Wikipedia

Factor D

(Redirected from Adipsin)

Factor D (EC 3.4.21.46, C3 proactivator convertase, properdin factor D esterase, factor D (complement), complement factor D, CFD, adipsin) is a protein which in humans is encoded by the CFD gene.[3] Factor D is involved in the alternative complement pathway of the complement system where it cleaves factor B.

complement factor D (adipsin)
Factor D in Homo sapiens[1][2]
Identifiers
SymbolCFD
Alt. symbolsDF, PFD
NCBI gene1675
HGNC2771
OMIM134350
RefSeqNM_001928
UniProtP00746
Other data
LocusChr. 19 p13.3
Search for
StructuresSwiss-model
DomainsInterPro

Function

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The protein encoded by this gene is a member of the trypsin family of serine proteases secreted by adipocytes into the bloodstream. The encoded protein is a component of the alternative 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 inhibits lipolysis.[4]

Clinical significance

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The level of Factor D is decreased[5] in obese patients. This reduction may be due to high activity or resistance but exact cause is not fully known.

Structure

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All members of the chymotrypsin family of serine proteases have very similar structures. In all cases, including factor D, there are two antiparallel β-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 surface loops 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]

Mechanism of Action

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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-Lys235 scissile 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 with C3b 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 pathway C3-convertase.[12]

 
The non-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]
 
The canonical 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]

Regulation

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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 in proximal 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]

Role in Diseases

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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, specifically Neisseria 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 include paroxysmal 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 with eculizumab. 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]

