Peptidyl dipeptidases

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. 

Penicillin Binding Protein Pentasaccharide Peptide Mass Fingerprint Peptide YY Peptidoglycans Peptidyl Transferase Center Peptidyl-Dipeptidase PERI... 

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

Formed by sequential enzymatic cleavage by renin and then peptidyl dipeptidase (kinase 11)... 

Lowers blood pressure in hypertensive patients by inhibition of peptidyl dipeptidase... 

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. 

Peptidyl-dipeptidase A 3.4.15.1 Lung, kidney, vascular wall... 

Membrane alanyl aminopeptidase (microsomal aminopeptidase, amino-peptidase M, EC 3.4.11.2) and peptidyl-dipeptidase A (angiotensin I converting enzyme, EC 3.4.15.1) located in the vascular endothelium and smooth muscle cell surface modulate the levels of vasoactive peptides [23], One of the roles of membrane-bound enzymes is to switch off the action of peptides in the vicinity of the target or to prevent them from gaining access to a region containing receptors that are activated only by locally released peptides. 

Peptidyl-dipeptidase A (angiotensin-I converting enzyme, ACE, EC 3.4.15.1) plays a pivotal role in the control of blood pressure [80]. It has been established that its active site contains an essential Zn-atom that functions like that of carboxypeptidase A [2], ACE is inhibited by peptides having a proline or aromatic amino acid at the C-terminal position. These observations as well as the similarities with the active site of carboxypeptidase A have allowed a rational design of effective inhibitors of ACE (e.g., captopril (3.4) and enalapril (3.5)) used in the treatment of hypertension [81]. 

Bradykinin (Fig. 6.34) is a vasoactive nonapeptide that is hydrolyzed by a variety of peptidases. Its N-terminus is susceptible to cleavage, but only by aminopeptidase P (X-Pro aminopeptidase, EC 3.4.11.9). Dipeptidyl-pepti-dase IV can then cleave the N-terminus dipeptide of bradykinin-(2-9). However, most cleavage reactions have been found to occur at or close to the C-terminus, with angiotensin-converting enzyme (ACE, peptidyl-dipeptidase A, EC 3.4.15.1) playing an important role. In fact, aminopeptidase P and ACE accounted for ca. 30 and 70%, respectively, of total bradykininase activity in the isolated perfused rat heart [164], As shown in Fig. 6.34, ACE... 

In another series of investigations, [D-Ala6]LHRH was incubated with various cell types and found to have a rate of hydrolysis 3-8 times lower than that of LHRH [174][176], The use of enzyme inhibitors showed [d-Ala6]LHRH to be resistant to the endopeptidases neprilysin and thimet olig-opeptidase, but to remain sensitive to the peptidyl-dipeptidase ACE. 

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

ACE (peptidyl dipeptidase, EC 3.4.15.1), known to catalyse the hydrolysis of dipeptides from the C-terminus of pol)rpeptides, belongs to a family of zinc metalloproteinases, which require a zinc atom in the active site. In these... 

This lysosomal enzyme [EC 3.4.22.1], also known as cathepsin Bl, is a member of the peptidase family Cl. The catalyzed reaction is the hydrolysis of peptide binds with a broad specificity. The enzyme prefers the ArgArg—Xaa bond in small peptide substrates (thus distinguishing this enzyme from cathepsin L). The enzyme also exhibits a peptidyl-dipeptidase activity, releasing C-terminal dipeptides from larger polypeptides. 

The kallikrein-kinin system. Kininase II is identical to converting enzyme peptidyl dipeptidase (ACE). 

The angiotensin I-converting enzyme (ACE), designated peptidyl-dipeptidase A (E.C.3.4.15.1), is identical to the bradykinin-metabolizing enzyme kininase II (38). Its early history and initial characterizations have been reviewed (51-54). It was discovered by Skeggs and co-workers (55), and in their pioneering work they showed it to be inhibited by ethylene-diaminetetraacetic acid (EDTA) (37), to remove a dipeptide from the carboxyl terminus of angiotensin I (then called hypertensin I [56]) and to be activated by sodium chloride (55). The fact that ACE is a Zn2+-contain-ing peptidase was first reported by Das and Sofler in 1975 (57). 

Wade et al. reported the use of a novel statistical approach for the comparison of analytical methods to measure angiotensin converting enzyme [peptidyl-dipeptidase A] activity, and to measure enalaprilat and benazeprilat [8]. Two methods were used to measure peptidyl-dipeptidase A, namely hippuryl histidyl leucine (HHL-method) [9], and inhibitor binding assay (IBA method) [10]. Three methods were used to measure enalaprilat, namely a radioimmunoassay (RIA) method [11], the HHL method, and the IBA method. Three methods were used to measure benazeprilat (then active metabolite of benazepril) in human plasma, namely gas chromatography-mass spectrometry (GC-MS method) [12], the HHL method, and the IBA method, and were statistically compared. First, the methods were compared by the paired t test or analysis of variance, depending on whether two or three different methods were under comparison. Secondly, the squared coefficients of variation of the... 

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