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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
One of the most interesting and unique features of the soluble metalloendopeptidase is its substrate specificity. The substrate specificity of most proteinases can be readily described e.g. prolyl oligopeptidase (cleavage at the carboxyl side of a proline residue), neprilysin (cleavage at the amino side of a hydrophobic amino acid), trypsin (cleavage at the carboxyl side of a basic amino acid), etc. Although soluble metalloendopeptidase-catalyzed cleavages commonly occur at the carboxyl side of a hydrophobic amino acid, neurotensin is degraded by cleavage between two arginyl residues, a His-Trp bond is one of the cleavage sites in LHRH and a Pro-Gin bond in substance P is hydrolyzed. When a series of synthetic substrates was studied, a preference for aromatic amino acid residues in the P1 and P2 positions was seen. In addition there was a marked beneficial effect when an aromatic amino acid was present in the P3’ position. The latter substituent decreased the Km and increased the kcat. It could account in part for the unusual specificity.
Xenobiotic Biotransformation
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Aldehyde dehydrogenases (EC 1.2.1.3.) catalyze the oxidation of aldehydes to acids by using NAD as co-factor. The physiological substrates for the enzymes are unknown; the substrate specificity is broad. Classical substrates include acetaldehyde, formaldehyde, and glycolaldehyde, which are the biotransformation products of ethanol, methanol, and ethylene glycol, respectively. The enzymes are present in all organs and in cytosol, mitochondria and microsomes. Liver has the highest activity, but kidney also possesses high activity. The enzymes exist as several isozymes within the cytosolic, mitochrondrial, and microsomal compartments. One cytosolic isozyme is specific for the oxidation of formaldehyde complexed with glutathione and is referred to as formaldehyde dehydrogenase. Additional isozymes within the cytosol are differentiated by selective induction with PB or TCDD and 3-MC. The isozyme induced by TCDD and 3-MC has received special study due to its increased activity in tumor cells [see Marselos and Lindahl (1988)]. Since acetaldehyde is preferentially oxidized in mitochondria, an isozyme for its oxidation may be localized in these structures. Additional mitochrondrial isozymes can be differentiated by selective inhibition with the prototype aldehyde dehydrogenase inhibitor, disulfiram.
Disposition and Metabolism of Drugs of Dependence
Published in S.J. Mulé, Henry Brill, Chemical and Biological Aspects of Drug Dependence, 2019
Biotransformation of barbiturates is mediated primarily by the liver microsomal enzymes which, in the presence of reduced triphosphopyridine nucleotide and molecular oxygen, hydroxylate a wide variety of barbiturates. These microsomal enzymes possess very low substrate specificity.21 Studies on biotransformation of barbiturates in vitro or in vivo by liver microsomes have only been done in experimental animals, not in humans.
Bio-nano scale modifications of melittin for improving therapeutic efficacy
Published in Expert Opinion on Biological Therapy, 2022
Mostafa Akbarzadeh-Khiavi, Mitra Torabi, Amir-Hossein Olfati, Leila Rahbarnia, Azam Safary
In recent years, nanocarriers, liposomes, microcapsules, and formulations with modified-surface have been developed to control release drug delivery systems [92]. Nano-based drug delivery systems have been widely used for MLT delivery, which can help overcome MLT’s cytotoxicity, hemolysis effects, and safe intravenous delivery of peptides. Different nanocarriers such as inorganic carriers (e.g. iron oxide [93], quantum dots [94], and perfluorocarbon (PFC) [76]), polymer-carriers (e.g. Liposome [95], poly lactic-co-glycolic acid (PLGA) [96], and β-cyclodextrin [97]), and nonionic surfactant-based vesicles (e.g. Niosomes [83]) have been evaluated to reduce the MLT toxicity and targeted delivery to the intended sites. In addition, enzyme-responsive NPs have been established for delivering antitumor agents. Enzymes with high affinity to their targets and substrate specificity are considered the most potent tools in designing innovative therapeutic platforms [98,99]. In a study by Yu et al., activatable protein NPs (APNPs) were designed to prolong the circulation time of peptides in the blood and targeted delivery into disease sites by locally enriched proteases. They showed that MLT-loaded APNPs disassembled in response to MMP enzymes and the toxicity of the released MLT was comparable with the native form of peptide [100].
Trypsinogen and chymotrypsinogen: potent anti-tumor agents
Published in Expert Opinion on Biological Therapy, 2021
Aitor González-Titos, Pablo Hernández-Camarero, Shivan Barungi, Juan Antonio Marchal, Julian Kenyon, Macarena Perán
Trypsinogen and Chymotrypsinogen belong to the serine protease family which is mainly composed of hydrolases [12]. The structure of Trypsinogen/Trypsin and Chymotrypsinogen/Chymotrypsin is very similar and consists of two beta-barrels with eight loops around the active site. The active site is found between these barrels and is composed of three amino acids. The first two correspond to His-57 and Asp-102 that belong to the N-terminal beta-barrel, whereas the other amino acid Ser-195 comes from the C-terminal barrel (Figure 1). In addition, the proteins are fairly stabilized by six disulfide bridges to resist the reducing environment in the gastrointestinal tract [13]. Although Trypsinogen and Chymotrypsinogen have similar tridimensional structures, the substrate specificity of their active sites is different. The difference in the active sites is the result of the distinct residues that form the binding pockets. Whereas Trypsin has an aspartic acid, Chymotrypsin has a serine which produces specificity for aromatic residues [14]. The active site of Trypsin is specific for arginine and lysine residues, while Chymotrypsin is specific for aromatic residues like tyrosine, phenylalanine and tryptophan [6]. Therefore, the differences between the two enzymes rely on the breaking down of different amino acids and how they can consequently digest different proteins. Furthermore, their different substrate specificity also promotes the activation of different molecular targets which may imply the activation of different molecular pathways and the promotion of distinct biological effects (see below).
Investigation of the toxicological and inhibitory effects of some benzimidazole agents on acetylcholinesterase and butyrylcholinesterase enzymes
Published in Archives of Physiology and Biochemistry, 2021
Mammals; one of them is AChE which hydrolyses ACH selectively and the other has two types of cholinesterase, butyrylcholinesterase (BChE), which can hydrolyze ACh and other choline esters. Cholinesterases have a wide distribution in cholinergic and non-cholinergic tissues including plasma and other body fluids. They were divided into two groups according to their substrate specificity, their behaviour in the presence of excess substrate and their sensitivity to inhibitors. All AChE inhibitors, which differ from each other in terms of their pharmacological properties, function in common to provide inhibition of ACh's degradation. AChE or true cholinesterase (Acetylcholine acetyl hydrolase, AChE, E.C.3.1.1.7) and butyrylcholinesterase (Acylcholine acylhydrolase, BChE, E.C.3.1.1.8) are known as nonspecific cholinesterase or pseudocholinesterase. AChE is found in high concentration in brain and erythrocytes; BChE is found in serum, pancreas, liver and central nervous system. Eighty percent of the cholinesterase activity in the brain is considered to be responsible for AChE and the remaining 20% is responsible for BChE (Ellman et al.1961, Obregon et al.2005, Ahmed and Gilani 2009).