Peptidase exopeptidase

These proteolytic enzymes are all endopeptidases, which hydrolyse links in the middle of polypeptide chains. The products of the action of these proteolytic enzymes are a series of peptides of various sizes. These are degraded further by the action of several peptidases (exopeptidases) that remove terminal amino acids. Carboxypeptidases hydrolyse amino acids sequentially from the carboxyl end of peptides. They are secreted by the pancreas in proenzyme form and are each activated by the hydrolysis of one peptide bond, catalysed by trypsin. Aminopeptidases, which are secreted by the absorptive cells of the small intestine, hydrolyse amino acids sequentially from the amino end of peptides. In addition, dipeptidases, which are structurally associated with the glycocalyx of the entero-cytes, hydrolyse dipeptides into their component amino acids. 

An exopeptidase that sequentially releases a dipeptide from the N-terminus of a protein or peptide. Dipeptidy 1-peptidases are included in Enzyme Nomenclature subsubclass 3.4.14 along with tripeptidyl-peptidases. 

There are several different types of exopeptidases aminopeptidases, carboxypeptidases, dipeptidyl-peptidases, tripeptidy 1-peptidases, peptidyl-... 

Gener ally, a family of peptidases contains either exopeptidases or endopeptidases, but there are exceptions. Family Cl contains not only endopeptidases such as cathepsin L, but also the aminopeptidase bleomycin hydrolase. Some members of this family can act as exopeptidases as well as endopeptidases. For example, cathepsin B also acts as a peptidyl-dipeptidase, and... 

An exopeptidase that does not cleave standard peptide bonds. An example is pyroglutamyl-peptidase I (MEROPS C15.010), which releases an N-terminal pyroglutamyl from hormones such as thyrotropinreleasing hormone and luteinizing hormone. Omega peptidases are included in Enzyme Nomenclature subsubclass 3.4.19. 

Proteases, which can be classified as either peptidases or proteinases. These cleave polypeptide chains eventually into their component amino acids. Peptidases can be further classified as endopeptidases (which act on the main-chain amido groups along the polypeptide molecule) or as exopeptidases (which act only at terminal amino acid residues). 

The NC-IUBMB classifies peptidases (EC 3.4) into exopeptidases (EC 3.4.11-19), which remove one or a few amino acids, and endopeptidases (proteinases, EC 3.4.21-99), which catalyze the cleavage of peptide bonds away from either end of the polypeptide chain (Fig. 2.1). Exopeptidases are further subdivided into enzymes that carry out hydrolysis at the N-terminus or the C-terminus (Figs. 2.1 and 2.2). Thus, aminopeptidases (EC 3.4.11) cleave a single amino acid from the N-terminus [3] those removing a dipep-... 

The NC-IUBMB has introduced a number of changes in the terminology following the proposals made by Barrett, Rawlings and co-workers [7] [8]. The term peptidase should now be used as a synonym for peptide hydrolase and includes all enzymes that hydrolyze peptide bonds. Previously the term peptidases was restricted to exopeptidases . The terms peptidase and protease are now synonymous. For consistency with this nomenclature, the term proteinases has been replaced by endopeptidases . To complete this note on terminology, we remind the reader that the terms cysteine endopeptidases and aspartic endopeptidases were previously called thiol proteinases and acid or carboxyl proteinases , respectively [9],... 

One of the general principles of the Nomenclature Committee is that enzymes should be classified and named according to the reaction they catalyze. However, the overlapping specificities of and great similarities in the action of different peptidases render naming solely on the basis of function impossible [10]. For example, some enzymes can act as both endo- and exopeptidases. Thus, cathepsin H (EC 3.4.22.16) is not only an endopeptidase but also acts as an aminopeptidase (EC 3.4.11), and cathepsin B (EC 3.4.22.1) acts as an endopeptidase as well as a peptidyl-dipeptidase (EC 3.4.15). The actual classification of peptidases is, therefore, a compromise based not only on the reaction catalyzed but also on the chemical nature of the catalytic site, on physiological function, and on historical priority. 

The evolutionary classification has a rational basis, since, to date, the catalytic mechanisms for most peptidases have been established, and the elucidation of their amino acid sequences is progressing rapidly. This classification has the major advantage of fitting well with the catalytic types, but allows no prediction about the types of reaction being catalyzed. For example, some families contain endo- and exopeptidases, e.g., SB-S8, SC-S9 and CA-Cl. Other families exhibit a single type of specificity, e.g., all families in clan MB are endopeptidases, family MC-M14 is almost exclusively composed of carboxypeptidases, and family MF-M17 is composed of aminopeptidases. Furthermore, the same enzyme specificity can sometimes be found in more than one family, e.g., D-Ala-D-Ala carboxypeptidases are found in four different families (SE-S11, SE-S12, SE-S13, and MD-M15). 

