Question

The final step in lysine biosynthesis is decarboxylation of meso2,6-diaminopimelate. The reaction requires PLP as cofactor and occurs through the usual PLP-amino acid imine. Propose a mechanism.

Short answer

Decarboxylation of meso-2,6-diaminopimelate involves a PLP-mediated mechanism that proceeds through formation and breakdown of a Schiff base, resulting in lysine formation.

Step-by-step solution

Formation of the Schiff Base

The first step involves the formation of a Schiff base between the amino group of meso-2,6-diaminopimelate and the aldehyde group of pyridoxal phosphate (PLP). This step activates the amino group for the subsequent reaction by forming an imine (Schiff base linkage).

Formation of the External Aldimine

The internal aldimine, formed in Step 1, undergoes a nucleophilic attack by meso-2,6-diaminopimelate, displacing the enzyme. This forms an external aldimine complex where meso-2,6-diaminopimelate is attached to PLP.

Decarboxylation Process

The external aldimine undergoes decarboxylation, where the carboxyl group of meso-2,6-diaminopimelate is removed as carbon dioxide (CO₂). This step is facilitated by the electron-withdrawing nature of the PLP cofactor, stabilizing the resulting carbanion at the α-carbon.

Re-protonation and Formation of Lysine

The carbanion formed in Step 3 is stabilized by PLP and involves the rearrangement of electrons. The conjugate base acquires a proton, typically from a solvent, leading to the formation of lysine linked to PLP.

Release of Lysine

Finally, lysine is released from the enzyme complex by reversing the initial Schiff base linkage, regenerating the PLP and completing the reaction.

Key concepts

PLP cofactor

Pyridoxal phosphate (PLP) is a vital cofactor found in numerous enzymatic reactions, particularly those involving amino acids. It is derived from vitamin B6 and functions primarily by stabilizing different reaction intermediates. PLP facilitates reactions by forming covalent bonds with substrates to create new intermediates, thereby increasing reaction efficiency.

In lysine biosynthesis, PLP plays a crucial role during the decarboxylation of meso-2,6-diaminopimelate. It interacts with substrates, forming a structure known as an "external aldimine". This structure allows the PLP to stabilize carbanions during the reaction, ensuring important transformations in the molecules.

• PLP is unique because it can temporarily transform itself into an electrophilic center, which makes it crucial for stabilizing negatively charged intermediates.
• During reactions, PLP forms a Schiff base with amino acids, which is key to the overall mechanism.

Understanding PLP is important for grasping its role in facilitating transformations that are otherwise energetically unfavorable.

Decarboxylation

Decarboxylation is a vital step in the biosynthesis of lysine from meso-2,6-diaminopimelate. This process involves the removal of a carboxyl group, releasing it as carbon dioxide (CO₂). In amino acid metabolism, decarboxylation is often necessary to transform one substrate into a biologically active form.

In the lysine biosynthesis mechanism, after the formation of an external aldimine, PLP stabilizes the intermediate, allowing for the easy removal of the carboxyl group. This step is critical. It shapes the framework of the molecule to allow for further transformations needed to produce lysine. The electron-withdrawing nature of the PLP cofactor is instrumental here, stabilizing the resulting carbanion at the α-carbon.

• The reaction simplifies complex molecules for cellular processes.
• This transformation often requires cofactors like PLP to stabilize transient states.

Decarboxylation in biosynthesis exemplifies nature’s strategies for modifying molecular structures to enhance biological function.

Schiff base

A Schiff base is a pivotal structure in numerous biochemical pathways, formed by the reaction between an aldehyde or ketone and a primary amine. This interaction results in a covalent bond formation involving an "imine" linkage, a common feature in enzyme-mediated processes.

In the lysine biosynthesis mechanism, a Schiff base is initially formed between meso-2,6-diaminopimelate and the aldehyde group of PLP. This step is crucial because it *activates* the amino group for further transformations. This activation is the first step in facilitating subsequent reaction steps, including forming an external aldimine.

• The formation of Schiff bases is central to protein stabilization and activation for further chemical reactions.
• By forming a Schiff base, the amino acid substrate is anchored for further conversion steps.

Understanding Schiff bases helps in appreciating how enzyme-mediated reactions efficiently alter substrates into activated forms, crucial for biosynthesis mechanisms.