Pyruvate Metabolism and Enzyme Complexes

Thiamine Pyrophosphate (TPP)

Thiamine (Vitamin B1) is a precursor to thiamine pyrophosphate (TPP).
TPP has an amylopyrimidine ring and a thiazole ring.
A key feature of TPP is a carbon atom on the thiazole ring that is acidic, allowing it to release a proton and form a carbanion (an ylide form), which is crucial for its catalytic activity.
The carbanion acts as a nucleophile, attacking carbon-carbon bonds, leading to decarboxylation by stabilizing a tetragonal intermediate, facilitating the release of CO_2.

TPP is essential for decarboxylation reactions.
TPP stabilizes the carbanion, which attacks the carbon-carbon bond, leading to the release of CO_2.
Without TPP, this decarboxylation would not occur.

Alcohol dehydrogenase facilitates the chemistry using a positively charged zinc ion (Zn^{+2}).
The reaction involving alcohol dehydrogenase is reversible, with NADH releasing a hydride ion (H^-) and being oxidized to NAD^+.

Under aerobic conditions, pyruvate, produced during glycolysis, is converted into acetyl-CoA inside the mitochondria.
The mitochondrial inner membrane is impermeable unless specific protein transporters are present.
The energy for transport is derived from the proton gradient across the mitochondrial membrane.

CoA consists of pantothenic acid and a mercaptoethylamine moiety.
It contains a thioester bond, the hydrolysis of which is highly exergonic, with a very negative \Delta G.

The conversion of pyruvate to acetyl-CoA is a complex reaction catalyzed by the pyruvate dehydrogenase complex.

The pyruvate dehydrogenase complex is large enough to be seen via electron microscopy, unlike smaller enzymes such as isokinase.
It exhibits supramolecular chemistry, involving interactions between numerous lipid molecules to form an ordered structure.
The complex has a central cubic core with E2 units arranged with a non-cubic symmetry.
The structure features a triangle at the vertex of the complex with internal voids.

The complex consists of E1, E2, and E3 types of units.
The E2 unit has an internal domain and a carboxy-terminal domain.
Multiple active sites within the complex facilitate the transfer of the substrate from one enzymatic site to another via a mobile domain (K).

Symmetry in multi-subunit proteins is mathematically complex, involving symmetry groups related to crystallography.
Proteins like hemoglobin exhibit symmetry (e.g., D2 symmetry).

Allostery involves binding at one site affecting the conformation at a distant site.
Hemoglobin exists in tense (T) and relaxed (R) states, differing in oxygen-binding affinity.
Allosteric effects can occur without significant conformational changes, influenced by vibrational patterns within the protein.

Intrinsically disordered proteins or regions lack a well-defined three-dimensional structure.
These disordered regions are crucial for protein function.

Decarboxylation reactions, such as the conversion of pyruvate to acetyl-CoA, are irreversible.
Mammals cannot reverse this reaction to utilize carbon dioxide to synthesize glucose, unlike plants or green algae.

A similar reaction scheme occurs in the Krebs cycle with the alpha-ketoglutarate dehydrogenase complex.
This complex is structurally and functionally similar to the pyruvate dehydrogenase complex.
Another analogous complex is involved in branched-chain amino acid metabolism.