Exopeptidases dipeptidases

An exopeptidase that can only degrade a dipeptide. Examples are carnosine dipeptidase I (MEROPS M20.006), which degrades carnosine (beta-Ala-His), and membrane dipeptidase (MEROPS Ml9.001), which is important in the catabolism of glutathione, degrading the dipeptides Cys-Gly. Dipeptidases are included in Enzyme Nomenclature sub-subclass 3.4.13. 

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 sequentially releases dipeptides from the C-terminus of a protein or peptide. An example is angiotensin-converting enzyme (also known as peptidyl-dipeptidase A MEROPS XM02-001), which plays an important role in the control of blood pressure by converting angiotensin I to angiotensin II. Peptidyl-dipeptidases are included in Enzyme Nomenclature sub-subclass 3.4.15. 

There are two main classes of proteolytic digestive enzymes (proteases), with different specificities for the amino acids forming the peptide bond to be hydrolyzed. Endopeptidases hydrolyze peptide bonds between specific amino acids throughout the molecule. They are the first enzymes to act, yielding a larger number of smaller fragments, eg, pepsin in the gastric juice and trypsin, chymotrypsin, and elastase secreted into the small intestine by the pancreas. Exopeptidases catalyze the hydrolysis of peptide bonds, one at a time, fi"om the ends of polypeptides. Carboxypeptidases, secreted in the pancreatic juice, release amino acids from rhe free carboxyl terminal, and aminopeptidases, secreted by the intestinal mucosal cells, release amino acids from the amino terminal. Dipeptides, which are not substrates for exopeptidases, are hydrolyzed in the brush border of intestinal mucosal cells by dipeptidases. 

Metallo proteases Exopeptidase group Peptidyl dipeptidase-A (ACE) Aminopeptidase-M Carboxypeptidase-A... 

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. 

Increased permeability is just one prerequisite in the development of useful peptide prodrugs. Another condition is that efficient bioactivation must follow absorption. Mucosal cell enzymes able to hydrolyze peptides include exopeptidases such as aminopeptidases and carboxypeptidases, endopepti-dases, and dipeptidases such as cytosolic nonspecific dipeptidase (EC 3.4.13.18), Pro-X dipeptidase (prolinase, EC 3.4.13.4), and X-Pro dipeptidase (prolidase, EC 3.4.13.9). For example, L-a-methyldopa-Pro was shown to be a good substrate for both the peptide transporter and prolidase. This dual affinity is not shared by all dipeptide derivatives, and, indeed, dipeptides that lack an N-terminal a-amino group are substrates for the peptide transporter but not for prolidase [29] [33] [34],... 

Protein digestion occurs in two stages endopeptidases catalyse the hydrolysis of peptide bonds within the protein molecule to form peptides, and the peptides are hydrolysed to form the amino acids by exopeptidases and dipeptidases. Enteropeptidase initiates pro-enzyme activation in the small intestine by catalysing the conversion of trypsinogen into trypsin. Trypsin is able to achieve further activation of trypsinogen, i.e. an autocatalytic process, and also activates chymotrypsinogen and pro-elastase, by the selective hydro-... 

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. 

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. 

Peptidyl dipeptidases (C-terminal exopeptidases, releasing dipeptides)... 

The distinction between exopeptidases and endopeptidases is merged for some members of the subfamily CIA. Dipep-tidylpeptidase I acts principally as an exopeptidase, removing N-terminal dipeptides, but may have some endopeptidase activity. Cathepsins B and H both possess endopeptidase activity but also possess exopeptidase activities. Cathepsin B acts as a peptidyl-dipeptidase, releasing C-terminal dipeptides. Cathepsin X is a carboxypeptidase. 

Exopeptidases catalyse the hydrolytic removal of only terminal amino acids from the polypeptide chain. They can therefore be classified into IV-termin-al exopeptidases (aminopeptidases, e.g. leucine ami-nopeptidase) and C-terminal exopeptidases (e.g. car-boxypeptidases A, B, Y etc.). Thi- and dipeptidases are also classified as exopeptidases. 

The oligopeptides formed by the action of the endopeptidases are broken down into their constituent amino acids by the action of the exopeptidases. The carboxypeptidase of the pancreas splits amino acids one by one from the C-terminus so that, by the time they reach the absorbing cells of the small intestine, the dietary proteins have been converted into a mixture of amino acids and small peptides. The mucosal cells which contain both aminopeptidases and dipeptidase take up the small peptides which are then hydrolysed either within the brush border or in the layer immediately beneath it. Thus the final stages of protein digestion, like those of carbohydrates, are intracellular. Under normal circumstances no peptides pass across the mucosa to enter the bloodstream. 

Numerous peptidases with varying specificities have been described. Peptidases may be defined as enzymes that split peptide bonds of only terminal amino acids and thus are exopeptidases. Aminopeptidases hydrolyze peptide bonds involving acids with a free ai-amino group carboxypep-tidase requires that the a-carboxyl group be free. Dipeptidases and tripeptidases will split substrates in which there is only one peptide bond or only two peptide bonds, respectively. Peptidases such as prolinase, prolidase, leucineaminopeptidase, etc., exhibit side-chain specificity requirements as well as backbone requirements. Comprehensive reviews of peptidase activity have recently been written by Smith. 

This group includes exopeptidases, carboxypep-tidases A and B, aminopeptidases, dipeptidases, prolidase and prolinase, and endopeptidases from bacteria and fungi, such as Bacillus cereus, B. megaterium, B. subtilits, B. ther-moproteolyticus (thermolysin), Streptomyces griseus (pronase it also contains carboxy- and aminopeptidases) and Aspergillus oryzae. 

Enzymes that hydrolyze amide and ester bonds may be divided into three classes (1) those requiring a thiol group for activity, such as papain, ficin, and other plant enzymes (2) those inhibited by diisopropylphosphorofluo-ridate (DFP), such as a-chymotrypin, trypsin, subtilisin, cholinesterase, and thrombin (3) those that require a metal ion for activity. This last class includes dipeptidases, and exopeptidases such as carboxypeptidase and leucine aminopeptidase. The metal ion is involved in the stabilization of the tetrahedral intermediate (refer to Section 4.4.1). 

Exopeptidases Aminopeptidase Dipeptidase Intestinal mucosa Intestinal mucosa Terminal —NHs+ Dipeptides... 

Exopeptidases, as the name indicates, attack only the ends of a peptide chain Carboxypeptidase attacks the carboxyl end, with a preference for some amino acids (see below) amino-peptidase, the amino end. The first group of exopeptidases evidently requires, beside the peptide bonds, a negative charge the second group requires, beside the peptide bonds, a positive charge. Lastly, there are also dipeptidases, which need both charges and cleave only dipeptides. 

Dipeptidases are exopeptidases specific forNH2-XiX-COOH dipeptides. The PepD dipeptidase family has a broad specificity for various dipeptides. The pepD genes are distributed heterogeneously in LAB genomes and can vary in number from 0 to 6 paralogs. PepV is also encoded by multiple paralogous genes. It is present in all LAB and also has a broad specificity. 

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