Aron W. Fenton, Ph.D.
Professor, Biochemistry and Molecular Biology
Departmental Graduate Director, Departmental Graduate Director, Biochemistry and Molecular Biology
Scientific Director of the KUMC Mass Spectrometry/Proteomics Core Laboratory, Scientific Director, SOM-Kansas City
Biochemistry and Molecular Biologyafenton@kumc.edu
University of Kansas Medical Center, Kansas City, KS, Biochemistry and Molecular Biology, Assistant Professor, 2004 - 2010
University of Kansas Medical Center, Biochemistry and Molecular Biology, Associate Professor, 2010 - 2017
University of Kansas Medical Center, Biochemistry and Molecular Biology, Professor, 2017 - present
University of Kansas Medical Center, Director of Graduate Studies, Biochemistry and Molecular Biology, Professor, 2018 - present
Education and Training
- BS, Biochemistry, Oklahoma St. U.
- PhD, Biochemistry, Oklahoma St. U.
- Other, Biochemistry and Biophysics, Texas A&M University
Dissecting Molecular Mechanisms of Allosteric Regulation
Research in my lab focuses on understanding the mechanisms of allosteric regulation. Metabolic and signal transduction pathways need to be regulated to enable organisms to respond to ever changing environmental conditions. Allostery is often a key component to providing this necessary regulation. In fact, Monod (Nobel Prize winner) found allosteric regulation so important to biological functions that he referred to it as " the second secret to life".
At the single protein level, allosteric regulation is the altered functions that result when a regulatory molecule binds to a protein at a site distinct from the protein’ s active site. What is not well understood is how the binding of the effector molecule is communicated through the protein to alter the active site. If we could understand the mechanisms within proteins that give rise to allostery, then modulating allosteric properties would be useful to an enormous number of biological applications.
I want to understand both the molecular and thermodynamic mechanisms of allostery. Pyruvate kinase from human liver (L-PYK) is allosterically activated by Fru-1,6-BP and allosterically inhibited by ATP and Ala. This enzyme is also inhibited upon phosphorylation. This system is significant to biology due to the required regulation of L-PYK to maintain liver homeostasis between glycolysis and gluconeogenesis. This is also a great model system to study allosteric regulation. Using this system we have the opportunity to compare and contrast multiple allosteric mechanisms.
Instead of limiting our thoughts to a limited number of assumed confirmations, we consider allosteric regulation using thermodynamic arguments that are free of presumed conformational states. This approach also offers the theory for quantifying a "magnitude" of how much allosteric regulation is present instead of treating this regulation as on-or-off; plus-or-minus; all-or-none. At the current time we are focusing our attention on the areas of L-PYK that must by necessity play roles in allosteric regulation: the active site and the effector binding sites. We are using mutagenesis and ligand analogs to answer which coordinating interactions between protein and ligand contribute to the allosteric communication. Based on our previous results, our hypothesis is that most of the coordinating interactions contribute to ligand binding, but only a very limited number of the coordinating interactions contribute to the allostery.