Doctor of Philosophy, Case Western Reserve University, 2020, Chemistry

Stable isotopomers of biological molecules or xenobiotics can be utilized to probe the metabolic pathways with which these compounds are involved. By introducing these labeled substrates into living systems, we can use techniques such as mass spectrometry to track the fates of the isotopically labeled atoms. One set of projects described herein focuses on the synthesis of these substrates for use by collaborating laboratories. Of particular interest to our lab are biomolecules known as lipid peroxidation (LPO) products. These molecules are formed in increased concentrations during periods of oxidative stress. In the past, our lab has discovered metabolic pathways that allow for catabolism of the ubiquitous LPO product 4-hydroxynonenal. In order to better understand these pathways, we need to identify the enzymes that affect the steps of each pathway. It also stands to reason that there may be other pathways that exist for additional families of LPO products. To this end, I describe work done on the isolation of the kinase involved in 4-HNE metabolism as well as synthesis of epoxyketooctadecenoic acids for use in additional metabolic studies. The final topic of study involves the confirmation of the identity of a novel metabolite 4-(aminomethyl)malonate. Results from a previous study led us to hypothesize the existence of this molecule. Synthesis of both isotopically unlabeled and labeled analogues of this molecule was completed and utilized to confirm the identity of the molecule. An in vivo study was conducted where rats were fed β-alanine, the proposed metabolic precursor to this molecule. The tissue specific concentration of AMM formed during periods of high β-alanine was tracked and its effect on neurotransmitters was assessed.

Committee: Gregory Tochtrop Ph.D. (Advisor); Henri Brunengraber Ph.D. M.D. (Committee Member); Clemens Burda Ph.D. (Committee Member); Daniel Scherson Ph.D. (Committee Member); Robert Salomon Ph.D. (Committee Chair) Subjects: Chemistry