Table 2.
Enzymatic interactions between the RAS, the complement system and the KKS
| Enzyme | RAS | Complement system | KKS | |||
|---|---|---|---|---|---|---|
| Forms | Cleaves | Forms | Cleaves | Forms | Cleaves | |
| Renin | Ang I (ref.4) | – | C3b, C3a111 | – | – | – |
| ACE | Ang I (ref.240) | Ang I (ref.4) | – | – | – | BK39,53 |
| Ang II (ref.4) | Ang 1–9 (ref.92) | KD53 | ||||
| Ang 1–7 (ref.92) | Ang 1–7 (ref.92) | DABK53 | ||||
| Ang 1–12 (ref.4) | DAKD53 | |||||
| ACE2 | Ang 1–9 (ref.1) | Ang I (ref.1) | – | – | – | DABK170,171 |
| Ang 1–7 (ref.1) | Ang II (ref.1) | DAKD170 | ||||
| Alamandine1 | Ang A1 | |||||
| Chymase | Ang II (ref.1) | Ang I (ref.4) | – | – | – | BK241 |
| Ang 1–12 (ref.242) | KD241 | |||||
| NEP | Ang 1–7 (ref.243) | Ang I (ref.186) | – | – | – | BK, KD244 |
| Ang 1–9 (ref.92) | DABK230 | |||||
| DAKD245 | ||||||
| THOP | Ang 1–7 (ref.92) | Ang I (ref.92) | – | – | – | BK246 |
| PRCPa | Ang 1–7 (ref.247) | Ang II (ref.247) | – | – | – | DABK248 |
| KLK | Ang II (refs249,250) | – | C3a251 | – | BK | HK53 |
| KD53 | ||||||
| PKab | – | – | C3b, C3a252,253 | – | BK3 | HK3 |
| FXIIac | – | – | – | C1r254 | – | – |
| APN | Ang IV (ref.92) | Ang III (ref.92) | – | – | BK53 | KD |
| DAKD53 | ||||||
| APP | – | – | – | – | – | BK |
| DABK104 | ||||||
| APA | Ang III (ref.104) | Ang II (ref.104) | – | – | – | |
| PEP | Ang 1–7 (ref.92) | Ang I (ref.92) | – | – | – | – |
| Ang II | ||||||
| Ang 1–9 (ref.92) | ||||||
| AD | Ang A92 | Ang II (ref.92) | – | – | – | – |
| Alamandine92 | Ang 1–7 (ref.92) | |||||
| CPMd | – | – | – | – | DABK | BK255 |
| DAKD53 | KD53 | |||||
| CPNd | – | – | – | C3a | DABK | BK256 |
| C5a257 | DAKD53 | KD53 | ||||
| TAFIad | – | – | – | C3a256,258 | DABK258 | BK256,258 |
| C5a258 | ||||||
| MASP1 | – | – | – | – | BK33 | HK33 |
AD, aspartate decarboxylase; Ang, angiotensin; ACE, angiotensin-converting enzyme; APA, aminopeptidase A; APN, aminopeptidase N; APP, aminopeptidase P; BK, bradykinin; CPM, carboxypeptidase M; CPN, carboxypeptidase N; DABK, desArg9-bradykinin; DAKD, desArg10-kallidin; FXIIa, activated factor XII; HK, high-molecular-weight kininogen; KD, kallidin; KKS, kallikrein–kinin system; KLK, tissue kallikrein; MASP1, mannan-binding lectin serine protease 1; NEP, neprilysin; PEP, prolylendopeptidase; PKa, plasma kallikrein; PRCP, prolylcarboxypeptidase; RAS, renin–angiotensin system; TAFIa, activated thrombin-activatable fibrinolysis inhibitor (also known as carboxypeptidase U or carboxypeptidase B2); THOP, thimet oligopeptidase. aPRCP activates plasma prekallikrein to plasma kallikrein and also degrades Ang II to Ang 1–7. bIn addition to cleaving high-molecular-weight kininogen, releasing bradykinin domain 4, plasma kallikrein also cleaves C3 into C3b, and possibly even factor B into Bb253, thereby activating the alternative pathway of the complement system to form the C3 convertase. cFXIIa converts plasma prekallikrein to plasma kallikrein and thereby releases bradykinin in the fluid phase37, while it can also initiate complement activation by cleavage of C1r. dC3a and C5a are degraded by CPN and by TAFIa. TAFIa and CPN remove the carboxy-terminal arginine to form the desArg derivate of C3a and C5a. Both TAFIa and CPN cleave the Arg residue off bradykinin while generating the B1 receptor agonist desArg9-bradykinin. Similarly, CPM can digest carboxy-terminal Arg residues of kinins.