Activation of complement component C5: comparison of C5 convertases of the lectin pathway and the classical pathway of complement.
Although the initiating complex of lectin pathway (called M1 in this study) generates C3/C5 convertases similar to those assembled by the initiating complex (C1) of the classical pathway, activation of complement component C5 via the lectin pathway has not been examined. In the present study kinetic analysis of lectin pathway C3/C5 convertases assembled on two surfaces (zymosan and sheep erythrocytes coated with mannan (E(Man))) revealed that the convertases (ZymM1,C4b,C2a and E(Man)M1,C4b,C2a) exhibited a similar but weak affinity for the substrate, C5 indicated by a high K(m) (2.73-6.88 microm). Very high affinity C5 convertases were generated when the low affinity C3/C5 convertases were allowed to deposit C3b by cleaving native C3. These C3b-containing convertases exhibited K(m) (0.0086-0.0075 microm) well below the normal concentration of C5 in blood (0.37 microm). Although kinetic parameters, K(m) and k(cat), of the lectin pathway C3/C5 convertases were similar to those reported for classical pathway C3/C5 convertases, studies on the ability of C4b to bind C2 indicated that every C4b deposited on zymosan or E(Man) was capable of forming a convertase. These findings differ from those reported for the classical pathway C3/C5 convertase, where only one of four C4b molecules deposited formed a convertase. The potential for four times more amplification via the lectin pathway than the classical pathway in the generation of C3/C5 convertases and production of pro-inflammatory products, such as C3a, C4a, and C5a, implies that activation of complement via the lectin pathway might be a more prominent contributor to the pathology of inflammatory reactions.
Rawal
Nenoo
N
Department of Biochemistry, University of Texas Health Science Center, Tyler, Texas 75708, USA. nenoo.rawal@uthct.edu
Rajagopalan
Rema
R
Salvi
Veena P
VP
D000818:Animals; D002645:Chickens; D003175:Complement C2 / Q000378:metabolism; D050577:Complement C3-C5 Convertases / Q000378:metabolism*; D003179:Complement C3b / Q000378:metabolism; D015935:Complement C4b / Q000378:metabolism; D003182:Complement C5 / Q000378:metabolism*; D003171:Complement Pathway, Classical / Q000187:drug effects / Q000502:physiology*; D037582:Complement Pathway, Mannose-Binding Lectin / Q000187:drug effects / Q000502:physiology*; D004912:Erythrocytes / Q000201:enzymology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D012756:Sheep; D015054:Zymosan / Q000494:pharmacology
D003175:Complement C2; D003182:Complement C5; D018836:Inflammation Mediators; D003179:Complement C3b; D015935:Complement C4b; D015054:Zymosan; D050577:Complement C3-C5 Convertases