View source for Factor D

{{Short description|Class of enzymes}}
{{infobox protein
| Name = complement factor D (adipsin)
| caption = Factor D in Homo sapiens<ref>{{PDB|1HFD}}</ref><ref name="pmid8289289">{{cite journal |vauthors=Narayana SV, Carson M, el-Kabbani O, Kilpatrick JM, Moore D, Chen X, Bugg CE, Volanakis JE, DeLucas LJ |title=Structure of human factor D. A complement system protein at 2.0 A resolution |journal=Journal of Molecular Biology |volume=235 |issue=2 |pages=695–708 |year=1994 |pmid=8289289 |doi=10.1006/jmbi.1994.1021 }}</ref>
| image = Factor D.jpg
| width = 
| HGNCid = 2771
| Symbol = CFD
| AltSymbols = DF, PFD
| EntrezGene = 1675
| OMIM = 134350
| RefSeq = NM_001928
| UniProt = P00746
| PDB = 
| ECnumber = 
| Chromosome = 19
| Arm = p
| Band = 13.3
| LocusSupplementaryData = 
}}
'''Factor D''' ({{EC number|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]].<ref name="entrez">{{EntrezGene|1675}}</ref> Factor D is involved in the [[alternative complement pathway]] of the [[complement system]] where it cleaves [[complement factor B|factor B]].

== Function ==

The [[protein]] encoded by this gene is a member of the [[trypsin]] family of [[serine protease]]s secreted by [[adipocyte]]s 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.<ref name="entrez"/>

[[Image:Droga alternatywna.png|thumb|500px|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]].<ref name="pmid16584505">{{cite journal |vauthors=Ronti T, Lupattelli G, Mannarino E |title=The endocrine function of adipose tissue: an update |journal=Clinical Endocrinology |volume=64 |issue=4 |pages=355–65 |year=2006 |pmid=16584505 |doi=10.1111/j.1365-2265.2006.02474.x |s2cid=12455240 |doi-access= }}</ref>

== Clinical significance ==

The level of Factor D is decreased<ref>{{cite journal |vauthors=Flier JS, Cook KS, Usher P, Spiegelman BM |title=Severely impaired adipsin expression in genetic and acquired obesity |journal=Science |volume=237 |issue=4813 |pages=405–8 |year=1987 |pmid=3299706 |doi=10.1126/science.3299706 |bibcode=1987Sci...237..405F }}</ref> in obese patients. This reduction may be due to high activity or resistance but exact cause is not fully known.

== Structure ==

All members of the [[chymotrypsin]] family of [[serine protease]]s have very similar structures.  In all cases, including factor D, there are two antiparallel [[beta barrel|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 [[turn (biochemistry)|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.<ref name="pmid8845746">{{cite journal |vauthors=Volanakis JE, Narayana SV |title=Complement factor D, a novel serine protease |journal=Protein Science |volume=5 |issue=4 |pages=553–64 |year=1996 |pmid=8845746 |pmc=2143395 |doi=10.1002/pro.5560050401 }}</ref>

== Mechanism of Action ==

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 Arg<sup>234</sup>-Lys<sup>235</sup> [[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.<ref>{{cite journal |last1=Lesavre |first1=PH |last2=Müller-Eberhard |first2=HJ |title=Mechanism of action of factor D of the alternative complement pathway. |journal=The Journal of Experimental Medicine |date=1 December 1978 |volume=148 |issue=6 |pages=1498–509 |doi=10.1084/jem.148.6.1498 |pmid=82604|pmc=2185104 }}</ref> 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 Asp<sup>102</sup>, His<sup>57</sup> and Ser<sup>195</sup>. Other key components of Factor D are an Asp<sup>189</sup>-Arg<sup>218</sup> salt bridge that stabilizes a self-inhibitory loop (amino acid residues 212 to 218) and His<sup>57</sup> side chain in the non-canonical conformation.<ref>{{cite journal |last1=Jing |first1=H |last2=Babu |first2=YS |last3=Moore |first3=D |last4=Kilpatrick |first4=JM |last5=Liu |first5=XY |last6=Volanakis |first6=JE |last7=Narayana |first7=SV |title=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=Journal of Molecular Biology |date=9 October 1998 |volume=282 |issue=5 |pages=1061–81 |doi=10.1006/jmbi.1998.2089 |pmid=9753554}}</ref><ref>{{cite journal |last1=Jing |first1=H |last2=Macon |first2=KJ |last3=Moore |first3=D |last4=DeLucas |first4=LJ |last5=Volanakis |first5=JE |last6=Narayana |first6=SV |title=Structural basis of profactor D activation: from a highly flexible zymogen to a novel self-inhibited serine protease, complement factor D. |journal=The EMBO Journal |date=15 February 1999 |volume=18 |issue=4 |pages=804–14 |doi=10.1093/emboj/18.4.804 |pmid=10022823|pmc=1171173 }}</ref> 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 Arg<sup>234</sup> of Factor B and Asp<sup>189</sup> of Factor D.<ref>{{cite journal |last1=Karki |first1=RG |last2=Powers |first2=J |last3=Mainolfi |first3=N |last4=Anderson |first4=K |last5=Belanger |first5=DB |last6=Liu |first6=D |last7=Ji |first7=N |last8=Jendza |first8=K |last9=Gelin |first9=CF |last10=Mac Sweeney |first10=A |last11=Solovay |first11=C |last12=Delgado |first12=O |last13=Crowley |first13=M |last14=Liao |first14=SM |last15=Argikar |first15=UA |last16=Flohr |first16=S |last17=La Bonte |first17=LR |last18=Lorthiois |first18=EL |last19=Vulpetti |first19=A |last20=Brown |first20=A |last21=Long |first21=D |last22=Prentiss |first22=M |last23=Gradoux |first23=N |last24=de Erkenez |first24=A |last25=Cumin |first25=F |last26=Adams |first26=C |last27=Jaffee |first27=B |last28=Mogi |first28=M |title=Design, Synthesis, and Preclinical Characterization of Selective Factor D Inhibitors Targeting the Alternative Complement Pathway. |journal=Journal of Medicinal Chemistry |date=9 May 2019 |volume=62 |issue=9 |pages=4656–4668 |doi=10.1021/acs.jmedchem.9b00271 |pmid=30995036|s2cid=122356241 }}</ref><ref>{{cite journal |last1=Forneris |first1=F |last2=Ricklin |first2=D |last3=Wu |first3=J |last4=Tzekou |first4=A |last5=Wallace |first5=RS |last6=Lambris |first6=JD |last7=Gros |first7=P |title=Structures of C3b in complex with factors B and D give insight into complement convertase formation. |journal=Science |date=24 December 2010 |volume=330 |issue=6012 |pages=1816–20 |doi=10.1126/science.1195821 |pmid=21205667|pmc=3087196 |bibcode=2010Sci...330.1816F }}</ref> 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]].<ref>{{cite journal |last1=Vulpetti |first1=A |last2=Randl |first2=S |last3=Rüdisser |first3=S |last4=Ostermann |first4=N |last5=Erbel |first5=P |last6=Mac Sweeney |first6=A |last7=Zoller |first7=T |last8=Salem |first8=B |last9=Gerhartz |first9=B |last10=Cumin |first10=F |last11=Hommel |first11=U |last12=Dalvit |first12=C |last13=Lorthiois |first13=E |last14=Maibaum |first14=J |title=Structure-Based Library Design and Fragment Screening for the Identification of Reversible Complement Factor D Protease Inhibitors. |journal=Journal of Medicinal Chemistry |date=9 March 2017 |volume=60 |issue=5 |pages=1946–1958 |doi=10.1021/acs.jmedchem.6b01684 |pmid=28157311}}</ref>

