Lipidaation

Lipidation is the covalent attachment of lipid groups to a molecule, most commonly proteins, in a process that often occurs during protein maturation or signaling. Lipidic attachments increase hydrophobicity, promote membrane association, and influence protein localization, stability, and interactions. Lipidation can be co-translational, occurring as a protein is synthesized, or post-translational.

The major forms of protein lipidation include N-myristoylation, which adds a myristoyl group to an N-terminal glycine after removal of the initiator methionine and is mediated by N-myristoyltransferase; S-palmitoylation, the reversible attachment of a palmitoyl group to cysteine residues via a thioester bond, catalyzed by DHHC palmitoyltransferases and reversed by thioesterases; prenylation, attachment of farnesyl or geranylgeranyl groups to a cysteine near the C-terminus within a CAAX motif by farnesyltransferase or geranylgeranyltransferase, followed by proteolysis and methylation; and GPI anchoring, the addition of a glycosylphosphatidylinositol anchor to the C-terminus of certain proteins, producing a GPI-anchored protein.

Biological roles of lipidation include regulation of membrane targeting, subcellular localization, and protein–protein interactions. Palmitoylation is notably dynamic, enabling rapid relocalization, while prenylation and GPI anchoring often direct proteins to specific membranes or lipid microdomains.

Clinical relevance: dysregulation of lipidation pathways has been linked to cancer, neurodegenerative diseases, and infectious diseases. Enzyme inhibitors targeting lipidation enzymes, such as farnesyltransferase inhibitors, have been explored in cancer therapy, and inhibitors of N-myristoyltransferase are under investigation for antiviral and anticancer applications.