Kallikreins

Kallikreins are a subgroup of the serine protease enzyme family, three of which have been assigned a specific biological role. 

The human kallikrein (hK) gene locus spans a region of approximately 300kb of chromosome 19ql3.4, which 

Reverse transcription-polymerase chain reaction (RT-PCR), northern and western blotting, and immunoassays have been used for detection of kallerin mRNA and protein in tissue extracts of ovarian, breast, testicular, and prostate tumors. Immunohistochemical techniques have been used for the detection of KLK7 in ovarian tumors and KLKIO in ovarian and testicular tumors. The serum levels of KLK3 (PSA) and KLKll are evaluated by immunoassay. 

PSA is one of the most promising tumor markers of this decade. It is one of the few organ-specific tumor markers. Prostate cancer is the leading cancer in older men. When detected early (organ confined), it is potentially curable by radical prostatectomy. Therefore early detection is important. The role of PSA in prostate cancer has been reviewed.  

PSA was discovered by Kara and colleagues in 1971. They called this seminal plasma protein y-seminoprotein. Li and BeUng isolated the same protein from seminal plasma and called it protem El because it has a slow (3-mobility in electrophoresis and a molecular weight (MW) of 31,000. In 

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Dennis, M.S., Herzka, A., Lazarus, R.A. Potent and selective Kunitz domain inhibitors of plasma kallikrein designed by phage display. /. Biol. Chem. 270 25411-25417, 1995. 

H-kininogen Plasma kallikrein bradykinin (RPPGFSPFR) B2 receptor... 

B2 knockout embryos subjected to salt stress in utero show suppressed renin expression and an abnormal kidney phenotype and develop early postnatal hypertension. Consistently, although basal bradykinin formation is defective tissue kallikrein-null mice have normal blood pressure however suffer from cardiovascular abnormalities. However suggesting a function of kinin signaling during development. 

In rare cases of a systemic release, kinins have the potential to cause severe hypotension. Uncontrolled activation of the contact system (Fig. 3) is thought to trigger a massive formation of kinins under certain pathological conditions [3]. For instance, this situation is seen in patients with underlying diseases such as systemic inflammatory response syndrome (SIRS) due to sepsis or trauma. SIRS progression is accompanied by depletion of contact system factors and low levels of H-kininogen and plasma kallikrein are indicative of a... 

Mahabeer R, Bhoola KD (2000) Kallikrein and kinin receptor genes. Pharmacol Ther 88 77-89... 

Blais Jr, Marceau F, Rouleau JL et al (2000) The kallikrein-kininogen-kinin system lessons from the quantification of endogenous kinins. Peptides 21 1903—1940... 

Pixley RA, Colman RW (1997) The kallikrein-kinin system in sepsis syndrome. In Farmer SG (ed) Handbook of immunopharmacology - the kinin system. Academic Press, New York, pp 173-186... 

PA S1 S01.162 Kallikrein hK3 Potential drug target for prostatic and other cancers... 

Kainate Receptor Kallidin, Lysyl-Bradykinin Kallikrein KCNQ-Channels KCOs... 

The various interactions of the constituents required for the formation of bradykinin are shown in figure 2. The initiating step is a slow autoactivation of factor XII [10]. However, once this has occurred and prekallikrein is converted to kallikrein, there is... 

HK it can interact with surface-bound factor XII on an adjacent particle thereby disseminating the reaction [25, 28]. As a result the effective kallikrein/factor XII ratio is increased in the presence of HK [25], Finally, in plasma, HK can displace other adhesive glycoproteins such as fibrinogen from binding to the surface [29]. In this sense, HK, like factor XII and prekallikrein, is also a coagulation cofactor because it is required for the generation of kalUkrein (a factor XII activator) as well as the activation of factor XI. 

An alternative pathway for activating the cascade has recently been demonstrated in which factor XII is absent from the reaction mixture [42-45]. Two different groups have isolated two different proteins, each of which seems to activate the HK-prekallikrein complex. One is heat-shock protein 90 [46] and the other is a prolylcarboxypeptidase [47]. Neither protein is a direct prekallikrein activator as is factor Xlla or factor Xllf because each activator requires HK to be complexed to the prekallikrein. In addition, the reaction is stoichiometric, thus the amount of prekallikrein converted to kallikrein equals the molar input of heat-shock protein 90 (or prolylcarboxypeptidase). These proteins can be shown to contribute to factor Xll-independent prekallikrein activation and antisera to each protein have been shown to inhibit the process. When whole endothelial cells are incubated with normal plasma or factor Xll-deficient plasma, the rate of activation of the deficient plasma is very much slower than that of the normal plasma, the latter being factor Xll-dependent [45]. Under normal circumstances (with factor XII present), formation of any kallikrein will lead to factor Xlla formation even if the process were initiated by one of these cell-derived factors. 

Factor Xlla converts prekallikrein to kallikrein and kallikrein cleaves HK to generate bradykinin. There is also an important positive feedback in the system in which the kallikrein generated rapidly converts unactivated factor XII to activated factor XII, and the rate of this reaction is hundreds of times faster than the rate of autoactivation [11]. Therefore, much of the unactivated factor XII can be cleaved and activated by kallikrein. Cl inhibitor inhibits all functions of factor Xlla and it is one of two major plasma kallikrein inhibitors. Thus all functions of kallikrein are also inhibited, including the feedback activation of factor XII, the cleavage of HK, and the activation of plasma pro-urokinase [66] to lead to plasmin formation. Cl inhibitor also inhibits the fibrinolytic enzyme plasmin, although it is a relatively minor inhibitor compared to a2-antiplasmin or a2-macroglobulin. 

Mori K, Nagasawa S Studies on human high molecular weight (HMW) kininogen. If. Structural change SS of HMW kininogen by the action of human plasma kallikrein. J Biochem 1981 89 1465-1473. 

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