CFD

CFD Full Name

complement factor D (adipsin)

CFD Introduction

CFD encodes complement factor D, a serine protease that occupies a unique and rate-limiting position in the alternative pathway of complement activation. The complement system is a cascade of proteases that tags and destroys microbes, clears debris, and amplifies inflammation, and the alternative pathway is the branch that is constitutively active and can be triggered by virtually any foreign or altered surface. Factor D is the enzyme that cleaves factor B after it has bound to C3b on an activating surface, generating the C3 convertase that amplifies the cascade; because factor D circulates at very low concentrations and its substrate is only presented in the context of an assembled complex, factor D is the bottleneck that controls the pace of alternative pathway activation. CFD is also famous in endocrinology as the gene for adipsin, an adipocyte-derived factor whose messenger RNA was found to be markedly reduced in the fat tissue of obese animals, providing some of the earliest evidence that adipose tissue is an endocrine organ. This dual identity links the innate immune system to systemic metabolism, and factor D activity has been implicated both in inflammatory diseases driven by excessive complement activation and in the metabolic complications of obesity. Because of its gatekeeper role, factor D has become a target for therapeutic inhibition in diseases such as paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome, and orally available factor D inhibitors have been developed and evaluated clinically.

Figure 1. The structure of CFD.

Serine Protease Structure and Catalytic Mechanism
Factor D is a small serine protease of the chymotrypsin family, and it is among the smallest of the complement proteases.
The protein is synthesized as a zymogen and is activated by cleavage, which removes a short activation peptide and generates the mature enzyme with its characteristic catalytic triad of histidine, aspartate, and serine residues.
Factor D adopts the canonical two-beta-barrel fold of trypsin-like serine proteases, with the active site located in the cleft between the two barrels.
Unlike many complement proteases that are large and heavily regulated by inhibitors, factor D circulates in an essentially active but weakly catalytic form, and its activity is controlled less by conformational switching than by the availability of its macromolecular substrate.
The substrate of factor D is factor B, but factor D only cleaves factor B after factor B has bound to C3b and undergone a conformational change that exposes the cleavage site.
This requirement for a pre-assembled complex ensures that factor D acts selectively on surfaces where complement activation is already underway, providing tight spatial control of the cascade.
The CFD gene is located on human chromosome 19, within a cluster that also contains genes of the complement and immune systems.

Complement Regulation, Immune Defense, and Therapeutic Inhibition
Factor D-mediated cleavage of factor B generates the alternative pathway C3 convertase, which amplifies complement activation and leads to the opsonization and lysis of target cells and to the generation of inflammatory mediators.
Because factor D is present at very low concentrations and is not consumed stoichiometrically during the reaction, it acts as the rate-limiting enzyme of the alternative pathway, and small changes in its activity translate into large changes in complement output.
Excessive or dysregulated alternative pathway activation underlies several human diseases, including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and C3 glomerulopathy, and reducing factor D activity is an effective way to dampen the pathway.
As adipsin, factor D is secreted by adipocytes, and its discovery as an obesity-regulated gene helped establish the concept of adipose tissue as an endocrine organ; subsequent work has linked adipocyte-derived factor D to systemic metabolism and to the regulation of insulin secretion.
Genetic deficiency of factor D predisposes to recurrent bacterial infections, particularly with Neisseria species, because the alternative pathway is essential for defense against these organisms.
Orally bioavailable small-molecule inhibitors of factor D have advanced into clinical trials for complement-mediated diseases, offering a convenient alternative to injectable complement inhibitors.

Alternate Names for CFD

CFD; complement factor D (adipsin); D component of complement (adipsin) , DF, PFD, properdin factor D; complement factor D; ADN; properdin factor D; C3 convertase activator; complement factor D preproprotein; D component of complement (adipsin); DF; PFD; ADIPSIN; lampalizumab; 1278466-20-8