HMWK is produced by the liver together with prekallikrein. It acts mainly as a cofactor on coagulation and inflammation, and has no intrinsic catalytic activity.
LMWK is produced locally by numerous tissues, and secreted together with tissue kallikrein.
Polypeptides
Bradykinin, which acts on the B2 receptor and slightly on B1, is produced when kallikrein releases it from HMWK. It is a nonapeptide with the amino acid sequence Arg–Pro–Pro–Gly–Phe–Ser–Pro–Phe–Arg.
Kallidin is released from LMWK by tissue kallikrein. It is a decapeptide. KD has the same amino acid sequence as Bradykinin with the addition of a Lysine at the N-terminus, thus is sometimes referred to as Lys-Bradykinin.
Kallikreins are serine proteases that liberate kinins from the kininogens, which are plasma proteins that are converted into vasoactive peptides. Prekallikrein is the precursor of plasma kallikrein. It can only activate kinins after being activated itself by factor XIIa or other stimuli.
Carboxypeptidases are present in two forms: N circulates and M is membrane-bound. They remove arginine residues at the carboxy-terminus of BK and KD.
Angiotensin converting enzyme, also termed kininase II, inactivates a number of peptide mediators, including bradykinin. It is better known for activating angiotensin.
Inhibition of ACE with ACE inhibitors leads to decreased conversion of angiotensin I to angiotensin II but also to an increase in bradykinin due to decreased degradation. This explains why some patients taking ACE inhibitors develop a dry cough, and some react with angioedema, a dangerous swelling of the head and neck region. There are hypotheses that many of the ACE-inhibitors' beneficial effects are due to their influence on the kinin-kallikrein system. This includes their effects in arterial hypertension, in ventricular remodeling and possibly diabetic nephropathy.
Role in disease
Defects of the kinin-kallikrein system in diseases are not generally recognized. The system is the subject of much research due to its relationship to the inflammation and blood pressure systems. It is known that kinins are inflammatory mediators that cause dilation of blood vessels and increased vascular permeability. Kinins are small peptides produced from kininogen by kallikrein and are broken down by kininases. They act on phospholipase and increase arachidonic acid release and thus prostaglandin production.
C1-inhibitor is a serine protease inhibitorprotein. C1-INH is the most important physiological inhibitor of plasma kallikrein, fXIa and fXIIa. C1-INH also inhibits proteinases of the fibrinolytic, clotting, and kinin pathways. Deficiency of C1-INH permits plasma kallikrein activation, which leads to the production of the vasoactive peptide bradykinin.
