China
Africa
Explore chapters and articles related to this topic
Enzymatic Degradation of Bradykinin
Published in Sami I. Said, Proinflammatory and Antiinflammatory Peptides, 2020
Randal A. Skidgel, Ervin G. Erdös
Membrane-bound aminopeptidase P cleaves peptides containing proline in the second position such as Bk and neuropeptide Y with a neutral pH optimum (Simmons and Orawski; 1992, Orawski and Simmons, 1995). The tripeptide substrate Gly-Pro-Hyp has been used to measure its activity, but the N-terminal tripeptide of Bk (Arg-Pro-Pro) is cleaved faster (Simmons and Orawski, 1992; Orawski and Simmons, 1995). Longer peptides are also substrates, but not shorter ones; the dipeptide Arg-Pro is not cleaved (Simmons and Orawski, 1992; Orawski and Simmons, 1995). Aminopeptidase P contains one zinc per mole of enzyme (Hooper et al., 1990) and can be activated by Mn2+ with some substrates; it is inhibited by chelating agents. Other inhibitors include SH compounds and SH-reactive reagents, e.g.,/?-chloromercuriphenylsulfonate (Hooper et al., 1990; Simmons and Orawski, 1992; Orawski and Simmons, 1995). Many ACE inhibitors also inhibit aminopeptidase P, although with a Kt in the micromolar range (Hooper et al., 1992); Mn2+ can enhance their inhibitory effect (Orawski and Simmons, 1995). This inhibition is likely due to proline or proline-like structures and effective zinc-binding moieties in ACE inhibitors. Inhibitors with large substituents on the proline ring inhibit less or not at all (Hooper et al., 1992). The specific inhibitor of aminopeptidase P, apstatin, has a Kf for aminopeptidase P of 2.6 μM, but it does not inhibit other kininases such as ACE, neutral endopeptidases 24.11 and 24.15, or prolylendopeptidase (Scicli et al., personal communication).
Peptidases and Peptides at the Blood-Brain Barrier
Published in Gerard O’Cuinn, Metabolism of Brain Peptides, 2020
Janet Brownlees, Carvell Williams
Both angiotensin I and bradykinin are good substrates for ACE, an enzyme quite active in cerebral microvessels (see Table 2). Although ACE is known to convert angiotensin I to angiotensin II, studies in vitro have shown that both can be inactivated by aminopeptidase A (see above). Similarly, alternative pathways may exist for inactivation of bradykinin. In addition to its cleavage by a carboxypeptidase in the microvasculature, bradykinin is also attacked at the N-terminal Arg1-Pro2 bond.143 This N-terminal activity has not been identified but is known not to be aminopeptidase N (since this will not cleave an X-Pro bond), ACE, E-24.11, DPP IV or post-proline cleaving enzyme (PPCE). Perhaps it may be due to aminopeptidase P activity. This enzyme has not so far been reported to exist in cerebral microvessels but has been detected in pulmonary arterial endothelial cells.188 Kallidin was cleaved only by the carboxypeptidase activity. Similarly, the enkephalins are good substrates for ACE but inhibition of this enzyme by captopril causes only a slight decrease in the microvascular degradation of Met-enkephalin.133 The enkephalins are also degraded by aminopeptidase N which removes Tyr1. Since this enzyme is reasonably abundant in microvessels of brain it is reasonable to think that it may be involved in enkephalin degradation there. ACE is partly responsible for the degradation of leucine enkephalin exposed to monolayers of microvessel endothelia from bovine brain, although the major degrading enzyme appears to be a cytosolic aminopeptidase sensitive to inhibition by bestatin.189 The actions of ACE, carboxypeptidase N and aminopeptidase P on circulating bradykinin and several analogues, and the effects on agonist/antagonist potency, have recently been investigated.190,191 It is likely to be the case that the sub–cellular localization of peptidases within the cerebral microvasculature may be the crucial factor in determining which peptides are cleaved by which enzyme(s) and whether peptides are attacked at the cell surface or in cytosolic compartments after internalization. Unfortunately the ultrastructural localization of peptidases in the cerebral microvasculature is at present largely unexplored. Such peptidases may not necessarily be located within the endothelial cell to be classified as BBB peptidases. The intimate association of pericytes and some astrocytes with the microvasculature suggests that these cells may well participate in regulating the passage of peptides at the BBB. Indeed, cultivated astrocytes have recently been shown to contain several peptidase activities including DPP II192 and endopeptidases 24.16 and 24.15, the latter being capable of degrading somatostatin and neurotensin.193
