Abstract
Prolidase [EC 3.4.13.9], known as PEPD, cleaves di- and tripeptides containing carboxyl-terminal proline or hydroxyproline. For decades, prolidase has been thoroughly investigated, and several mechanisms regulating its activity are known, including the activation of the β1-integrin receptor, insulin-like growth factor 1 receptor (IGF-1) receptor, and transforming growth factor (TGF)-β1 receptor. This process may result in increased availability of proline in the mitochondrial proline cycle, thus making proline serve as a substrate for the resynthesis of collagen, an intracellular signaling molecule. However, as a ligand, PEPD can bind directly to the epidermal growth factor receptor (EGFR, epidermal growth factor receptor 2 (HER2)) and regulate cellular metabolism. Recent reports have indicated that PEPD protects p53 from uncontrolled p53 subcellular activation and its translocation between cellular compartments. PEPD also participates in the maturation of the interferon α/β receptor by regulating its expression. In addition to the biological effects, prolidase demonstrates clinical significance reflected in the disease known as prolidase deficiency. It is also known that prolidase activity is affected in collagen metabolism disorders, metabolic, and oncological conditions. In this article, we review the latest knowledge about prolidase and highlight its biological function, and thus provide an in-depth understanding of prolidase as a dipeptidase and protein regulating the function of key biomolecules in cellular metabolism.
Highlights
Proline has a unique pyrrolidine ring that protects the polypeptide structure from hydrolysis
PEPD as an enzyme is regulated by signaling pathways dependent on the β1-integrin receptor, insulin-like growth factor 1 receptor (IGF-1) receptor, and transforming growth factor (TGF)-β1 receptor
The catalytic function of PEPD enables the provision of proline or hydroxyproline, which modulate intracellular signaling in the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and ERK1/2 pathways as well as energetic processes
Summary
Proline has a unique pyrrolidine ring that protects the polypeptide structure from hydrolysis. Yang et al shed new light on the function of prolidase by publishing several papers [26,27,28,29,30] in which the authors demonstrated that PEPD is a ligand of receptors belonging to the family of epidermal growth factor receptors (ErbB1/EGFR and ErbB2/HER2) They showed that the affinity of prolidase to these receptors is lower than EGF, but the effects of EGFR-dependent signal induction last longer. EGFR-downstream signaling pathways lead to increased DNA synthesis in a dose-dependent manner upon prolidase stimulation These findings appear promising for the improvement of regenerative therapy, aiming to promote cell proliferation and growth. The receptor undergoes slow internalization followed by degradation in lysosomes Another beneficial anti-tumor effect of PEPD is related to increased cancer cell sensitivity to drug treatment. It was observed that drug-resistant HER2-positive breast cancer cells are more sensitive to the enzymatically inactive PEPDG278D mutant, giving basis for the development of new therapeutic options for this group of cancers
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