Pyruvate dehydrogenase kinases (PDKs): an overview toward clinical applications.

Xiuxiu Wang,Xiaoyue Shen,Hongmin Li,Yuting Yan

doi:10.1042/bsr20204402

Abstract

Pyruvate dehydrogenase kinase (PDK) can regulate the catalytic activity of pyruvate decarboxylation oxidation via the mitochondrial pyruvate dehydrogenase complex, and it further links glycolysis with the tricarboxylic acid cycle and ATP generation. This review seeks to elucidate the regulation of PDK activity in different species, mainly mammals, and the role of PDK inhibitors in preventing increased blood glucose, reducing injury caused by myocardial ischemia, and inducing apoptosis of tumor cells. Regulations of PDKs expression or activity represent a very promising approach for treatment of metabolic diseases including diabetes, heart failure, and cancer. The future research and development could be more focused on the biochemical understanding of the diseases, which would help understand the cellular energy metabolism and its regulation by pharmacological effectors of PDKs.

Highlights

The pyruvate dehydrogenase complex (PDC) is the key enzyme system in the body that catalyzes the oxidative decarboxylation of pyruvate to form acetyl coenzyme A
Using a high-fat (HF) diet induced insulin resistance in C57BL/6 J mice, Tuikka et al [41] found that long-term high fatty acid intake activated PGC-1α and female ERRα, increased PDK4 expression, inhibited the effect of pyruvate dehydrogenase, and led to insulin resistance, suggesting that PDK4 is a possible contributor to high-fat diet-induced insulin resistance
The results suggest that inhibition of PDK4 can avoid myocardial insulin resistance caused by ANG, and may provide new treatment strategies for diastolic dysfunction and heart disease

Summary

Introduction

The pyruvate dehydrogenase complex (PDC) is the key enzyme system in the body that catalyzes the oxidative decarboxylation of pyruvate to form acetyl coenzyme A. Enhancing the activity of PDC by inhibiting PDK provide potential drug targets for the treatment of diabetes, heart disease, and tumors. Nutritional factors and hormones regulate the expression of PDK2 and PDK4, and the body reduces the activity of PDC by increasing PDK activity.

Results

Conclusion