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Intracellular Peptide Turnover: Properties and Physiological Significance of the Major Peptide Hydrolases of Brain Cytosol
Published in Gerard O’Cuinn, Metabolism of Brain Peptides, 2020
In further studies on the properties of endo-oligopeptidase A, Camargo and co-workers reported that this bradykinin degrading enzyme could also hydrolyze neurotensin by cleavage at the Arg8-Arg9 bond106. When a D-Tyr was substituted in the 11 position (corresponding to the P3′ position with respect to the scissile bond), the resulting peptide was not cleaved. Moreover these investigators demonstrated the formation of enkephalins from enkephalin-containing peptides107.
Lipoprotein(a) and Fibrinolysis
Published in Pia Glas-Greenwalt, Fibrinolysis in Disease Molecular and Hemovascular Aspects of Fibrinolysis, 2019
Lindsey A. Miles, Edward F. Plow
The kringle stretch of apo(a) is followed by a region with 88% amino acid identity to the plasminogen protease domain. Although the critical Arg, His, and Ser residues necessary for formation of the catalytic triad of serine proteases are present in human apo(a) (but not apo(a) from rhesus monkeys), the Arg-Val cleavage site for plasminogen activators is replaced by a Ser-Val peptide bond in apo(a), precluding cleavage by and, therefore, activation by plasminogen activators. In addition to changes in the scissile bond, a deletion of 9 amino acids is present in apo(a). When the susceptibility of apo(a) to plasminogen activators was tested experimentally, McLean et al.12 were unable to demonstrate either cleavage or activation by the plasminogen activators, t-PA and urokinase, in Lp(a) samples from seven individuals. In contrast, both intrinsic43,44 and inducible45 proteolytic activity of apo/Lp(a) have been reported. These differences may be due to differences in isoforms. Clearly, if a specific apo(a) isoform did retain proteolytic activity, profibrinolytic rather than antifibrinolytic activity would be predicted.
Peptidases and Neuropeptide-Inactivating Mechanisms in the Circulation and in the Gastrointestinal Tract
Published in Edwin E. Daniel, Neuropeptide Function in the Gastrointestinal Tract, 2019
Endopeptidase 24.15 (also called soluble metallopeptidase) appeared to cleave peptide bonds in which the carboxyl group was contributed by an aromatic amino acid residue.67 Furthermore, the specificity studies had suggested that the active site of this enzyme could accommodate at least five amino-acids, with two and three residues located on the N-terminal and C-terminal sides of the scissile bond, respectively.67 Sites of hydrolysis of several biologically active peptides67,101 had been found to be consistent with this specificity, which was deduced from studies with synthetic model substrates (see Table 8).
Serpina3n: Potential drug and challenges, mini review
Published in Journal of Drug Targeting, 2020
Mehwish Saba Aslam, Liudi Yuan
Interestingly all serpins exhibit similar conserved secondary structure consists of 8–9 α-helices, 3 beta-sheets, and centrally located about 17 amino-acids long RCL [5,9,32,33], which specifies the function of the serpin as well as their target protease [9,33]. In RCL, functionally the most important residue is located at P1 position, flanked by recognition residues at P4-P4´ position [5,34,35]. The bond between P1-P1´ named as scissile bond [33], binds the aminoacyl end (P1) to the carboxyl end (P1´) [32,35]. Serpina3n has methionine at P1 position flanked by phenylalanine and leucine at P4-P4´ respectively. The scissile bond is formed between Met and serine at position P1-P1´ [8]. Compatibility of these residues specifies the functional target protease of Serpina3n (Figure 1(a)). Serpina3n’s RCL residues are identical to human SERPINA1 (α1-antitrypsin) while shares 61% homology with SERPINA3 excluding RCL and functionally lies between the human SERPINA1 and SERPINA3 exhibiting diversity for target substrates. SERPINA3 possesses leucine at P1 position of RCL [7] (Figure 1(b)). Any mutation in the critical residues may also adversely effect the serpin substrate specificity. For example, substitution of Met to Arg at P1 in Serpina3n starts targetting thrombin instead of neutrophil elastase leading to uncontrolled bleeding [9].
Design, synthesis, and in vitro evaluation of aza-peptide aldehydes and ketones as novel and selective protease inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Thomas S. Corrigan, Leilani M. Lotti Diaz, Sarah E. Border, Steven C. Ratigan, Kayla Q. Kasper, Daniel Sojka, Pavla Fajtova, Conor R. Caffrey, Guy S. Salvesen, Craig A. McElroy, Christopher M. Hadad, Özlem Doğan Ekici
Eight novel compounds were synthesised and evaluated for their ability to inhibit their respective target proteases in vitro, and were shown to be low-to-mid-µM range inhibitors. Each inhibitor was also tested for cross-reactivity with cathepsin B and α-chymotrypsin, and resulted in no inhibition (>50 µM). X-ray crystallographic data with caspase-3 revealed a tetrahedral adduct with compound 6, providing insight into the mechanism of inhibition. The micromolar range of inhibitory potency for these aza-peptide aldehydes and ketones could be attributed to the fact that the point of the nucleophilic attack is one chemical bond away towards the C-terminus from where the scissile bond normally would reside (Figure 1). However, it is also advantageous that the proteasome, caspases-3, and -6, and legumains still tolerate this aza-P1 design, whereas the classical cysteine protease cathepsin B and α-chymotrypsin do not. These differences provide an opportunity for tuneability as well as selectivity, and possibly less off-target reactivity as observed for bortezomib, carfilzomib and ixazomib.
Inherited ADAMTS13 mutations associated with Thrombotic Thrombocytopenic Purpura: a short review and update
Published in Platelets, 2023
Zoe Markham-Lee, Neil V. Morgan, Jonas Emsley
The ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif 13) gene encodes a plasma metalloprotease, crucial to the regulation of blood coagulation via cleavage of large Von Willebrand factor (VWF) multimers. VWF is a large glycoprotein central to coagulation, mainly through recruitment of platelets and formation of a hemostatic plug at sites of vessel damage [1]. Through cleavage of VWF at the scissile bond (Tyr1605-Met1606), ADAMTS13 prevents accumulation of ultra-large VWF multimers in circulation and therefore perturbs excessive aggregation of platelets to maintain the delicate haemostatic thrombotic balance [2].