Human plasma kallikrein: roles in coagulation, fibrinolysis, inflammation pathways, and beyond

Abstract

Human plasma kallikrein (PKa) is obtained by activating its precursor, prekallikrein (PK), historically named the Fletcher factor. Human PKa and tissue kallikreins are serine proteases from the same family, having high- and low-molecular weight kininogens (HKs and LKs) as substrates, releasing bradykinin (Bk) and Lys-bradykinin (Lys-Bk), respectively. This review presents a brief history of human PKa with details and recent observations of its evolution among the vertebrate coagulation proteins, including the relations with Factor XI. We explored the role of Factor XII in activating the plasma kallikrein–kinin system (KKS), the mechanism of activity and control in the KKS, and the function of HK on contact activation proteins on cell membranes. The role of human PKa in cell biology regarding the contact system and KSS, particularly the endothelial cells, and neutrophils, in inflammatory processes and infectious diseases, was also approached. We examined the natural plasma protein inhibitors, including a detailed survey of human PKa inhibitors’ development and their potential market.

Selective Detection of Active Extracellular Granzyme A by Using a Novel Fluorescent Immunoprobe with Application to Inflammatory Diseases

“…As shown in Figure B, there was a significant difference in probe-1 activity in WT and GzmA KO mice, although the differences were less pronounced than in the case of tissue/cell samples (5A) suggesting the presence of other proteases in serum that could process probe-1. This result agrees with our data showing that probe-1 is also cleaved by proteases like plasmin, trypsin, and kallikrein all of which have been shown to be released in serum during inflammatory processes. − …”

Unveiling Therapeutic Frontiers: DON/DRP-104 as Innovative Plasma Kallikrein Inhibitors Against Carcinoma-Associated Hereditary Angioedema Shocks - A Comprehensive Molecular Dynamics Exploration

“…These functions collaboratively modulate the proteolytic activity of PKa [3,4]. The key function of PKa lies in releasing kinins, specifically bradykinin (Bk) and Lys-bradykinin (Lys-Bk), from high-molecular-weight kininogens (HKs) and low-molecular-weight kininogens (LKs), respectively [5,6]. The C1 inhibitor (C1-INH) is a crucial regulator in controlling the physiological activity of plasma kallikrein.…”

“…This process is essential for maintaining the balance of the kallikrein-kinin system (KKS) and preventing unwanted inflammation or other physiological effects associated with elevated bradykinin levels. Additionally, other circulating inhibitors like α2-macroglobulin and antithrombin III also contribute to the regulation of PKa activity [5,7]. Upon bradykinin release, the activation of bradykinin receptors (B1R and B2R) initiates intracellular signaling cascades, resulting in increased calcium levels, the release of various mediators, and physiological responses, including inflammation, vasodilation, and pain.…”

“…Management of HAE involves targeting PKa effects, with PKa inhibitors serving as the primary on-demand first-line drug agents [2,8,9]. Besides targeting HAE, PKa inhibitors are under development for the treatment of uncontrolled PKa related conditions, such diabetic retinopathy, macular edema, and sepsis [5,10]. Presently, ecallantide [11], lanadelumab [12], and berotralstat [13] are the Food and Drug Administration (FDA)-approved PKa inhibitor drugs for managing Hereditary Angioedema (HAE).…”