Oxidative decarboxylation

Then, with the catalysis of E2, TPP sends the hydroxyethyl to lipoamide, which is reoxidized to acetyl to produce thioester bond.

At this time, E3 needs to participate in the catalytic reaction, and the hydrogen removed from dihydrolipoamide will be transferred to FAD to make it FADH2, FADH2 reacts with NAD+ to generate NADH and H+.

As a preliminary to following the central path of aerobic metabolism from glycolysis to the citric acid cycle, we put pyruvate in perspective by considering its various possible fates.

Central to the operation of the PDH complex is a key catalytic cofactor, thiamine pyrophosphate (TPP).

TPP is the key catalytic cofactor used by enzymes catalyzing non-oxidative and oxidative decarboxylation of α-keto acids.

A hydrogen attached to the C2 carbon of the thiazole ring of TPP shows an unusually low pKa.

The PDH complex serves as the link between glycolysis and the citric acid cycle and is required for oxidative metabolism.

Multiple copies of three different enzymes compose a supramolecular structure that coordinates a four-step process converting the α-keto acid pyruvate to the thioester (with coenzyme A) of acetate, as well as electron transfer (redox) reactions that yield NADH.

This addition compound can readily undergo decarboxylation (loss of carbon dioxide), with the product hydroxyethyl TPP stabilized by resonance.

In the next step, as TPP departs as a leaving group, taking electrons from the bond to the hydroxyethyl group with it, the hydroxyethyl recruits the electrons from the O-H bond, assisted by a conveniently located enzyme-derived base to accept the resulting hydrogen ion.

The acetyl group is transferred from reduced lipoamide to coenzyme A (CoA) by the activity of the E2, or dihydrolipoyl transacetylase, component of the complex.

The free dihydrolipoamide (reduced form of lipoamide) must be re-oxidized, and this is accomplished by the activity of E3, or dihydrolipoyl dehydrogenase, component of PDH complex.

A very similar series of reactions is carried out as part of the citric acid cycle by the α-ketoglutarate dehydrogenase multienzyme complex, which is also closely related to the PDH complex in composition and structure, using the same E3 component, and an E1 that acts on α-ketoglutarate as a substrate in place of pyruvate.