Explain how pyruvate enters the mitochondrial matrix from the cytoplasm
-A specific pyruvate translocase transports the pyruvate molecule through the inner mitochondrial membrane into the mitochondrial matrix either in exchange for OH or in an H+ symport mechanism, this is possible b/c pyruvate is not phosphorylated
Describe the pyruvate dehydrogenase
-mitochondrial enzyme complex
-Three enzymes
-Five cofactors
PDH Enzymes
-Three enzymes: pyruvate dehydrogenase (E1), lipoate acetyltransacetylase (E2), and lipoamide dehydrogenase (E3)
PDH Cofactors
thiamine pyrophosphate, lipoic acid, flavin adenine dinucleotide,
Describe the reaction catalyzed by the pyruvate dehydrogenase enzyme
in the mitochondrial matrix, the PDH complex converts pyruvate to acetyl-SCoA in a reaction that is highly exergonic and essentially irreversible in the cell
The 3 PDH enzymes that convert pyruvate to acetyl CoA are
1. Pyruvate dehydrogenase
2. Dihydrolipoyl transacetylase
3. Dihydrolipoyl dehydrogenase
Reaction mechanism of pyruvate dehydrogenase complex
1. Decarboxylation of pyruvate
2. Oxidation of hydroxyethyl TPP
3. Acetyl-SCoA formation
4. Oxidation of lipoamide
PDH Inactivation by phosphorylation
- inhibited by covalent phosphorylation
- this blocks the initial decarboxylation of pyruvate
- the kinase is activated by increases in ATP, acetyl-SCoA or NADH (the products of pyruvate oxidation)
- the kinase is inhibited by pyruvate and ADP (the starti
PDH Activation by Dephosphorylation
-when the cell is energy-depleted, the kinase is inhibited and a calcium-dependent pyruvate dehydrogenase phosphatase is turned on
-the phosphatase converts the PDH complex to the active dephosphorylated form
-insulin is an activator of the PDH complex, a
Allosteric Control of PDH
-High levels of either Acetyl-SCoA or NADH product allosterically inhibit the pyruvate dehydrogenase complex
-Acetyl-SCoA block dihydrolipoyl transacetylase
-NADH inhibits the dihydrolipoyl dehydrogenase
Describe the central role of acetyl-SCoA as a crossroads in metabolism.
-high levels of Acetyl-SCoA point towards biosynthesis or storage
-When acetyl-SCoA levels decline, there is an increased flux through pyruvate dehydrogenase and the citric acid cycle with the production of energy.
Beriberi (Thiamine Deficiency)
(Disordered pyruvate oxidation)
Thiamine pyrophosphate, formed from thiamine by pyrophosphorylation, is an essential cofactor for pyruvate dehydrogenase. A deficiency in this B vitamin causes beriberi that can be treated by dietary manipulation.
-Symptoms: limb paralysis, cardiac issues
Arsenic or Mercuric Poisoning
(Disordered pyruvate oxidation)
-can be fatal
-adverse affect on PDH Complex and glyceraldehyde 3-phosphate dehydrogenase, reducing ATP formation
-can be worsened by thiamine deficiencies
-It also uncouples oxidative phosphorylation
-affects neurological tissue