Intracellular aminopeptidase

Intracellular aminopeptidases are a diverse group of enzymes responsible for the hydrolysis of amino acids from the N-terminus of peptides within the cytosol and organelles (UniProt). They play a critical role in the final stages of protein degradation, recycling amino acids for new protein synthesis and maintaining the intracellular amino acid pool (PubMed: 18483270). Beyond general proteolysis, specific aminopeptidases like ERAP1 and ERAP2 are essential for trimming peptides for MHC class I antigen presentation, making them key players in immune surveillance (PubMed: 24550914). In oncology, these enzymes are targeted to induce "amino acid starvation" and trigger apoptosis in rapidly dividing cancer cells, which have a higher demand for protein turnover (PubMed: 11592457). Therapeutic inhibitors such as Tosedostat (CHR-2797) have been developed to target multiple intracellular aminopeptidases, showing clinical potential in treating hematological malignancies by disrupting cellular homeostasis (ClinicalTrials.gov). These enzymes are also implicated in neurodegenerative diseases and inflammatory conditions due to their role in peptide hormone processing and protein aggregate clearance (PubMed: 21145456). The inhibition of these enzymes leads to the accumulation of small peptides and a shortage of free amino acids, which activates the GCN2 kinase-mediated integrated stress response (PubMed: 20430871). This pathway ultimately results in cell cycle arrest and programmed cell death, particularly in cells with high metabolic requirements (PubMed: 18483270).

Other names

Cytosolic aminopeptidaseN-terminal exopeptidaseAminopeptidase

Inhibition of N-terminal amino acid cleavage from peptide substrates, leading to intracellular amino acid depletion, induction of the integrated stress response, and inhibition of protein synthesis.