An Overview of Pyruvate Dehydrogenase Complex Deficiency
Pyruvate Dehydrogenase Complex
In glucose catabolism, pyruvate produced through the glycolytic pathway is converted into acetyl CoA. Pyruvate dehydrogenase complex catalyzes the reaction, converting pyruvate to acetyl-CoA through substrate channeling. That means once the substrate enters into the enzyme, it never leaves the enzyme before being converted into the product.
Thus, it links the glycolysis with the citric acid cycle. It is a multi-enzyme complex composed of three different enzymes and requires five coenzymes to function normally. All three enzyme components of PDH complex catalyze their own reaction cooperatively to convert pyruvate into acetyl-CoA.
This reaction is unidirectional and any alteration or changes in the structure of PDH complex or pyruvate dehydrogenase complex deficiency can cause a serious health problem.
3D Structure of PDH Complex
What is Pyruvate Dehydrogenase Complex?
Pyruvate dehydrogenase complex is composed of three different enzymes. These enzymes are pyruvate dehydrogenase (E1), dihydrolipoyl transacetylase (E2) and dihydrolipoyl dehydrogenase (E3). Each of these enzymes requires different cofactors like E1 requires thiamine pyrophosphate, E2 requires CoA and lipoate, and E3 requires FMN and NAD+. The cooperative action of these three enzymes is necessary to convert substrate into the product through the process of substrate channeling. This reaction is unidirectional and is one of the most important reaction in central metabolism.
This enzyme links the citric acid cycle with glycolysis and therefore pyruvate from the glycolysis enters into the citric acid cycle through the PDH complex (pyruvate dehydrogenase complex. Thus, it is a bridge of glycolysis and the citric acid cycle). This enzyme is found in the mitochondria and pyruvate formed in the cytosol has to pass into the mitochondrial matrix to be converted into the acetyl-CoA.
Role and Consequences of Pyruvate Dehydrogenase Complex Deficiency
As carbohydrate is one of the major sources of energy and is taken as one of the major components in our diet. It most be metabolized to produce energy enough to cellular activity. Therefore, its deficiency can lead to the ineffective catabolism of carbohydrate and our cellular demand of energy starts to be fulfilled by the other means like fatty acid oxidation, protein breakdown.
Some tissues like brain cells need glucose more preferentially than another source of energy, if they are deficient of this enzyme, then there would be the problem with glucose utilization. They become scarce of energy because glycolysis alone cannot support energy requirement of these cells and they become energy deficient.
Pyruvate may start being converted into the lactate catalyzed by lactate dehydrogenase to produce NAD+ required for the glycolysis to continue. This process may cause an increase in pH in the cellular environment because lactate is an acid. The increase in pH of the cytosol may cause denaturation of other important enzymes and proteins.
Any alteration in the enzyme components of the pyruvate dehydrogenase complex, like their defective production, defective cofactor binding affinity, or any mutation in the genes, may lead to the defective enzyme complex or it can also be affected by arsenate ions leading to arsenic poisoning. The defective enzyme may not perform its role and the tissues and cells relying on the glucose are ultimately affected.
Pyruvate dehydrogenase complex deficiency is related to the neurodegenerative disorder. Brain cells are mostly dependent on glucose utilization and the defective pyruvate dehydrogenase complex in these tissues/cells lead to the energy scarcity in these tissues. As you know, if the brain is affected by its metabolism, it may degenerate.
This is the way pyruvate dehydrogenase complex deficiency leads to the neurodegenerative disorder. Energy scarcity in brains cells and neurons can lead to their death because they cannot use other sources of energy.
© 2015 Shrawan Kumar Upadhyay