Pyruvate kinase allostery resist hyperglycemia, obesity and inflammation by inducing TCA vortex and glucose U turn

Abstract

SummaryMany plant extracts such as celastrol (CLT) have excellent pharmacological effects. However, exploring their drug targets is challenging. Here we show that CLT imitates ATP and binds to its pocket on pyruvate kinase PKM (PKM) while inhibiting the enzyme activity. Quantum calculation predicts hydrogen bond formation between CLT and asparagine. Liquid chromatography-mass spectrometry further identifies PKM as CLT’s target. The inhibition of PKM is stronger and longer for CLT while weak and short for ATP. Notably, CLT-PKM interaction perfectly underlies the hypoglycemic effects by forming glucose carbon flux U turn before PKM. Besides, the PKM inhibition induces tricarboxylic acid (TCA) vortex which could promote amino acid and lipid degradation as the energy compensation, leading to a significant weight-loss. Additionally, CLT exerts efficient antioxidant effects by altering the glucose flux to strengthen the pentose phosphate pathway. Consequently, the CLT-PKM interaction vividly reproduces ATP-PKM interaction named “ATP resistance” in the diabetes pathogenesis.