palmitoylproteiinithioesteraasit

Palmitoylproteiinithioesteraasit are a class of enzymes that catalyze the reversible attachment of palmitic acid to cysteine residues of proteins through a thioester linkage. This post‑translational modification, known as S‑palmitoylation, is essential for regulating protein trafficking, membrane association, stability, and signaling pathways. The enzymes responsible for adding palmitate are typically lysophosphatidic acid acyltransferases (LPATs) or DHHC‑domain palmitoyl‑protein acyltransferases, whereas the enzymes that remove the modification are called acyl‑protein thioesterases. In humans, prominent palmitoyl‑protein thioesterases include palmitoyl‑protein thioesterase 1 (PPT1) and 2 (PPT2). These thioesterases are lysosomal hydrolases that hydrolyze the thioester bond, thereby depalmitoylating substrates and facilitating turnover or recycling of modified proteins.

The catalytic mechanism of PPT1 and PPT2 involves a conserved serine–histidine-aspartate catalytic triad. Substrates enter a hydrophobic pocket that positions the thioester bond for nucleophilic attack by the active‑site serine. Following bond cleavage, a thioester intermediate is resolved to release free palmitate and the deacylated protein. Mutations or deficiencies in these enzymes lead to lysosomal storage disorders: PPT1 deficiency causes infantile neuronal ceroid lipofuscinosis (CLN1), characterized by progressive neurodegeneration and accumulation of autofluorescent lipopigments; PPT2 deficiency is associated with late-onset cysteine storage disease. Dysregulation of S‑palmitoylation has also been implicated in cancer, cardiovascular disease, and neuropsychiatric disorders.

Research continues to elucidate the breadth of palmitoyl‑protein substrates, the regulatory networks that dictate site specificity, and the therapeutic potential of modulating palmitoylproteiinithioesteraasit activity. Small-molecule inhibitors of palmitoyl acyltransferases and activators of thioesterases are being explored as strategies to correct aberrant palmitoylation patterns in disease.