References

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  1. ^ PDB: 1HFD​
  2. ^ 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. PMID 8289289.
  3. ^ a b EntrezGene 1675
  4. ^ Ronti T, Lupattelli G, Mannarino E (2006). "The endocrine function of adipose tissue: an update". Clinical Endocrinology. 64 (4): 355–65. doi:10.1111/j.1365-2265.2006.02474.x. PMID 16584505. S2CID 12455240.
  5. ^ Flier JS, Cook KS, Usher P, Spiegelman BM (1987). "Severely impaired adipsin expression in genetic and acquired obesity". Science. 237 (4813): 405–8. Bibcode:1987Sci...237..405F. doi:10.1126/science.3299706. PMID 3299706.
  6. ^ Volanakis JE, Narayana SV (1996). "Complement factor D, a novel serine protease". Protein Science. 5 (4): 553–64. doi:10.1002/pro.5560050401. PMC 2143395. PMID 8845746.
  7. ^ Lesavre, PH; Müller-Eberhard, HJ (1 December 1978). "Mechanism of action of factor D of the alternative complement pathway". The Journal of Experimental Medicine. 148 (6): 1498–509. doi:10.1084/jem.148.6.1498. PMC 2185104. PMID 82604.
  8. ^ 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. PMID 9753554.
  9. ^ Jing, H; Macon, KJ; Moore, D; DeLucas, LJ; Volanakis, JE; Narayana, SV (15 February 1999). "Structural basis of profactor D activation: from a highly flexible zymogen to a novel self-inhibited serine protease, complement factor D." The EMBO Journal. 18 (4): 804–14. doi:10.1093/emboj/18.4.804. PMC 1171173. PMID 10022823.
  10. ^ Karki, RG; Powers, J; Mainolfi, N; Anderson, K; Belanger, DB; Liu, D; Ji, N; Jendza, K; Gelin, CF; Mac Sweeney, A; Solovay, C; Delgado, O; Crowley, M; Liao, SM; Argikar, UA; Flohr, S; La Bonte, LR; Lorthiois, EL; Vulpetti, A; Brown, A; Long, D; Prentiss, M; Gradoux, N; de Erkenez, A; Cumin, F; Adams, C; Jaffee, B; Mogi, M (9 May 2019). "Design, Synthesis, and Preclinical Characterization of Selective Factor D Inhibitors Targeting the Alternative Complement Pathway". Journal of Medicinal Chemistry. 62 (9): 4656–4668. doi:10.1021/acs.jmedchem.9b00271. PMID 30995036. S2CID 122356241.
  11. ^ Forneris, F; Ricklin, D; Wu, J; Tzekou, A; Wallace, RS; Lambris, JD; Gros, P (24 December 2010). "Structures of C3b in complex with factors B and D give insight into complement convertase formation". Science. 330 (6012): 1816–20. Bibcode:2010Sci...330.1816F. doi:10.1126/science.1195821. PMC 3087196. PMID 21205667.
  12. ^ Vulpetti, A; Randl, S; Rüdisser, S; Ostermann, N; Erbel, P; Mac Sweeney, A; Zoller, T; Salem, B; Gerhartz, B; Cumin, F; Hommel, U; Dalvit, C; Lorthiois, E; Maibaum, J (9 March 2017). "Structure-Based Library Design and Fragment Screening for the Identification of Reversible Complement Factor D Protease Inhibitors". Journal of Medicinal Chemistry. 60 (5): 1946–1958. doi:10.1021/acs.jmedchem.6b01684. PMID 28157311.
  13. ^ Maibaum, J; Liao, SM; Vulpetti, A; Ostermann, N; Randl, S; Rüdisser, S; Lorthiois, E; Erbel, P; Kinzel, B; Kolb, FA; Barbieri, S; Wagner, J; Durand, C; Fettis, K; Dussauge, S; Hughes, N; Delgado, O; Hommel, U; Gould, T; Mac Sweeney, A; Gerhartz, B; Cumin, F; Flohr, S; Schubart, A; Jaffee, B; Harrison, R; Risitano, AM; Eder, J; Anderson, K (December 2016). "Small-molecule factor D inhibitors targeting the alternative complement pathway". Nature Chemical Biology. 12 (12): 1105–1110. doi:10.1038/nchembio.2208. PMID 27775713.
  14. ^ Vulpetti, A; Ostermann, N; Randl, S; Yoon, T; Mac Sweeney, A; Cumin, F; Lorthiois, E; Rüdisser, S; Erbel, P; Maibaum, J (10 May 2018). "Discovery and Design of First Benzylamine-Based Ligands Binding to an Unlocked Conformation of the Complement Factor D." ACS Medicinal Chemistry Letters. 9 (5): 490–495. doi:10.1021/acsmedchemlett.8b00104. PMC 5949727. PMID 29795765.
  15. ^ Hayashi, M; Machida, T; Ishida, Y; Ogata, Y; Omori, T; Takasumi, M; Endo, Y; Suzuki, T; Sekimata, M; Homma, Y; Ikawa, M; Ohira, H; Fujita, T; Sekine, H (15 September 2019). "Cutting Edge: Role of MASP-3 in the Physiological Activation of Factor D of the Alternative Complement Pathway". Journal of Immunology. 203 (6): 1411–1416. doi:10.4049/jimmunol.1900605. PMID 31399515. S2CID 199518699.
  16. ^ Lorthiois, E; Anderson, K; Vulpetti, A; Rogel, O; Cumin, F; Ostermann, N; Steinbacher, S; Mac Sweeney, A; Delgado, O; Liao, SM; Randl, S; Rüdisser, S; Dussauge, S; Fettis, K; Kieffer, L; de Erkenez, A; Yang, L; Hartwieg, C; Argikar, UA; La Bonte, LR; Newton, R; Kansara, V; Flohr, S; Hommel, U; Jaffee, B; Maibaum, J (13 July 2017). "Discovery of Highly Potent and Selective Small-Molecule Reversible Factor D Inhibitors Demonstrating Alternative Complement Pathway Inhibition in Vivo". Journal of Medicinal Chemistry. 60 (13): 5717–5735. doi:10.1021/acs.jmedchem.7b00425. PMID 28621538.
  17. ^ Dobó, J; Kocsis, A; Gál, P (2018). "Be on Target: Strategies of Targeting Alternative and Lectin Pathway Components in Complement-Mediated Diseases". Frontiers in Immunology. 9: 1851. doi:10.3389/fimmu.2018.01851. PMC 6092519. PMID 30135690.
  18. ^ 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. PMID 3844050.
  19. ^ Pascual, M; Steiger, G; Estreicher, J; Macon, K; Volanakis, JE; Schifferli, JA (October 1988). "Metabolism of complement factor D in renal failure". Kidney International. 34 (4): 529–36. doi:10.1038/ki.1988.214. PMID 3199673.
  20. ^ Biesma, DH; Hannema, AJ; van Velzen-Blad, H; Mulder, L; van Zwieten, R; Kluijt, I; Roos, D (July 2001). "A family with complement factor D deficiency". The Journal of Clinical Investigation. 108 (2): 233–40. doi:10.1172/JCI12023. PMC 203023. PMID 11457876.
  21. ^ Hiemstra, PS; Langeler, E; Compier, B; Keepers, Y; Leijh, PC; van den Barselaar, MT; Overbosch, D; Daha, MR (December 1989). "Complete and partial deficiencies of complement factor D in a Dutch family". The Journal of Clinical Investigation. 84 (6): 1957–61. doi:10.1172/JCI114384. PMC 304077. PMID 2687330.
  22. ^ Yuan, X; Gavriilaki, E; Thanassi, JA; Yang, G; Baines, AC; Podos, SD; Huang, Y; Huang, M; Brodsky, RA (March 2017). "Small-molecule factor D inhibitors selectively block the alternative pathway of complement in paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome". Haematologica. 102 (3): 466–475. doi:10.3324/haematol.2016.153312. PMC 5394948. PMID 27810992.
  23. ^ Risitano, AM (January 2014). "Anti-Complement Treatment in Paroxysmal Nocturnal Hemoglobinuria: Where we Stand and Where we are Going". Translational Medicine @ UniSa. 8: 43–52. PMC 4000462. PMID 24778997.
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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