The pyruvate dehydrogenase kinases (PDHK) are a small and ubiquitous group of aPKs which are known to be responsible for phosphorylating the E1 (pyruvate decarboxylase) subunit of the pyruvate dehydrogenase multienzyme complex. PDHK regulates the activity of this complex by an inactivating phosphorylation. This complex is responsible for catalysing the oxidative decarboxylation of pyruvate, an important regulatory step in oxidative metabolism, and the phosphorylation of the E1 subunit results in a loss of pyruvate decarboxylase enzyme activity. PDHKs thus play a central role in controlling the balance between glucose and lipid oxidation according to substrate supply. The five PDHKs members identified in human each displays a distinct tissue-specific expression profile and present distinct regulatory properties.



An Overview of PDHK

Pyruvate dehydrogenase kinase (PDHK) is a family of silk/tyrosine proteins with high sequence homology to prokaryotic histone kinases. PDHK has very low homology to the silk/tyrosine protein kinase sequence of eukaryotes. The metabolic regulation function of PDHK mainly inhibits the activity of PDHE1 by catalyzing the serine phosphorylation of pyruvate dehydrogenase E1 (PDHE1), which leads to the inactivation of pyruvate dehydrogenase complex (PDC), the inhibition of oxidative phosphorylation pathway in mitochondria, and the enhancement of glycolysis metabolism in cell. Under normal conditions, when PDHK is in a state of inhibition, PDC is activated by pyruvate dehydrogenase phosphate phosphatases (PDP), catalyzing the oxidative decarboxylation of pyruvic acid to produce acetyl-CoA, and then entering the tricarboxylic acid cycle to produce a large amount of ATP to meet the energy requirements of the body. In starvation, PDHK is activated, PDC activity is inhibited by PDHK, and pyruvate accumulates in the cytosol due to the inability to undergo decarboxylation.

Major types of PDHK

Four PDHK isozymes are currently identified in humans and rodents: PDHK1, PDHK2, PDHK3, and PDHK4. PDHK1 is detected in the heart, islets and skeletal muscle. PDHK2 is the most widely distributed and is expressed at high levels in the heart, liver and kidneys. PDHK3 tissue expression is relatively limited (testis, kidney and brain). PDHK4 is highly abundantly expressed in tissues with high fatty acid oxidizing power and high levels of lipid oxidative transcription factor PPARα or PPARγ in heart, oxidized muscle, liver and kidney.

Inhibition of PDHK

According to its mechanism of action, inhibitors of PDHK can be divided into three categories. The first category is the ATP competitive inhibitor radicicol. The second is the compounds AZD7545 and Nov3r which act on the substrate complex. The third category is the conformational modifier, dichloroacetate.

PDHK and diseases

As a key node kinase controlling glycolytic and oxidative phosphorylation pathway, PDHK plays an important role in the rapid proliferation, invasion, migration and apoptosis resistance of tumor cells. PDHK is abnormally expressed in various tumor tissues, and its abnormal expression is closely related to the sensitivity, drug resistance, prognosis and survival of tumor patients. Therefore, PDHK has become a promising target for targeting tumor metabolism and anti-tumor strategies.


Popov K.M., Kedishvili N.Y, Zhao Y., et al. (1993) Primary structure of pyruvate dehydrogenase kinase establishes a new family of eukaryotic protein kinases. Journal of Biological Chemistry, 268(35): 26602-26606.