Pyruvate Dehydrogenase

Kinase inhibitors for modern

therapeutic purpose.
What is PDK?

 PDK is one of the two regulatory enzymes PDC has.

 PDC is a complex of three enzymes that’s main responsibility is to
convert pyruvate into acetyl-CoA by a process called pyruvate
decarboxylation.
 Four PDK isoforms have been found in the mitochondria
 PDK1: Easily detected in pancreatic islets, heart and skeletal muscles.
 PDK2: Expressed universally in all the tissues.
 PDK3: Present more in kidney, testes and brain.
 PDK4: Abundant in heart, skeletal muscles, kidney and pancreatic islets.
Role of PDKs In PDC.

 PDC catalyzes the oxidative decarboxylation of pyruvate to produce

acetyl CoA. And is important gatekeeper enzyme that links pyruvate to the
tricarboxylic acid (TCA) cycle.
 PDKs’s main responsibility is to regulate the activity of PDC. They can
phosphorylate PDC resulting in its inactivation.
 As PDC is Inactivated the pyruvate is utilized in the pathway of
gluconeogenesis to produce lactate.
Links Between Diseases and PDKs

 Under Hypoxia, Glucose is converted into the lactate. However in cancer

cells glucose are converted into lactate even under the presence of
oxygen. Known as Warburg effect.
 Under several diseased condition the most common feature is over
expression of PDKs. In particular PDK1 is more associated with the cancer
malignancy.
 By forcing cell into more aerobic metabolism could suppress the growth of
cancer cells. For this we require up regulation of PDC. For which we have to
inhibit the influences of PDKs on the PDC.
 Type 2 Diabetes mellitus is a mutagenic diseases characterized by
hyperglycemia and altered balance between glucose and lipid
metabolism. Altered glucose utilization and lipid metabolism was observed
in the patients suffering from T2DM. This kind of inflexibility was also
detected in the diseases like pulmonary hypertension, cardiomyopathy,
neurological disorders and many other metabolic syndromes.
 Therefore inhibitors targeting PDKs can open gate to treating various other
diseases.
PDKs and Glucose Homeostasis

 Under the survey of previous research done. It was found that up regulation
of PDHK 4 in tissue (except liver) is quite important during the starvation for
phosphorylating PDC Complex and maintaining glucose homoeostasis.
 This was tested by knocking out PDHK4 from the system of the mice which
were kept under the starved condition. Once the PDHK4 was knocked out
off the system. There was lower rate of gluconeogenesis due to the
substrate supply limitations.
 This limitation of substrate might have been due to the up regulation of PDC
due to the absence of PDHK4. The pyruvate available might have been
converted into the Acetyl-CoA. An important substrate for TCA cycle.
References

 Zhang, S. et al. (2015) Development of pyruvate dehydrogenase kinase

inhibitors in medicinal chemistry with particular emphasis as anticancer
agents. Drug Discovery Today 1112-1119.
 Jeoung. N. et al. (2006) Role of pyruvate dehydrogenase kinase isoenzyme
4 (PDHK4) in glucose homoeostasis during starvation. Biochem. j.397, 417-
425