Physapubescin,A Natural Withanolide As A Kidney-type Glutaminase (KGA) Inhibitor

In the process of tumor tumorigenesis and development,a series of changes occurred in tumor cells.An important characteristic of cancer cells is the change of metabolism in material and energy.In order to maintain the rapid growth and proliferation,cancer cells must speed up the synthesis of ATP,nucleotides,proteins,lipids and other biological macromolecules.An increased reliance on glycolysis for their bioenergetic and biosynthetic requirements,even in the presence of oxygen,was found in cancer cells.Glutamine is an important source of energy for highly proliferative cells via glutaminolysis.Kidney-type glutaminase(KGA),which accelerates glutamine metabolism and plays an important role in the Warburg effect,is one of the causes of abnormal metabolism in tumor cells.Inhibiting the activity of KGA enzyme can effectively block the energy source of tumor cells and achieve the purpose of anti-tumor effects.Solanaceous,a traditional medicinal plant,contains a large amount of withanolides.It was found that physapubescin fited the binding pocket of KGA enzyme so well through molecular docking studies.After the enzyme activity and MST measurement,physapubescin showed potent inhibition activity and binding activity on KGA enzyme in vitro.The results of CCK-8 test also showed that physapubescin had good cytotoxic activity and selectivity for tumor cells.It is a potential anti-tumor lead compound.