Graduate Studies

 

First Advisor

Wayne R. Riekhof

Degree Name

Doctor of Philosophy (Ph.D.)

Committee Members

Clay Cressler, Etsuko Moriyama, Oleh Khalimonchuk, Richard Wilson

Department

Biological Sciences

Date of this Version

8-2025

Document Type

Dissertation

Citation

A dissertation presented to the Graduate College of the University of Nebraska in partial fulfillment of requirements for the degree of Doctor of Philosophy

Major: Biological Sciences (Genetics, Cell and Molecular Biology)

Under the supervision of Professor Wayne R. Riekhof

Lincoln, Nebraska, August 2025

Comments

Copyright 2025, Amanda Marie Maliva. Used by permission

Abstract

Phosphatidylcholine (PtdCho) is a prominent structural building block of cell and organelle membranes in animal, plant, and fungal cells and some bacteria. Due to its abundant nature in the plasma membrane and intracellular organelle membranes in eukaryotes, the biosynthesis of PtdCho must remain regulated to preserve the correct membrane lipid composition. Dysregulations in PtdCho metabolism can lead to mitochondrial dysfunction, cell death, and the development of diseases including cancer, atherosclerosis, and hepatic diseases. Knowledge of PtdCho has remained limited to the genes involved in its three biosynthetic pathways (Kennedy (K), methylation (M), and acyltransferase (A)), despite the growing realization of PtdCho’s interconnectedness with numerous different biological processes. The observed inequivalence of the three redundant PtdCho biosynthetic pools in terms of associated cellular functions adds a further layer of complexity in the consideration of pathway-specific related biological processes. The goal of this dissertation was to genetically dissect PtdCho biosynthesis in terms of its coordination with other biological processes and modes of intracellular trafficking, and then correlate these findings within the context of antifungal research. The utilization of a novel PtdCho M-pathway inhibitor and implementation of chemical genetic screens, lipidomic analyses, and bioinformatic analyses with the model eukaryotic organism Saccharomyces cerevisiae aided in the accomplishment of this goal. The conducted research identified novel epistatic genetic interactions with the PtdCho biosynthetic M-pathway; trafficking mechanisms implicit in PtdCho biosynthesis via the A-pathway; and the corroborated antifungal effectiveness of PtdCho targeting and discovery of a novel antagonistic drug interaction between terbinafine and an M-pathway inhibitor. Collectively, the findings presented in this dissertation expand on the multifaceted roles of PtdCho beyond its basic function as a structural lipid and serve as a foundation for the continued elucidation of the exhaustive biological and molecular responsibilities of PtdCho.

Advisor: Wayne Riekhof

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