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Enzymatic Degradation of Bradykinin
Published in Sami I. Said, Proinflammatory and Antiinflammatory Peptides, 2020
Randal A. Skidgel, Ervin G. Erdös
Carboxypeptidases cleave the C-terminal amino acid of peptides and proteins. Carboxypeptidases involved in Bk metabolism can be divided into two groups, the serine carboxypeptidases and the metallocarboxypeptidases. Most investigations have focused on the role of metallocarboxypeptidases, as, historically, carboxypeptidase N was the first human kininase discovered (Erdös and Sloane, 1962).
The Small IntestineSecretions, Digestion and Motility
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
Proteins found in the intestines are derived from endogenous sources (secretory proteins and desquamated cells) and exogenous proteins (dietary protein). Although 10%–15% of protein in the gastrointestinal tract is digested by gastric pepsin, protein digestion products in the stomach are important because they stimulate the secretion of proteases by the pancreas. Most protein digestion results from the actions of pancreatic proteolytic enzymes. Trypsinogen and chymotrypsinogen are activated by enterokinase or by autocatalysis with trypsin. Trypsin and chymotrypsin, which are endopeptidases, cleave internal peptide linkages to produce dipeptides, tripeptides and other small peptide chains that can be absorbed by intestinal cells. Carboxypeptidase (exopeptidase) is also produced by the pancreas and intestinal epithelial cells. Carboxypeptidases cleave the ends of a peptide chain, producing free amino acids, which are readily absorbed by the intestine. The last step in the digestion of protein is achieved by enterocytes that line the villi. At the brush border, aminopeptidases split larger polypeptides into tripeptides, dipeptides and some amino acids. These are transported into the enterocytes where multiple peptidases digest the dipeptides and tripeptides to amino acids, which then enter the blood.
Molecular Imaging of Viable Cancer Cells
Published in Shoogo Ueno, Bioimaging, 2020
In order to expand the range of target cancers, we next focused on cancer-associated carboxypeptidases. Especially, we focused on the glutamate carboxypeptidase activity of prostate-specific membrane antigen (PSMA), which is a type II transmembrane glycoprotein that is overexpressed in prostate cancer.53–55 Based on our finding that aryl glutamate conjugates with an azoformyl linker are recognized by PSMA and have a sufficiently low LUMO energy level to quench the fluorophore through photoinduced electron transfer, we established a new design strategy for activatable fluorescence probes to visualize carboxypeptidase activity, and developed a first-in-class activatable fluorescence probe for detecting the carboxypeptidase activity of PSMA (Figure 2.11).56 We confirmed that the developed probe allowed us to visualize the CP activity of PSMA in living cells and in clinical specimens from prostate cancer patients. This probe is expected to be useful for rapid intraoperative detection and diagnosis of prostate cancer.
Recent advances in proteolytic stability for peptide, protein, and antibody drug discovery
Published in Expert Opinion on Drug Discovery, 2021
Xianyin Lai, Jason Tang, Mohamed E.H. ElSayed
Carboxypeptidases (EC 3.4.16–3.4.18) are peptidases that cleave a peptide bond at the carboxy-terminal (C-terminal) end of a peptide or protein. Carboxypeptidases are named with a combination of one letter and one number following the word carboxypeptidase at the beginning. There are at least 17 carboxypeptidases, belonging to two major groups. One uses serine as an active site residue named as serine carboxypeptidases, and the other uses zinc at the active site, known as metallocarboxypeptidases, which are further separated into two subgroups based on amino acid sequence similarities [66]. Among the carboxypeptidases, some of them have low tissue specificity with expression in many tissues and are secreted into bodily fluids with a low concentration, such as carboxypeptidases D and X2. Some are in specific tissues without leaking into bodily fluids or with a low concentration in bodily fluids, such as carboxypeptidase A4 in the esophagus and skin, carboxypeptidase A6 in the intestine, prostate, and retina, carboxypeptidase E in the brain, carboxypeptidase M in the adipose, carboxypeptidase O in the intestine, X1 in the placenta, and carboxypeptidase Z in the ovary. And others are produced in specific tissues and then secreted into either small intestinal fluid or blood. Carboxypeptidases A1, A2, and B1 are produced in the pancreas and activated in the duodenum. All three proteins are zinc-containing metallopeptidases [67]. Compared to the high abundance of trypsin, chymotrypsin and elastase in the small intestine, carboxypeptidases such as A1, A2, and B1, have a much lower concentration.
