Date of Award
Spring 2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry
First Advisor
Crawford, Jason
Abstract
The increased incidents of many chronic diseases such as asthma, allergies, diabetes, heart disease, and mental disorders cannot be fully explained by genetic factors. The exposure to environment, diet, and behavioral changes is equally or sometimes even more greatly associated with disease progression. Such non-genetic factors could be reflected in chemical fingerprints that cellular processes leave behind. Metabolite profiling provides biochemical information that is not available at the gene or protein level. The emerging technological advances such as sensitive metabolomic approaches have allowed to assess these metabolic changes in a way that was not possible before. As a consequence, in the past twenty years, the field of metabolism has been revisited with new questions. This research led to detailed insights about changes in primary metabolism and immune cell responses, such as Warburg effect in activated T cells and M1 macrophages, unexpected “moonlighting” roles of glycolytic enzymes, and novel immune functions of succinate, itaconate, citrate, and tryptophan. Some studies have also focused on the role of host‐microbial interactions and impacts of microbially derived metabolites on chemical signaling and chronic diseases. Despite this substantial progress, the majority of studies have focused on well-established metabolic pathways and metabolites. Many mechanisms behind metabolic reprogramming by human enzymes, oxidative stress, and the microbiota remain open areas of investigation. In this dissertation, our aims were therefore to characterize novel host and microbial metabolites associated with enzyme detoxification mechanisms, and GPCR signaling. Chapter 1 describes metabolomics studies of human aldo-keto reductase family 1 member C3 (AKR1C3). Altered human aldo-keto reductase family 1 member C3 (AKR1C3) expression has been associated with poor prognosis in diverse cancers, ferroptosis resistance, and metabolic diseases. Despite its clinical significance, the endogenous biochemical roles of AKR1C3 remain incompletely defined. Using untargeted metabolomics, we identified a major transformation mediated by AKR1C3, in which a spermine oxidation product “sperminal” is reduced to “sperminol.” Sperminal causes DNA damage in vitro and activates the DNA double-strand break response, whereas sperminol induces autophagy. AKR1C3 also pulls down acyl-pyrones and pyrone-211 inhibits AKR1C3 activity. Through G protein-coupled receptor (GPCR) ligand screening, we determined that pyrone-211 is also a potent agonist of the ‘orphan’ receptor GPR84. Strikingly, mammalian fatty acid synthase (FAS) produces acyl-pyrones in vitro, and this production is modulated by NADPH. Taken together, our studies support a detoxification role of AKR1C3 in an expanded polyamine pathway and a model linking fatty acid synthesis and NADPH levels to GPR84 signaling. Chapter 2 is dedicated to characterization and synthesis of new bacterial metabolite termed lipomonosaccharide (LMS) with m/z of 448.2910. Chapter 3 describes N-acyl amides and a hydrazine metabolite with m/z of 260.1605 produced by X. nematophila and its biosynthetic pathway.
Recommended Citation
Dudkina, Natavan, "Decoding Novel Metabolic Functions and Binding Products of Human Aldo-Keto Reductase 1C3" (2024). Yale Graduate School of Arts and Sciences Dissertations. 1480.
https://elischolar.library.yale.edu/gsas_dissertations/1480