The proteolytic activity of some multicatalytic peptidases is stimulated by ATP, whereas that of others is not influenced by ATP [32], The ATP-dependent proteolytic system first found in reticulocytes requires the presence of a heat-stable polypeptide called ubiquitin, one of the roles of which is to mark particular proteins for subsequent degradation [33. ATP-Indepen-dent multicatalytic peptidases can degrade proteins that have a free amino or an /V-acctylatcd terminus, as well as oxidatively altered or phosphorylat-ed proteins [34], The small peptides generated are resistant to multicatalytic peptidases and are further degraded by cytoplasmic endopeptidases and exopeptidases. 

Peptide hydrolases (peptidases or proteases, i.e., enzymes hydrolyzing peptide bonds in peptides and proteins, see Chapt. 2) have received particular attention among hydrolases. As already described in Chapt. 2, peptidases are divided into exopeptidases (EC 3.4.11 -19), which cleave one or a few amino acids from the N- or C-terminus, and endopeptidas-es (proteinases, EC 3.4.21-99), which act internally in polypeptide chains [2], The presentation of enzymatic mechanisms of hydrolysis in the following sections will begin with peptidases and continue with other hydrolases such as esterases. 

The exopeptidases attack peptides from their termini. Peptidases that act at the N terminus are known as aminopeptidases, while those that recognize the C terminus are called carboxypeptidases. The dipeptidases only hydrolyze dipeptides. 

Elastase mainly cleaves on the C side of the aliphatic amino acids Gly, Ala, Val, and lie. Smaller peptides are attacked by carboxy-peptidases, which as exopeptidases cleave individual amino acids from the C-terminal end of the peptides (see p. 176). 

The International Union of Biochemistry and Molecular Biology recommends that the term peptidase be used synonymously with the term peptide hydrolase (IUBMB, 1992). Thus, in this unit the term peptidase is used in reference to any enzyme that catalyzes the hydrolysis of peptide bonds, without distinguishing between exo- and endopeptidase activities. Peptidases may be assayed using native or modified proteins, peptides, or synthetic substrates. In this unit, the focus is on assays based on the hydrolysis of common, commercially available, protein substrates. Thus, the assays are not intended to be selective for a given peptidase they are designed to provide estimates of overall peptidase activity. Other units in this publication focus on synthetic or model substrates, which can be designed for the measurement of specific endo- and/or exopeptidase activities. 

Peptidases are often classified as either exopeptidases or endopeptidases, depending on the positional specificity of the bonds they hydrolyze. Exopeptidases act at peptide bonds located at either the N or C terminus of the protein. Those acting at the C terminus are referred to as carboxypeptidases, those acting at the N terminus as aminopeptidases. Endopeptidases, on the other hand, act at peptide bonds internal to the polypeptide chain. 

Proteolytic enzymes such as proteases and peptidases are ubiquitous throughout the body. Sites capable of extensive peptide and protein metabolism are not only limited to the liver, kidneys, and gastrointestinal tissue, but also include the blood and vascular endothelium as well as other organs and tissues. As proteases and peptidases are also located within cells, intracellular uptake is per se more an elimination rather than a distribution process [13]. While peptidases and proteases in the gastrointestinal tract and in lysosomes are relatively unspecific, soluble peptidases in the interstitial space and exopeptidases on the cell surface have a higher selectivity and determine the specific metabolism pattern of an organ. The proteolytic activity of subcutaneous tissue, for example, results in a partial loss of activity of SC compared to IV administered interferon-y. 

The major group of enzymes produced by the pancreas and secreted into the duodenum as an aqueous bicarbonate solution is the peptidases. There are three endopeptidases, trypsin, chymotrypsin and elastase, and two exopeptidases,... 

The lysosomal enzymes most relevant to our discussion are the peptidases and the nucleases. The peptidases, also referred to as the cathepsins, comprise at least eight exopeptidases and nine endopeptidases, which between them have a broad range of specificities that enable them to reduce any proteins or peptides to their constituent amino acids. 

Exopeptidases cleave peptides and proteins at their N and C termini and include aminopeptidases, carboxypeptidases and dipeptidyl peptidase. 

As described in Section 1.6.1 exopeptidases cleave at N- and C-termini and include aminopeptidases, carboxypeptidases and dipeptidyl peptidase, whereas endopeptidases cleave at an internal peptide bond and include enkephalinase and cathepsin B. Small peptides are relatively resistant to the action of endopeptidases but their activity is significant for large peptides. 

Endopeptidases are proteolytic peptidases that break peptide bonds of nonterminal amino acids (i.e. within the molecule), in contrast to exopeptidases, which break peptide bonds from their terminal end-pieces. 

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