dependent mechanism for disulfide bond formation required for proper folding, which represents a paradox when they are expressed under hypoxic conditions. Here we confirm the existence of oxygen independent pathways for disulfide bond formation. For the first time we demonstrate that key hypoxia-induced proteins such as vascular endothelial growth factor (VEGF-A) and carbonic anhydrase 9 (CA9) remain fully competent at disulfide bond formation in the absence of oxygen, supporting their efficient expression in hypoxia. This work highlights that the ability of individual proteins to undergo protein folding in the absence of oxygen ultimately determines their expression in the extracellular space in hypoxia.In parallel, we explored the cellular and physiological roles of a relatively uncharacterized oxygen sensing enzyme, ADO. ADO synthesizes hypotaurine and directly regulates protein stability through catalyzing a post translational modification in an oxygen dependent manner. Here we show that ADO is essential for the growth and survival of cancer cells and promotes tumor xenograft growth. ADO mitigates reactive oxygen species (ROS) through regulating proline metabolism. These data provide novel insights into how depletion of an oxygen dependent enzyme may elicit a metabolic imbalance leading to loss of redox homeostasis.Taken together, this thesis explores the role and the importance of oxygen and oxygen dependent enzymes that drive acute responses such as affecting the disulfide bond formation of protein folding and deregulation of the cancer metabolome.
