Pyruvate Dehydrogenase (PDH) Complex : Machanism, Regulation and Inhibitors

The PDH complex also known as the pyruvate dehydrogenase complex is a multi-enzyme complex.

PDH complex is present on the inner mitochondrial membrane. The molecular weight of the PDH complex is 9×10⁶ kDa.

  Pyruvate is produced in the cytosol as the end product of aerobic glycolysis. It enters mitochondria by a pyruvate protons import which is present in the inner mitochondrial membrane.

  In the mitochondrial matrix pyruvate is oxidatively Decarboxylated to form Acetyl- CoA (acetyl coenzyme A).

The oxidation of pyruvate to acetyl coenzyme A is an irreversible reaction. This is the link reaction between glycolysis and the citric acid cycle.

PDH Complex

The PDH complex consists of 3 Enzymes and 5 coenzymes.
• The 3 enzymes are :
- Pyruvate Dehydrogenase with TPP as a coenzyme
- Dihydrolipoyl Transacetylase
- Dihydrolipoyl Dehydrogenase

• The 5 coenzymes are :
- Thymine pyrophosphate or vitamin B1
- FAD or vitamin B2
- NAD or vitamin B3
- Coenzyme A or vitamin B5
- Lipoic acid.

Reactions of the PDH  complex

Pyruvate Dehydrogenase with TPP as coenzyme,  decarboxylates pyruvate to Hydroxyethyl TPP (thiamine pyrophosphate).

• Then Dihydrolipoyl Transacetylase catalyzes conversion of Hydroxyethyl Thiamine Pyrophosphate into acetyl lipoamide and then transfers the acetyl group to coenzyme A to produce acetyl coenzyme A.

Dihydrolipoyl Dehydrogenase catalyses conversion of reduced Lipamind into Oxidized lipamind by transferring the reduced equivalence of FAD and this completes the cycle.

• FADH2 in turn transfers the reducing equivalents to NAD+ to give NADH and H+.

• This NADH and H+ enters a respiratory chain to give 2.5 ATP by oxidative phosphorylation.

• As a whole five ATP are released in the PDH complex and from two moles of pyruvate which is formed from glucose by glycolysis.

• All these intermediates of PDH catalysed reaction are not free but bound with an enzyme complex together called as the PDH complex.

A comparable enzyme with PDH is alpha ketoglutarate dehydrogenase complex of the citric acid cycle which catalyses the oxidative decarboxylation of alpha-keto glutarate into succinyl CoA.

Regulation of PDH Complex

Regulation of the pyruvate dehydrogenase complex is mainly an example of end product inhibition. It is also regulated by phosphorylation and dephosphorylation.

- PDH is active as Dephosphoenzyme which means in dephosphorylated state.

- While it is inactive as phosphoenzyme that is phosphorylated state.

• PDH phosphatase which is responsible to maintain PDH complex an active state is promoted by Calcium(Ca²+) Magnesium( Mg²+) and mainly insulin. Insulin activates PDH complex.

• PDH kinase which are responsible for the inactive PDH is promoted by ATP, NADH and acetyl coenzyme A.
  while PDH complex is inhibited by NAD+, coenzyme A and pyruvate.

• Net result is that in the presence of high-energy molecules like ATP, NADH.

• The pyruvate dehydrogenase complex is turned off because when enough amount of ATP is already present there is no need for the pyruvate dehydrogenase complex to continue.

Clinical application

Arsenic poisoning :

• Arsenite binds to thiol Which is sulfhydryl-SH group of lipoic acid and makes it unavailable to serve as a cofactor.

• By this way in arsenic poisoning enzymes of the pyruvate dehydrogenase complex and alpha-keto glutarate complex are inhibited by arsenite.

Inherited or Acquired (Alcoholics) deficiency :

• Inherited or acquired alcoholics deficiency of PDH causes lactic acidosis due to rapid conversion of accumulated pyruvate into lactic acid.

• Pyruvate is derived from carbohydrates. An acetyl coenzyme A mainly derived from fats which are triglycerides, fatty acids, cholesterol.

• Carbohydrates in excess can form fats but fats can never be converted to carbohydrates because linked reaction is irreversible.
  An exception to this rule is Glycerol and Propionic acid which are derived from fats, but they can be converted to glucose.

No comments: