α-Aspartyl dipeptidase E

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α-Aspartyl dipeptidase E (ASPE) is an enzyme that plays a crucial role in various biological processes. We aim to provide a comprehensive overview of ASPE, including its structure, functions, clinical significance, and other relevant information.

Structure

ASPE is an intracellular enzyme found mainly in the cytoplasm and lysosomes of various tissues including the brain, liver, kidney, and lung. It is a homodimeric protein consisting of two identical subunits, each containing 346 amino acids. The enzyme belongs to the M20 family of metallopeptidases and requires divalent metal ions such as zinc for its catalytic activity.

Functions

• Peptide Degradation: The primary function of ASPE is that of an exopeptidase, catalyzing the hydrolysis of dipeptides at the N-terminus of peptide substrates. It has broad specificity for dipeptides, especially those containing aspartic acid (Asp) at the N-terminus.
• Neuropeptide Metabolism: ASPE is involved in the metabolism of neuropeptides (e.g., substance P, neurokinin A, and neurokinin B) by cleaving the dipeptide from the N-terminus. This enzymatic activity is essential for the regulation of neuropeptide levels and activity in the nervous system.
• Amino Acid Homeostasis: ASPE is involved in the catabolism of Asp-containing peptides and dipeptides, and thus in the maintenance of amino acid homeostasis. It plays an important role in the recycling of Asp and the release of free amino acids for cellular processes.

Regulation and Modulation

The activity of ASPE can be modulated by a variety of factors including pH, temperature and the presence of divalent metal ions. In addition, a number of compounds and inhibitors have been identified as modulators of ASPE activity. These include synthetic peptidomimetics and natural products that enhance or inhibit ASPE activity. The search for ASPE modulators may open new avenues for the treatment of diseases associated with ASPE dysregulation.

Clinical Significance

• Neurological disorders: ASPE has been implicated in the pathogenesis of a number of neurological disorders, including Alzheimer's disease and Parkinson's disease. Studies have shown that ASPE activity and expression levels are altered in the brains of patients with these diseases, suggesting that ASPE may be involved in disease progression.
• Peptide therapeutics: ASPE activity can severely affect the pharmacokinetics and efficacy of peptide therapeutics, and ASPE-mediated peptide degradation can limit the half-life and bioavailability of therapeutic peptides, thereby affecting their clinical efficacy. Therefore, understanding the role of ASPE in peptide metabolism is essential for optimizing drug design.
• Cancer: ASPE has also been implicated in cancer progression and metastasis. Elevated expression of ASPE has been observed in certain types of cancer, such as lung and hepatocellular carcinoma. It is thought that ASPE may promote tumor growth and invasion by altering neuropeptide signaling and the balance of amino acids in the tumor microenvironment.

Conclusion

α-Aspartyl dipeptidase E (ASPE) is a multifunctional enzyme involved in peptide degradation, neuropeptide metabolism and amino acid homeostasis. Its role in numerous physiological and pathological processes highlights its clinical significance. Dysregulation of ASPE has been associated with neurological disorders and cancer, suggesting its potential as a therapeutic target and biomarker. In order to fully understand the importance of ASPE in human health and disease, further research into the mechanism of action and potential therapeutic applications of ASPE is necessary.