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17.4: Thiamine Diphosphate, Lipoamide and the Pyruvate Dehydrogenase Reaction

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    The enzyme pyruvate dehydrogenase is one of the most central of all the enzymes of central metabolism: by converting pyruvate to acetyl-\(CoA\), it links glycolysis (where glucose is broken down into pyruvate) to the citric acid cycle, into which carbons enter in the form of acetyl-\(CoA\). Five ceonzymes are involved: coenzyme A, nicotinamide, thiamine diphosphate, \(FAD\), and finally lipoamide, one which is new to us at this point.

    Reaction catalyzed by pyruvate dehydrogenase:

    Pyruvate reacts with ThDP, lipoamide, FAD, HSCoA, and NAD plus to produce carbon dioxide, NADH, and acetyl CoA.

    You will learn more about the structure and metabolic role of this complex and remarkable enzyme in a biochemistry course. Here, we will focus on the multi-step organic reaction it catalyzes, which we are at long last equipped to understand.

    Looking at the reaction, you should recognize that, first of all, the pyruvate substrate is being oxidized - it starts out as a ketone, and ends up as a thioester, losing carbon dioxide in the process. Ultimately, the oxidizing agent in this reaction is \(NAD^+\), but the reduction of \(NAD^+\) is linked to the oxidative decarboxylation of pyruvate by \(FAD\) and a disulfide-containing coenzyme called lipoamide, which is lipoic acid attached by an amide linkage to a lysine residue on the enzyme.

    Bond line drawings of lipoic acid and lipoamide. The reactive part of the coenzyme is highlighted in red while the lysine residue in the active site is boxed on lipoamide.

    The second thing to notice is that, because the reaction involves breaking the bond between the ketone carbon and an adjacent carbon, thiamine diphosphate (\(ThDP\)) coenzyme is required. In fact, the first phase of the reaction (steps 1 and 2 below) is identical to that of pyruvate decarboxylase, an enzyme we discussed a few pages ago.

    The pyruvate decarboxylase reaction mechanism

    Phase 1: Decarboxylation of pyruvate

    clipboard_e66751468bbc9960b12bfb59ee957cd51.png

    The \(ThDP\)-stabilized carbanion then acts as a nucleophile, cleaving the disulfide bridge of lipoamide (step 3 below). It is in this step that oxidation of the substrate is actually occurring. After the resulting thioester product is released from \(ThDP\) (step 4 below), it undergoes transesterification form acetyl-\(CoA\), the product of the reaction.

    Phase 2 of the pyruvate decarboxylase reaction mechanism: lipoamide-mediate oxidation to acetyl-\(CoA\)

    The products are reduced dihydolipoamide and acetyl-CoA.

    We are not done yet! In order for the catalytic cycle to be complete, the reduced dihydrolipoamide must be regenerated back to its oxidized state through disulfide exchange with a disulfide bond on the enzyme. The pair of enzymatic cysteines is then oxidized back to disulfide form by an \(FAD\)-dependent reaction.

    Phase 3 of the pyruvate decarboxylase reaction mechanism: regeneration of lipoamide

    clipboard_e62f92f562e2af11e4d4bdc8293853661.png

    Finally, \(FAD\) is regenerated with concurrent reduction of \(NAD^+\):

    Phase 4: Regeneration of \(FADH_2\):

    clipboard_ecab04e0e9d219fe883a0c9ec1fcba286.png

    This page titled 17.4: Thiamine Diphosphate, Lipoamide and the Pyruvate Dehydrogenase Reaction is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Tim Soderberg via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.