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J. Biol. Chem., Vol. 283, Issue 12, 7853-7863, March 21, 2008

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Activation of Complement Component C5

COMPARISON OF C5 CONVERTASES OF THE LECTIN PATHWAY AND THE CLASSICAL PATHWAY OF COMPLEMENT^*

From the Department of Biochemistry, University of Texas Health Science Center, Tyler, Texas 75708

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_ManM1,C4b,C2a) exhibited a similar but weak affinity for the substrate, C5 indicated by a high K_m (2.73-6.88 µM). 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 µM) well below the normal concentration of C5 in blood (0.37 µM). 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.

Received for publication, September 11, 2007 , and in revised form, December 5, 2007.

^* This work was supported by National Institutes of Health Grant HL-073804 (to N.R.). N. R. is an officer and has a financial interest in Complement Technology, a supplier of complement reagents. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biochemistry, 11937, US Highway 271, Tyler, TX 75708-3154. Tel.: 903-877-5840; Fax: 903-877-5882; E-mail: nenoo.rawal{at}uthct.edu.

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