News & Events

When

Date - January 18, 2019
1:00 pm - 2:00 pm

What

Assistant Professor
Department of Chemistry
Eastern Carolina University
Talk Title: Allosteric regulation of lipoxygenase C-H activation: how quantum biology may guide the design of next-generation anti-inflammatory drugs

Abstract:

Human 15-lipoxygenase-2 (15-LOX-2) is responsible for both anti- and pro-inflammatory responses and the enzymatic activity of  15-LOX-2 has been linked to both cardiovascular disease and acute renal failure. Our goal is to develop small molecule regulators and inhibitors that could serve to define the functional role of 15-LOX-2 in human health. To accomplish this goal, we are utilizing multi-temperaturehydrogen-deuterium exchange mass spectrometry (mtHDXMS) to resolve changes in the protein conformation upon interactions of the lipoxygenase enzyme with small molecule effectors and  proteins that regulate catalysis through long-range allostery. Using the model enzyme soybean lipoxygenase (SLO) and effector oleyl sulfate (OS) as proof-of-principle, we have detected OS-induced conformational changes both at the N-terminal regulatory domain and within the substrate portal nearly 30 Å away. Extension of this approach to 15-LOX-2 reveals unique patterns of OS-induced altered conformational plasticity, suggesting that mtHDXMS may provide specific dynamical fingerprints of allosteric regulation.  Because lipoxygenase-catalyzed C-H activation of polyunsaturated fatty acids can be described by a quantum mechanical hydrogen tunneling mechanism, isotope effects provide a highly resolved window into the complete shape of the reaction coordinate and the corresponding impact from allosteric effectors. From the latter, the role of OS-induced changes in protein flexibility in the context of changes in the mechanism of substrate acquisition will be discussed.