Molecular mechanism of 15-lipoxygenase allosteric activation and inhibition

Physical Chemistry Chemical Physics : PCCP
Hu MengLuhua Lai

Abstract

Human reticulocyte 15-lipoxygenase (15-LOX) plays an important role in inflammation resolution and is also involved in many cancer-related processes. Both an activator and an inhibitor will serve as research tools for understanding the biological functions of 15-LOX and provide opportunities for drug discovery. In a previous study, both allosteric activators and inhibitors of 15-LOX were discovered through a virtual screening based computational approach. However, why molecules binding to the same site causes different effects remains to be disclosed. In the present study, we used previously reported activator and inhibitor molecules as probes to elucidate the mechanism of allosteric regulation of 15-LOX. We measured the influences of the allosteric activator and inhibitor on the enzymatic reaction rate and found that the activator increases 15-LOX activity by preventing substrate inhibition instead of increasing the turnover number. The inhibitor can also prevent substrate inhibition but decreases the turnover number at the same time, resulting in inhibition. Molecular dynamics simulations were conducted to help explain the underlying mechanism of allostery. Both the activator and inhibitor were demonstrated to be able to prev...Continue Reading

References

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Citations

Feb 19, 2019·Physical Chemistry Chemical Physics : PCCP·Miao YuZhirong Liu
Dec 17, 2019·Biophysical Journal·Asuka A OrrPhanourios Tamamis
Apr 4, 2021·International Journal of Molecular Sciences·Igor IvanovHartmut Kuhn
Jun 4, 2021·The Journal of Physical Chemistry Letters·Qiaojing HuangLuhua Lai
May 28, 2021·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Jacqueline Wen Hui LeowEric Chun Yong Chan
Feb 15, 2019·Journal of Chemical Information and Modeling·Karolina Mikulska-RuminskaIvet Bahar

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