Proton coupled electron transfer and the mechanism of MAO catalysis

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With the support of the Chemistry of Life Processes (CLP) Program in the Division of Chemistry, Professors James M. Tanko and Pablo Sobrado of Virginia Polytechnic Institute and State University are studying the mechanism of action for monoamine oxidase-A and -B (MAO-A and MAO-B). These are important enzymes present in mammals, which play a key role in the metabolism of neurotransmitters such as dopamine, norepinephrine, epinephrine and serotonin. For these natural (biogenic) amines, the mechanism of this oxidation appears to be well understood. MAOs have also been linked to central nervous system disorders such as depression and Parkinson’s disease, and considerable effort has gone into the development of MAO inhibitors. However, some of these MAO inhibitors such as L-deprenyl or pargyline cannot react by the same mechanism as the biogenic amines. Other compounds, which possess similar structural features have proven to be potent neurotoxins. Professors Tanko and Sobrado will test and further develop a new hypothesis that with certain amines, specific structural features are present that activate an alternative mechanism of oxidation (proton coupled electron transfer or PCET) that is fundamentally different from the mechanism typically followed by the enzyme with most natural substrates. This collaborative project, linking biological, organic, physical, and quantum chemistry, is expected to lead to a better understanding of how these processes work (or break down) and, in the case of disease, inform strategies for treatment based upon fundamental chemical principles. Radicals and radical ions are important chemical species in chemistry and biology and their study will be a focus here. As part of the education/outreach component of this proposal, a series of videos entitled "Organic Chemistry: The Missing Chapters" will be developed to address the limited discussion of these species in many introductory organic chemistry textbooks. Topics to be covered include radicals and radical ions in the context of biological chemistry (enzyme catalyzed processes, autoxidation, etc.) and organic chemistry (mechanisms and synthesis).The MAO catalytic pathway couples the initial net two-electron oxidation of the substrate to its iminyl metabolite with a two-electron reduction of the oxidized flavin cofactor. The core hypothesis of this work is that electron transfer between the substrate and flavin cofactor is always present as an unfavorable equilibrium, but only becomes important when the resulting radical cation is extremely acidic; in essence, this unfavorable electron transfer occurs because it is coupled to an extremely favorable proton transfer. The structural features that cause the radical cation to be acidic are present in many common MAO inhibitors, and in a compound known as MPTP-a potent neurotoxin that leads to symptoms of Parkinson's disease in humans. These experiments will involve a biomimetic approach, using flavin-based chemical model compounds that mimic the chemistry of the enzyme, to develop the fundamental understanding of the reaction mechanism. The insight gained from these experiments will then inform experiments conducted under biologically relevant conditions, using recombinant MAO-A and MAO-B.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.