Kininogen

Kininogen is a family of plasma glycoproteins that serve as precursors to kinins in the kallikrein-kinin system. In humans, the two main forms are high-molecular-weight kininogen (HMWK) and low-molecular-weight kininogen (LMWK). These proteins are synthesized mainly by the liver and circulate in the blood, where they act as substrates for kallikrein and are involved in contact activation on endothelial or other surfaces.

Activation of the contact system, often initiated by factor XIIa on damaged endothelium or collagen, leads kallikrein to cleave kininogens to release kinins. HMWK yields bradykinin, a nonapeptide, while LMWK yields kallidin (lys-bradykinin); kallidin can be shortened to bradykinin by aminopeptidases. Kinins exert their effects primarily via the B2 receptor, causing vasodilation, increased vascular permeability, and pain; B1 receptors mediate effects during inflammation.

Physiological and clinical relevance: The kinin–kallikrein system contributes to inflammatory responses, blood pressure regulation, and coagulation cross-talk. Dysregulation can cause hereditary angioedema due to excessive bradykinin. Inhibitors of angiotensin-converting enzyme (ACE) can raise bradykinin levels, sometimes triggering cough or angioedema. Kininogens are also used as substrates in laboratory assessments of the contact system.

Structure and properties: Kininogens are large secreted glycoproteins with several repeating domains. HMWK can bind prekallikrein and platelets and participates in surface-based activation; LMWK is derived from the same precursor proteins and shares sequence elements. The kininogens serve as storage pools for kinins and regulatory cofactors in vascular and inflammatory processes.