Kinin structures

In their initial studies on the effects of vasoactive peptides on mast-cell secretion, Johnson and Erdos [31] concluded that the ability of peptides to elicit a secretory response from mast cells depended upon the number of basic groups a peptide contained, and not on the structure of the N-terminal or C-terminal amino acids per se. They found, for example, that Polistes kinin, with... 

The pathway for the formation and metabolism of kinins is shown in Figure 17-4. Three kinins have been identified in mammals bradykinin, lysylbradykinin (also known as kallidin), and methionyllysylbradykinin. Each contains bradykinin in its structure. 

Overall, the kinins are an important part of a well-organized physiological system. The various aspects and interdependencies of the kinin system have been, and continue to be, the focus of intensive research efforts in many laboratories. Many pharmaceutical companies have identified this system as an ideal site for therapeutic intervention in many inflammatory diseases. Hence, there have been many diverse approaches taken toward the discovery of antagonists (peptide and nonpeptide) of B2 and B1 receptors. This review focuses on the structure-based design strategies pursued in our laboratories during the past several years. 

There have been a variety of single alanine point mutations experimentally introduced into both rat and human bradykinin B2 receptors. Several of these have been shown to decrease the affinity of bradykinin to the receptor and have been implicated structurally near the agonist binding site. In contrast, at the time of this manuscript, there have been no mutations reported that adversely affect the ability of any peptide antagonists to bind to the receptor. Furthermore, antibodies raised against the certain extracellular domains of the kinin receptor compete with bradykinin for binding to the receptor but have no inhibitory... 

It has been suggested that y-turns are present in the solution structures of several peptides, and furthermore implicated in their bioactive conformations 101 including brady-kinin, 111 substance P,1121 cyclic somatostatin analogues, 131 cyclolinopeptide, 141 and the 6-opioid receptor bound conformation of enkephalin. 151 Yet, despite the fact that y-tums are frequently hypothesized to represent important features of secondary structure 161 based upon computational,1171 IR absorption,1181 NMR spectroscopic,119 201 and X-ray diffraction crystallographic determinations,1211 verification of the role of this predicted secondary structural element remains a difficult, but nonetheless critical step. 

Note that each kinin contains bradykinin in its structure. Each kinin is formed from a kininogen by the action of a different enzyme. Bradykinin is released by plasma kallikrein, lysylbradykinin by glandular kallikrein, and methionyllysylbradykinin by pepsin and pepsin-like enzymes. The three kinins have been found in plasma and urine. Bradykinin is the predominant kinin in plasma, while lysylbradykinin is the major urinary form. 

Chatterjee, C. and Mukhopadhyay, C. (2005) Interaction and structural study of kinin peptide bradykinin and ganglioside monosialylated 1 micelle. Biopolymers 78, 197-205. 

A vasodilating peptide with smooth-muscle stimulating action was described by Rocha e Silva, Beraldo and Rosenfeld in 1949 and named bradykinin. It is produced by the action of trypsin or snake venoms on plasma. A similar substance, kallidin, was prepared shortly afterwards by Werle and Berek using the protease kalUkrein. Other peptides with similar properties have been described and the general term kinins or, when derived from plasma proteins, plasma kinins has been recommended. The best-known kinin, bradykinin, has recently been shown to be a nonapeptide, and its structure confirmed by synthesis - . When injected subcutaneously into laboratory animals and man, bradykinin causes vasodilatation, increased vascular permeability, leucocyte infiltration and pain. 

The (myo) kinin family of peptides is especially a very interesting one, because its members have two very different functional activities in insects. The first members of this family were originally isolated on the basis of stimulation of the cockroach hindgut in vitro from extracts of whole heads of L. maderae [151]. This species contains 8 isoforms of kinins. Shortly after their first isolation, it was reported that these kinins also stimulate diuretic activity of isolated Malpighian tubules of the yellow fever mosquito Aedes aegypti [175], This function of kinins has now been shown regularly in conspecific diuretic assays with a number of other insect species. To date, the structure of kinins (see Table 5) have been fully elucidated in insects from the American cockroach (8 isoforms), the house cricket, Acheta domesticus (5 isoforms), the migratory locust (1 isoform), the mosquitoes, Culex salinarius and A. 

Insect diuretic peptides, two structurally distinct families of diuretic peptides (DP) that stimulate primary urine production by insect Malpighian tubules and regulate water loss from the excretory system. CRH-related diuretic peptides and insect kinins have been found in a number of species, and they may be ubiquitous in insects. CRH-related diuretic peptides belong to the vertebrate CRH/sauvagine/urotensin I/urocortin... 

D.F. Elliott, G.P. Lewis, E.W. Horton, The structure of bradykinin—a plasma kinin from ox blood. Biochem. Biophys. Res. Commun. 3 87-91 (1960)... 

Another possible function of C2 is in relation to the liberation of a kinin mediator (C-kinin) in the serum of patients with HANE (Donaldson et aL, 1969, 1970). It was found that HANE results from a severe deficiency of the Cl-INH protein or from structurally abnormal and functionally inactive Cl-INH (Donaldson et aL, 1963 Harpel et al, 1975). Thus activated Cl is increased in the serum of these patients, and on incubation a dialyzable and heat-stable mediator is released which increases vascular permeability and contracts smooth muscle without causing tachyphylaxis. The activity was inactivated by carboxypeptidase B and, unlike bradykinin, by trypsin, suggesting that the active principle is a polypeptide distinct from bradykinin, C3a and C5a anaphylatoxins (Donaldson et al, 1969). The liberation of this activity required Ci, C4, and C2 and was inhibited by added Cl-INH or antiserum to C4 or C2 but not by anti-C3 (Donaldson et al, 1969, 1970). In addition, the active principle was detected in the incubation mixture of refined ( s, C4, and C2 (Klemperer et al, 1969). Intradermal injection of active Cls increased vascular permeability in normal but not in C2-deficient patients (Klem-... 

Kinins have been classified as hypotensive peptides resembling bradykinin in both structure and pharmacologic activity (1). 

Figure 1. Chemical structure of kinins isolated from plasma.

The chemical structures of bradykinin, kallidin and methionyl-lysyl-brady-kinin ( = methionyl-kallidin) are shown in Figure 6. 

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