PROJECT SUMMARY/ABSTRACT
Methionine metabolism is a central regulator of protein synthesis, mitochondrial function, antioxidant
defense, and other critical cellular processes. Tightly regulating methionine flux via the methionine metabolism
pathway is essential for healthy cellular function. Not surprisingly, an imbalance in this fundamental metabolic
pathway has been attributed to numerous diseases. Yet, the molecular link between alterations in methionine
availability and dysregulation of downstream cellular processes remains obscure. Methionine and ATP are the
sole precursors for the production of the methyl donor S-adenosylmethionine (SAM), the principal and rate-
limiting methyl donor for methyltransferases (MTs), which catalyze a variety of methylation reactions via the
transfer of methyl groups onto different substrates. Although reprogramming of methionine metabolism has
been observed with different pathological conditions, it is not known which downstream MTs link methionine
metabolism to the development of these pathological conditions and what mediates the specificity of this
interaction, representing a significant knowledge gap. I hypothesize that the identification of specific MTs
will reveal novel mechanisms by which methionine metabolism regulates essential cellular processes. The
goal of our research is to mechanistically understand how alterations in methionine are transduced into
biological effects. To accomplish this goal, my laboratory will build and sustain three research projects.
Through a preliminary screen, we identified several MTs that promote resistance to starvation or oxidative
stress similar to manipulations of the methionine metabolism pathway. I will test several models to determine
which MTs function downstream to methionine metabolism and complete the screen of the remaining MTs
(Project 1). Secondly, I will test whether the tissue-specific expression of selected MTs help explain the
specificity of how global changes in methionine levels affect specific MTs using a novel tissue-specific
methionine degradation system that we recently developed (Project 2). Finally, we will use an open-ended
proteomics approach to identify prospective downstream targets of the identified MTs and test how these MTs
affect functional responses to stress (Project 3). These platforms interdigitate but also work independently,
noting that we have already identified several MTs that promote resistance to different stresses, so Projects 2
and 3 can be performed independently of Project 1. We will employ innovative approaches by combining
novel genetic tools that allow us to manipulate methionine levels within specific tissues and using a state-of-
the-art approach to quantify methionine fate in vivo. The proposed research is significant because it will
uncover how a central metabolic pathway (methionine) controls many basic cellular processes. This basic
research is likely to further identify “druggable” targets relevant to multiple human pathologies associated with
reprogrammed methionine metabolism including cancer, obesity, neurodegeneration, and aging.