Newer approaches and novel drugs for inhalational therapy for pulmonary arterial hypertension
Published in Expert Opinion on Drug Delivery, 2020
Ali Keshavarz, Hossam Kadry, Ahmed Alobaida, Fakhrul Ahsan
The pulmonary vasculature plays a pivotal role in PAH, and therefore the diseases are likely to benefit from vascular-targeted drug delivery. Targeting lung-specific moieties provide an extraordinarily rapid and specific means to target pulmonary vasculature and potentially deliver therapeutic agents into the lung tissue. The roster of candidate molecules as endothelial targeting moieties includes peptidases such as aminopeptidase P (APP) [181], ECM component such as heparan sulfate [182], cell adhesion molecules and integrins [183,184], localized in different domains of the endothelial plasmalemma and differentially distributed throughout the vasculature. For example, PECAM and VE-cadherin are localized in cell-cell borders [185–187], whereas VCAM-1 and ICAM-1 are found in micro-domains of the cellular apical surface [188–190]. Glycoprotein gp85 localizes to the luminal surface of the plasmalemma that belongs to a thin organelle-free part of the endothelial cell separating alveoli from blood [191]. Endowing carriers with a high affinity to a specific layer of pulmonary arteries enables an exceptional level of precision of control of drug delivery through binding to selected cell phenotypes, reducing unwanted effects, and adjusting the duration of therapeutic effects.
Metabolic cooperativity between Porphyromonas gingivalis and Treponema denticola
Published in Journal of Oral Microbiology, 2020
Lin Xin Kin, Catherine A. Butler, Nada Slakeski, Brigitte Hoffmann, Stuart G. Dashper, Eric C. Reynolds
Tan et al. [22] showed that P. gingivalis W50 increased the rate of hydrolysis of glycine-containing peptides when grown in OB:CM compared with OBGM, contributing to an increased production of free extracellular glycine. However, RNA-seq examination of P. gingivalis W50 grown under these same conditions did not identify which proteases were potentially involved in this process. Although several protease-encoding genes such as rgpA (PG2024), rgpB (PG0506), kgp (PG1844), PG1788, PG0537, PG0418, and PG1548 were amongst the most highly expressed P. gingivalis transcripts, they were not differentially regulated; in fact, none of the P. gingivalis protease-encoding genes showed significant upregulation during growth in OB:CM compared with OBGM. Rather, expression of PG1542, that encodes PrtC, a Type I collagenase [47,48] was downregulated 2.3-fold in OB:CM (Supplementary Table S4). There were also significant reductions in the expression of genes encoding P. gingivalis ATP-dependent proteases PG0047 (2-fold), PG0620 (2-fold) and PG0010 (1.7-fold), and an annotated aminopeptidase P family protein (PG0889, 1.7-fold) (Supplementary Table S4). Therefore, a protein bioinformatics approach was taken to identify P. gingivalis peptidases that could be involved in peptide hydrolysis to release glycine.
Angioedema: a rare and sometimes delayed side effect of angiotensin-converting enzyme inhibitors
Published in Acta Cardiologica, 2019
Laurent Davin, Patrick Marechal, Patrizio Lancellotti, Christophe Martinez, Luc Pierard, Regis Radermecker
ACE is also the first peptidase incriminated in the degradation of BK (Figure 2) The kininogen precursor is cleaved by kallikrein to produce the active forms of BK that have very short half-lives as a result of their degradation by the ACE, neutral endopeptidase (NEP), aminopeptidase P (APP) and by dipeptidyl peptidase IV (DPPIV) [2]. ACE inhibitor prolongs the half-life of BK, which produces its effects through the stimulation of G-protein receptors, BK2 receptors and results in NO-related vasodilatation and hypotension which is also due to the prostaglandin formation linked to the release of prostacyclin [3]. The effects of ACE inhibitor on cardiac remodelling are related to decreased collagen accumulation and smooth muscle cell proliferation secondary to stimulation of BK2 receptors [4].