Factor D is a trypsin-like serine protease that cleaves only one substrate, namely, complement factor B. Furthermore, it only cleaves factor B when that protein is bound to a cofactor such as C3b, C3(H2O), or cobra venom factor. For further details about its function see the General Description above and Assays below.
The alternative pathway cannot activate without factor D and much pathological damage is done by primary or secondary activation of the alternative pathway of complement. Therefore, pharmaceutical companies have investigated various drugs to inhibit it. Due to the distorted active site, except when bound to it substrate, effective small molecule inhibitors have not yet been found. However, humanized anti-factor D is under investigation and has the advantage that very low plasma concentration of factor D requires little antibody. On the other hand, the high biosynthetic rate may need to be overcome with excess drug (see In vivo section below).
Serum concentration of factor D has been reported to be between 1 and 2 µg/mL and Biohub and others have determined 1.4 µg/mL to be closest to the normal concentration in human serum. Factor D is a trypsin-like serine protease that circulates in its activated form without its activation peptide, however, as mentioned above its proteolytic activity is substrate-induced. It is synthesized in the expressed in the kidney, adipocytes, and macrophages. Its primary site of synthesis appears to be adipose tissue and it is also known as adipsin. Adipsin is thought to also be involved in fat metabolism. Factor D is made as a zymogen that is apparently activated only by MASP-1 (Takahashi, M. et al. (2010)). MASP-1 deficient mice lack a functional alternative pathway and factor D was found to be circulating in zymogen form with its activation peptide still attached. Restoration of alternative pathway function in these mice was achieved with addition of MASP-1.