gens (HK and LK). Their processing by plasma and tissues serine proteases Klkb1 and Klk1, respectively, gives rise to two active peptides: the nonapeptide bradykinin (BK) and the decapeptide kallidin (KD). The two enzymes are known as kallikreins. Further C-terminal processing of these peptides by carboxypeptidase M (Cpm) and N (Cpn1) gives rise to the des-Arg metabolites. Other kinin metabolites are also produced but so far, they have only been reported in rat. The plasma kallikrein Klkb1, is secreted from the liver as an inactive prekallikrein which circulates bound to HK and whose activation is carried out by an activated factor XII, known as Hageman factor - F12a. The contact of plasma with a negative surface leads to binding and autoactivation of F12 which in turn activates prekallikrein - a first step in the kallikrein-kinin cascade and also in the coagulation cascade. F12a can also stimulate the classical complement pathway. Active Klkb1 cleaves HK in a two-step reaction to produce BK. It also further activates F12 whose initial conformational changes induced by contact only produce small amounts of F12a, thus providing a positive feedback loop. Prolylcarboxypeptidase (Prcp) can also activate prekallikrein, in addition to other substrates. Several inhibitors of F12 and Blkb1 are known with Serping1, known as C1INH being the principal regulator. Serping1 and alpha2-macroglobulin (A2m), account for more than 90% of Klkb1 inhibitory activity. The tissue kallikrein Klk1 is widely distributed and while it primarily cleaves LK to form KD, it may also cleave HK. The regulatory mechanisms of tissue kallikrein are less well characterized; Serpina4, known as kallistatin and found in several tissues and cell types, is a Klk1 inhibitor. The peptides are metabolized to inactive compounds by several kininases of which some are shared with the renin-angiotensin system, such as Ace and Mme. There, they act as angiotensinases converting the inactive angiotensin I to the potent AgtII and to Agt1-7, respectively. In the kallikrein-kinin system the enzymes act as kininases. Others include aminopeptidase P which has both a soluble (Xpnpep1) and a membrane-bound (Xpnpep2) form and both can hydrolyze the kinins to inactive metabolites. The human cytoplasmic XPNPEP1 uses Mn2+ at the active site, whereas the membrane-bound XNPEP2 uses Zn2+. Zn2+, used by most other proteases, inhibits XPNPEP1. Two bradykinin receptors - Bdkrb1 and Bdkrb2 - convey the signals of active kinins. Both receptors are G-protein coupled (GPCR) that stimulate phospholipase activity, increase intracellular calcium concentration and prompt the release of several compounds such as nitric oxide, arachidonic acid, prostaglandins and other inflammatory mediators. Of the two receptors, receptor type 2 is ubiquitously expressed and type 1 is inducible. BK and KD are the agonists of receptor type 2; the carboxy-terminal derived des-Arg peptides are the agonists of receptor type 1. Several antagonists have been developed for both receptors; first generation and second generation antagonists and third generation non-peptides compounds. Other kinin antagonists have been discovered as natural compounds. To see the ontology report for Gviewer, annotations and download, click here....(less)