PROLIDASE: A Review from Discovery to its Role in Health and Disease

Abstract

Prolidase (peptidase D), encoded by the PEPD gene, is a ubiquitously expressed cytosolic metalloproteinase, the only enzyme capable of cleaving imidodipeptides containing C-terminal proline or hydroxyproline. Prolidase catalyzes the rate-limiting step during collagen recycling and is essential in protein metabolism, collagen turnover, and matrix remodeling. Prolidase, therefore plays a crucial role in several physiological processes such as wound healing, inflammation, angiogenesis, cell proliferation, and carcinogenesis. Accordingly, mutations leading to loss of prolidase catalytic activity result in prolidase deficiency a rare autosomal recessive metabolic disorder characterized by defective wound healing. In addition, alterations in prolidase enzyme activity have been documented in numerous pathological conditions, making prolidase a useful biochemical marker to measure disease severity. Furthermore, recent studies underscore the importance of a non-enzymatic role of prolidase in cell regulation and infectious disease. This review aims to provide comprehensive information on prolidase, from its discovery to its role in health and disease, while addressing the current knowledge gaps.

MEFV, IRF8, ADA, PEPD, and NBAS gene variants and elevated serum cytokines in a patient with unilateral sporadic Meniere's disease and vascular congestion over the endolymphatic sac

“…PEPD encodes prolidase, which catalyzes the hydrolysis of a dipeptide containing a C-terminal proline or hydroxyproline into constituent amino acids, and the most studied substrates of the enzyme are imidodipeptides, which are generated during the breakdown of collagen. It was reported that oxidative stress stimulates collagen breakdown via inductions of matrix metalloproteinases and induces inflammatory homeostasis ( Eni-Aganga et al., 2021 ). The c.151G > A mutation is harmful for the function of prolidase.…”

Genomic Characterization by Whole-Exome Sequencing of Hypermobility Spectrum Disorder

“…Furthermore, a comparison of our list vs. the proteome profiling in dermal myofibroblasts of patients with hEDS [ 62 ] identified only five genes. One of them, prolidase (peptidase D), encoded by PEPD , is a ubiquitously expressed cytosolic metalloproteinase essential in protein metabolism, collagen turnover, and matrix remodeling [ 63 ], representing a potential candidate to be evaluated in larger cohorts of patients with HSD. On the other hand, a key factor identified by proteomic analysis in hEDS fibroblasts was S1004A, a calcium-binding protein involved in the fibroblast-to-myofibroblast transition, supporting a proinflammatory milieu characterized by an excessive matrix metalloproteinase-mediated ECM degradation [ 62 ].…”

Catabolism of Hydroxyproline in Vertebrates: Physiology, Evolution, Genetic Diseases and New siRNA Approach for Treatment

“…Collagen breakdown is carried out by sequential cleavage into dipeptides by matrix metalloproteinases [43]. The terminal and rate limiting stage of collagen degradation is catalyzed by prolidase (PEPD) [44]. This enzyme specifically splits dipeptides with C-terminal Pro or Hyp.…”