Theprotein encoded by this gene is a member of thetrypsin family ofserine proteases secreted byadipocytes into the bloodstream. The encoded protein is a component of thealternative complement pathway best known for its role in humoral suppression of infectious agents. Finally, the encoded protein has a high level of expression in fat, suggesting a role for adipose tissue in immune system biology.[3]
Alternative pathway. ( 4. Is factor D cleaving B to Bb and Ba)
Factor D is a serine protease that stimulates glucose transport for triglyceride accumulation in fats cells and inhibitslipolysis.[4]
All members of thechymotrypsin family ofserine proteases have very similar structures. In all cases, including factor D, there are two antiparallelβ-barrel domains with each barrel containing six β-strands with the same typology in all enzymes. The major difference in backbone structure between Factor D and the other serine proteases of the chymotrypsin family is in the surfaceloops connecting the secondary structural elements. Factor D displays different conformations of major catalytic and substrate-binding residues typically found in the chrotrypsin family. These features suggest the catalytic activity of factor D is prohibited unless conformational changes are induced by a realignment.[6]
Factor D is a serine protease present in blood and tissue in an active sequence but self-inhibited conformation. The only known natural substrate of Factor D is Factor B, and cleavage of the Arg234-Lys235scissile bond in Factor B results in two Factor B fragments, Ba and Bb. Before cleavage of the scissile bond in Factor B can occur, Factor B must first bind withC3b before to form the C3bB complex.[7] It is proposed that this conformational change of Factor B in the C3bB complex allows Factor B to fit into the binding site of Factor D.
The catalytic triad of Factor D is composed of Asp102, His57 and Ser195. Other key components of Factor D are an Asp189-Arg218 salt bridge that stabilizes a self-inhibitory loop (amino acid residues 212 to 218) and His57 side chain in the non-canonical conformation.[8][9] In its inhibited form, the self-inhibitory loop prevents access of Factor B to Factor D. When the self-inhibited conformation of Factor D is approached by the C3bB complex, C3bB displaces the salt bridge in Factor D and results in a new salt bridge between the Arg234 of Factor B and Asp189 of Factor D.[10][11] The displacement of the Factor D salt bridge results in a realignment of the self-inhibitory loop and a rotation of the active site histidine side chain, creating the canonical form of Factor D. Cleavage of the scissile bond in Factor B then ensues, releasing fragment Ba and forming C3bBb, the alternative pathwayC3-convertase.[12]
Thenon-canonical conformation of Factor D is inhibited by the self-inhibitory loop (blue). The Asp-Arg salt bridge (purple and orange side chains, respectively) stabilizes the self-inhibitory loop. The catalytic triad is shown in green.[13]
Thecanonical conformation of Factor D is not self-inhibited. The Asp-Arg salt bridge (purple and orange side chains, respectively) has been displaced resulting in a shift in the self inhibitory loop (blue). The catalytic triad is shown in green.[14]
Factor D is synthesized by the liver and adipocytes with the latter being the major source. The pro-form of Factor D that is secreted is cleaved by MASP-3 to form the active sequence that circulates in the body.[15] Factor D maintains an extremely high substrate specificity, and as a result has no known natural inhibitors in the body.[16] However, most of Factor D remains in the self-inhibited form that limits substrate access to the catalytic site. Factor D has a molecular weight of 23.5 kD and is present at a concentration of 1.8 mg/L of blood in healthy humans. The synthesis rate of Factor is approximately 1.33 mg/kg/day, and most of Factor D is eliminated through the kidney after catabolism inproximal tubules after re-absorption. The net effect is a high fractional metabolic rate of 60% per hour.[17] In patients with normal kidney function, no Factor D was detectable in urine. However, in patients with renal disease, Factor D was found at elevated levels. The alternative pathway is capable of operating even at low levels of Factor D, and deficiencies in levels of Factor D are rare.[18][19]
A point mutation resulting in the replacement of a serine codon (Ser42 in the unprocessed methionine form of Factor D) with a stop codon (TAG) in the Factor D gene on chromosome 19 has been documented as a cause of Factor D deficiency.[20] Deficiency in Factor D may cause an increased susceptibility to bacterial infections, specificallyNeisseria infections. The mode of inheritance of Factor D deficiency is autosomal recessive, and individuals with a mutation on only one allele may not experience the same susceptibility to reoccurring infections. In a patient with reoccurring infections, complete improvement in the condition was obtained by introducing purified Factor D.[21]
Diseases with excessive complement activation includeparoxysmal nocturnal hemoglobinuria (PNH), and inhibitors of Factor D may have utility in the treatment of PNH. Small molecule inhibitors of Factor D are under development for the treatment of PNH, and one small molecule inhibitor, ACH-4471, has shown promise in a Phase 2 clinical trial for Factor D inhibition when combined witheculizumab. Patients treated with Factor D inhibitors must be immunized against infections in order to avoid reoccurring infections as in patients with Factor D deficiency.[22][23]
^Narayana SV, Carson M, el-Kabbani O, Kilpatrick JM, Moore D, Chen X, Bugg CE, Volanakis JE, DeLucas LJ (1994). "Structure of human factor D. A complement system protein at 2.0 A resolution".Journal of Molecular Biology.235 (2):695–708.doi:10.1006/jmbi.1994.1021.PMID8289289.
^Jing, H; Babu, YS; Moore, D; Kilpatrick, JM; Liu, XY; Volanakis, JE; Narayana, SV (9 October 1998). "Structures of native and complexed complement factor D: implications of the atypical His57 conformation and self-inhibitory loop in the regulation of specific serine protease activity".Journal of Molecular Biology.282 (5):1061–81.doi:10.1006/jmbi.1998.2089.PMID9753554.
^Volanakis, JE; Barnum, SR; Giddens, M; Galla, JH (14 February 1985). "Renal filtration and catabolism of complement protein D.".The New England Journal of Medicine.312 (7):395–9.doi:10.1056/NEJM198502143120702.PMID3844050.
