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Enzymatic Degradation of Bradykinin
Published in Sami I. Said, Proinflammatory and Antiinflammatory Peptides, 2020
Randal A. Skidgel, Ervin G. Erdös
Prolylendopeptidase cleaves at the C-terminal side of prolyl residues in peptides of about 30 or less amino acids (Wilk, 1983). It hydrolyzes Bk at the Pro7-Phe8 bond (Fig. 1), the same site as ACE and NEP (Wilk, 1983). With the purified porcine kidney enzyme, Bk has a Km of 7.5 μM and a Vmax of 1.37 μmol/min/mg (Ward et al., 1987). Prolylendopeptidase can also cleave des-Arg9-Bk by releasing Phe8 (Fig. 2; Ward et al., 1987); thus, it inactivates ligands of both the B1 and B2 Bk receptors. Prolylendopeptidase cleaves a variety of other peptides containing proline, including Ang II (Wilk, 1983), and converts angiotensin I to angiotensin1–7, which has activity of its own (Welches et al., 1991).
Epigallocatechin-3-Gallate in Alzheimer’s Disease
Published in Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu, Phytomedicine and Alzheimer’s Disease, 2020
Khaleel Pasha Md, Magisetty Obulesu
Prolyl endopeptidase (PEP), a serine protease, has been found to show greater activity in AD subjects compared with people without AD (Aoyagi et al., 1991; Polito et al., 2018). EGCG, epicatechin gallate [(-)-ECG], and gallocatechin gallate (GCG), isolated from tea leaves, were potential PEP inhibitors and successfully achieved AD prevention (Kim et al., 2001; Polito et al., 2018). EGCG also inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities, leading to increased cholinergic transmission (Ali et al., 2016; Polito et al., 2018).
Dermatitis herpetiformis
Published in Lionel Fry, Atlas of Bullous Diseases, 2020
A microarray screen for candidate genes in CD has recently been reported18. The two genes suggested by the author were prolyl endopeptidase (PREP) and TM4SF4. The PREP gene encodes a cytosolic prolyl endopeptidase that hydrolyzes proline-rich fragments such as gluten. PREP was found to be up-regulated in CD patients on a gluten-containing diet, compared with those on a gluten-free diet (GFD). The gene was up-regulated in controls taking gluten and was low in CD patients on a GFD. Thus, the presence of gluten in the intestine tends to up-regu-late the PREP gene. It has been suggested that the enzyme function may be impaired in CD so that gluten is not broken down into small non-toxic peptides. Interestingly, it was proposed some 50 years ago that a failure of peptidases to digest gluten was the defect in CD.
Epithelial damage in the cystic fibrosis lung: the role of host and microbial factors
Published in Expert Review of Respiratory Medicine, 2022
Arlene M. A. Glasgow, Catherine M. Greene
MMP-9 (or gelatinase B) is found in neutrophils, macrophages, and epithelial cells. As well as ECM digestion, MMP-9 regulates nitric oxide-mediated airway epithelial repair [113]. It also contributes to PGP generation in concert with MMP-8 and the serine protease prolyl endopeptidase [111]. Whilst MMP-9 truncation of IL-8 yields a more active form of the cytokine (more than 10 times higher potency in neutrophil activation), its cleavage of growth-related oncogene alpha (GROα, or CXCL1) and platelet factor-4 (PF-4, or CXCL4) result in their inactivation [114]. It also performs sequential cleavage of CXCL5 at eight different sites, which is thought to initially cause potentiation of the cytokine but ultimately result in its inactivation [115]. MMP-9 is elevated in BALF and sputum from people with CF, and has been found to correlate negatively with FEV1 [90,109,116]. Furthermore, both the MMP-9/TIMP-1 ratio and active MMP-9 levels were found to increase with free NE levels and were associated with bronchiectasis progression [117].
Drug discovery strategies for novel leukotriene A4 hydrolase inhibitors
Published in Expert Opinion on Drug Discovery, 2021
Till A Röhn, Shin Numao, Heike Otto, Christian Loesche, Gebhard Thoma
PGP is a degradation product of collagen during inflammation by the combined activity of matrix metalloproteinase-9 (MMP-9) and prolyl endopeptidase (PE) [66]. From here, it can either be degraded to PG and proline through the action of LTA4H [22], or possibly undergo non-enzymatic acetylation into N-acetylated PGP (AcPGP) [67]. Unlike PGP, Ac-PGP is not a substrate for LTA4H but rather for angiotensin converting enzyme (ACE) [68]. Consistent with the model of PGP degradation, knocking out or inhibiting LTA4H results in the accumulation of PGP in bronchoalveolar lavage fluid (BALF) after stimulating an immune response and PGP is hydrolyzed rapidly by BALF taken from challenged mice [22,23].
Experimental and investigational phosphodiesterase inhibitors in development for asthma
Published in Expert Opinion on Investigational Drugs, 2019
Polyxeni Ntontsi, Aggeliki Detta, Petros Bakakos, Stelios Loukides, Georgios Hillas
When the neutrophilic endotyping mechanism and previous data retrieved from a small COPD study (where the administration of roflumilast in patients significantly altered the underlying inflammatory process and lowered the rate of exacerbations) [79] are considered, we can speculate that a similar benefit could be seen in severe low TH2 driven asthmatics. This beneficial clinical effect of treatment reported in COPD patients was most likely caused by reductions in pulmonary prolyl endopeptidase, AcPGP (self-propagating acetyl-proline-glycine-proline) pathway, and the respective neutrophilic inflammation.