protein lipoylation

Definition

Target type: biologicalprocess

The lipoylation of peptidyl-lysine to form peptidyl-N6-lipoyl-L-lysine. [RESID:AA0118]

Protein lipoylation is a critical post-translational modification that involves the covalent attachment of a lipoic acid molecule to a specific lysine residue within a protein. This modification is essential for the function of a variety of enzymes, particularly those involved in central metabolic pathways like pyruvate dehydrogenase complex (PDC), α-ketoglutarate dehydrogenase complex (KGDHC), and branched-chain α-ketoacid dehydrogenase complex (BCKDH).

The process begins with the biosynthesis of lipoic acid, which occurs in the mitochondria. Lipoic acid is a sulfur-containing fatty acid that exists in a cyclic disulfide form. The lipoylation process itself is catalyzed by a specific enzyme known as lipoyl ligase or lipoate protein ligase. This enzyme utilizes a two-step mechanism:

1. **Activation of lipoic acid:** Lipoyl ligase first activates lipoic acid by forming a thioester linkage with its carboxyl group.

2. **Transfer to the protein:** The activated lipoic acid is then transferred to the target lysine residue on the protein substrate. This transfer reaction involves the formation of an amide bond between the carboxyl group of lipoic acid and the ε-amino group of the lysine residue.

The specific lysine residue on the protein that is lipoylated is determined by the primary sequence of the protein and is often located within a conserved lipoyl domain. This domain typically consists of a short sequence of amino acids that is recognized by the lipoyl ligase.

Once lipoylated, the protein gains new functional properties. The lipoic acid moiety acts as a swinging arm, transferring electrons and acyl groups between different enzyme components. In the case of PDC, KGDHC, and BCKDH, lipoylation enables the transfer of acetyl groups from pyruvate, α-ketoglutarate, and branched-chain α-ketoacids, respectively, to coenzyme A. This transfer is crucial for the proper functioning of these enzyme complexes in the tricarboxylic acid (TCA) cycle and amino acid metabolism.

In summary, protein lipoylation is a vital post-translational modification that plays a critical role in various metabolic pathways. It involves the attachment of lipoic acid to a specific lysine residue within a protein, enabling the protein to participate in key enzymatic reactions. The lipoylation process is tightly regulated and essential for maintaining cellular energy production and metabolic homeostasis.'
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Proteins (1)

Compounds (2)