Trypsinlike serine protease

Activated Clr (often designated Clr but here and in Fig. 31-8 as Clr) is one of five different serine proteases involved in activation of complement.156 The substrate for the trypsinlike Clr is Cls, a proenzyme which is converted by the action of Clr into another trypsinlike serine protease Cls.157 160 Through a rather elaborate cascade mechanism, depicted in Fig. 31-8, the important proenzyme C2 is activated.161 Its active form C2a is a serine protease, which cleaves proteins C3 and C5 to the active forms C3b and C5b. Protein C4 is also cleaved to C4b by activated Cl. C4 and C3 are also activated, and protein C5 is cleaved... 

Studies on acylation and deacylation of trypsinlike enzymes by nophenyl eaters of substituted benzoic acids have shown (hat the rate of descylstion is influenced by the benzoic acid substituent. There is a linear correlation between the rate of deacylation and the inductive effect of the substituent (Fig. 3). This is also true of all trypsinlike serine proteases tested. However, the... 

Presumably, this concept of acy latcd enzymes may well be applied to further therapeutically interesting trypsinlike serine proteases. The pharmacological investigation into acylated enzymes has shown that, compared to the nonacylated enzymes, such preparations may well provide some advantages. 

Reaction at active site histidine residues of trypsinlike serine proteases. 

Figure 2 shows hydrolysis of an ester of /r-amidinophenol by trypsinlike enzymes. Deacylation is much slower than acylation, and accumulation of the acyl enzyme occurs. For preparation of a wide range of acyl derivatives of serine proteases, this type of substrate has become increasingly important. 

Isatoic anhydride (Fig. 45) is an example of a compound which inactivates serine proteases by formation of a stable acyl enzyme. Chymotrypsin is stoichio-metrically modified by isatoic anhydride with the incorporation of one anthrani-loyl group, as indicated by the absorbance spectrum of the derivatized enzyme (Moorman and Abeles, 1982). The anthraniloyl moiety is proposed to result from acylation of the active site serine followed by decarboxylation of the resulting carbamate (Fig. 45). The inactivation is irreversible by virtue of the electron-donating effect of the amino substituent of the benzoyl group, which is known to decrease dramatically the rate of deacylation of benzoylchymotrypsin (Caplow and Jencks, 1962). Substitution of the isatoic anhydride nucleus results in increased selectivity for trypsinlike proteases over chymotrypsin (Gelb and Abeles, 1986). 

---