Kininases

Structure and function of human plasma carboxypeptidase N, the anaphylatoxin inactivator

“…(Subsequent research some 2 decades later led to the discovery of a second kinin B 1 receptor activated by the carboxypeptidase metabolite that is its endogenous agonist -see below). Initially it was assumed that the enzyme represents a circulating form of pancreatic carboxypeptidase B, but this was disproved by the characterization of its enzymatic properties [5][6][7][8], which was later borne out by biochemical studies, sequence analysis [9][10][11][12][13][14][15] and ultimately X-ray crystallography [16]. To differentiate it from the pancreatic enzyme, it was named carboxypeptidase N (CPN; EC 3.4.17.3) and was the first member of a family of carboxypeptidases now known as the regulatory or CPN/E subfamily of metallocarboxypeptidases [17][18][19].…”

“…CPN is synthesized by the liver and secreted into the blood where its concentration is high, approximately 30 μg/ml ( 10 −7 M) [8,31]. As determined by Northern analysis (Tan and Skidgel, unpublished)[32], the liver is its only site of synthesis, however, only low levels of CPN can be extracted from the organ itself [9].…”

“…CPN contains zinc as a required cofactor, thus it is inhibited by chelating agents such as EDTA and o-phenanthroline [6,8,53]. Replacement of Zn ++ in the active center by Co ++ activates CPN by about 2 to 6-fold at neutral pH depending on the substrate [41,[53][54][55].…”

“…To differentiate it from the pancreatic enzyme, it was named carboxypeptidase N (CPN; EC 3.4.17.3) and was the first member of a family of carboxypeptidases now known as the regulatory or CPN/E subfamily of metallocarboxypeptidases [17][18][19]. It has since been re-discovered many times as other substrates were found and so has acquired aliases such as creatine kinase conversion factor, plasma carboxypeptidase B, arginine carboxypeptidase, lysine carboxypeptidase and protaminase [8,17,20,21]. The most notable was the finding by Bokisch and Müller-Eberhard in 1969 -70 [22,23] that the human plasma "anaphylatoxin inactivator" is identical with CPN.…”

“…CPN carries out this reaction in vivo as the concentration of des-Arg 9 -bradykinin in human blood is 3-fold higher than that of bradykinin itself [58]. Although CPN contributes in vivo to the degradation of circulating kinins, this pathway is secondary to kinin hydrolysis by angiotensin I converting enzyme (ACE) on pulmonary vascular and other endothelial cells [8].Consequently, CPN activity takes on added significance in patients receiving ACE inhibitors. Because peptide hormones like kinins are primarily autocrine or paracrine hormones and their sites of action are restricted to a small local area, the levels of circulating peptides are likely to represent "spillover" of peptides generated at local sites.…”