Targeting the complement system in neuromyelitis optica spectrum disorder
Published in Expert Opinion on Biological Therapy, 2021
Nithi Asavapanumas, Lukmanee Tradtrantip, Alan S. Verkman
In addition to MAC formation, complement activation produces fluid-phase anaphylatoxins C3a and C5a, which recruit and activate immune effector cells that express anaphylatoxin receptors C3aR and C5aR (CD88). C3aR and C5aR bind C3a and C5a, respectively, with binding affinity of approximately 1 nM. C3aR and C5aR are highly expressed on cells of myeloid lineage, including neutrophils, basophils, eosinophils, mast cells, macrophages and microglia. C3aR is also expressed on activated T and B cells [40]. In non-myeloid cells, C3aR and C5aR are expressed in neurons, reactive astrocytes, endothelial cells, and some epithelial and smooth muscle cells [41]. C3aR and C5aR signal transduction involves the pertussis-toxin-sensitive G-protein Gαi with downstream activation of intracellular calcium, PI3K, Akt, and MAPK pathway, resulting in production of reactive oxygen species, pro-inflammatory mediators (IL-6, TNF-α, histamine) and adhesion molecules [40]. The activities of C3a and C5a in serum are controlled by carboxypeptidase N and B, which cleave their C-terminal arginines to reduce activity [42]. Involvement of anaphylatoxins in NMOSD is supported by correlations between plasma C3a levels and NMOSD disease activity as assessed by the expanded disability status scale [24], which has suggested the potential utility of C3a as a biomarker in NMOSD. A recent study suggested C3a as a key mediator of microglial activation and CNS pathology in early NMOSD using an experimental animal model of AQP4-IgG seropositive NMOSD produced by intrathecal AQP4-IgG administration [43].
Endothelialitis plays a central role in the pathophysiology of severe COVID-19 and its cardiovascular complications
Published in Acta Cardiologica, 2021
Christiaan J. M. Vrints, Konstantin A. Krychtiuk, Emeline M. Van Craenenbroeck, Vincent F. Segers, Susanna Price, Hein Heidbuchel
ACE2, a homolog of the angiotensin-converting enzyme (ACE), was discovered 20 years ago [39,42]. This membrane-bound carboxypeptidase is universally present in the cardiovascular system as well as in the lung, intestine, and kidney. It hydrolyses angiotensin II (Ang II) to angiotensin 1–7 (Ang 1–7), which has vasodilator and cardioprotective effects through activation of the MAS receptor, coded by the MAS1 gene (mitochondrial assembly 1) [43,44] (Figure 3). By hydrolysing Ang II to Ang 1–7, ACE2 counterbalances the vasoconstriction induced by activation of the ACE-Ang II-angiotensin receptor 1 (AT1) axis of the RAS. In various diseases where the ACE-Ang II-AT1 axis is activated, ACE2 may mitigate the detrimental effects of Ang II [44]. As a consequence, impairment of the cardioprotective effects the ACE2-Ang [1-7]-MAS axis will accelerate the disease-promoting actions of an activated ACE-Ang II-AT1 axis. Furthermore, excess of Ang II in disease will further weaken the protective role of ACE2 by activating disintegrin and metalloprotease 17 (ADAM17), an enzyme that leads to shedding of the ectodomain of ACE2 from the cell membrane into the circulation [45,46]. A high concentration of this soluble ACE2 is a known marker of an unfavourable prognosis in patients with cardiovascular disease [47].