The PDH complex and TCA Cycle
The Pyruvate
Dehydrogenase (PDH)Complex
Regulation of the PDH Complex
TCA Cycle
The Pyruvate Dehydrogenase (PDH) Complex The bulk of ATP used by many cells to maintain homeostasis is produced by the oxidation of pyruvate in the TCA cycle. During this oxidation process, reduced nicotinamide adenine dinucleotide (NADH) is generated. The NADH is principally used to drive the processes of
oxidative phosphorylation, which are responsible for converting the reducing potential of NADH to the high energy phosphate in ATP.
The fate of pyruvate depends on the cell energy charge. In cells or tissues with a high energy charge pyruvate is directed toward fatty acid synthesis, but when the energy charge is low pyruvate is preferentially oxidized to CO2 and H2O in the TCA cycle, with generation of 15 equivalents of ATP per pyruvate. The enzymatic activities of the TCA cycle (and of oxidative phosphorylation) are located in the mitochondrion. When transported into the mitochondrion, pyruvate encounters two principal metabolizing enzymes: pyruvate carboxylase (a gluconeogenic enzyme) and
pyruvate dehydrogenase (PDH), the first enzyme of the PDH complex. With a high cell-energy charge coenzyme A (CoA) is highly acylated, principally as acetyl-CoA, and able allosterically to activate pyruvate carboxylase, directing pyruvate toward gluconeogenesis. When the energy charge is low CoA is not acylated, pyruvate carboxylase is inactive, and pyruvate is preferentially metabolized via the PDH complex and the enzymes of the TCA cycle to CO2 and H2O. Reduced NADH and FADH2 generated during the oxidative reactions can then be used to drive ATP synthesis via oxidative phosphorylation.
The PDH complex is comprised of multiple copies of 3 separate enzymes:
pyruvate dehydrogenase (20-30 copies),
dihydrolipoyl transacetylase (60 copies) and
dihydrolipoyl dehydrogenase (6 copies). The complex also requires 5 different coenzymes: CoA, NAD+, FAD+, lipoic acid and thiamine pyrophosphate (TPP). Three of the coenzymes of the complex are tightly bound to enzymes of the complex (TPP, lipoic acid and FAD+) and two are employed as carriers of the products of PDH complex activity (CoA and NAD+). The pathway of PDH oxidation of pyruvate to acetyl-CoA is diagrammed below.
http://www.med.unibs.it/~marchesi/pdh.gif