{|style="margin: 0 auto;"
| [[File:Factor D Non-Canonical.png|thumb|600px|upright|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.<ref>{{cite journal |last1=Maibaum |first1=J |last2=Liao |first2=SM |last3=Vulpetti |first3=A |last4=Ostermann |first4=N |last5=Randl |first5=S |last6=Rüdisser |first6=S |last7=Lorthiois |first7=E |last8=Erbel |first8=P |last9=Kinzel |first9=B |last10=Kolb |first10=FA |last11=Barbieri |first11=S |last12=Wagner |first12=J |last13=Durand |first13=C |last14=Fettis |first14=K |last15=Dussauge |first15=S |last16=Hughes |first16=N |last17=Delgado |first17=O |last18=Hommel |first18=U |last19=Gould |first19=T |last20=Mac Sweeney |first20=A |last21=Gerhartz |first21=B |last22=Cumin |first22=F |last23=Flohr |first23=S |last24=Schubart |first24=A |last25=Jaffee |first25=B |last26=Harrison |first26=R |last27=Risitano |first27=AM |last28=Eder |first28=J |last29=Anderson |first29=K |title=Small-molecule factor D inhibitors targeting the alternative complement pathway. |journal=Nature Chemical Biology |date=December 2016 |volume=12 |issue=12 |pages=1105–1110 |doi=10.1038/nchembio.2208 |pmid=27775713}}</ref>]]
| [[File:Factor D Canonical Configuration.png|thumb|600px|upright|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.<ref>{{cite journal |last1=Vulpetti |first1=A |last2=Ostermann |first2=N |last3=Randl |first3=S |last4=Yoon |first4=T |last5=Mac Sweeney |first5=A |last6=Cumin |first6=F |last7=Lorthiois |first7=E |last8=Rüdisser |first8=S |last9=Erbel |first9=P |last10=Maibaum |first10=J |title=Discovery and Design of First Benzylamine-Based Ligands Binding to an Unlocked Conformation of the Complement Factor D. |journal=ACS Medicinal Chemistry Letters |date=10 May 2018 |volume=9 |issue=5 |pages=490–495 |doi=10.1021/acsmedchemlett.8b00104 |pmid=29795765|pmc=5949727 }}</ref>]]
|}

== Regulation ==

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.<ref>{{cite journal |last1=Hayashi |first1=M |last2=Machida |first2=T |last3=Ishida |first3=Y |last4=Ogata |first4=Y |last5=Omori |first5=T |last6=Takasumi |first6=M |last7=Endo |first7=Y |last8=Suzuki |first8=T |last9=Sekimata |first9=M |last10=Homma |first10=Y |last11=Ikawa |first11=M |last12=Ohira |first12=H |last13=Fujita |first13=T |last14=Sekine |first14=H |title=Cutting Edge: Role of MASP-3 in the Physiological Activation of Factor D of the Alternative Complement Pathway. |journal=Journal of Immunology  |date=15 September 2019 |volume=203 |issue=6 |pages=1411–1416 |doi=10.4049/jimmunol.1900605 |pmid=31399515|s2cid=199518699 |doi-access=free }}</ref> Factor D maintains an extremely high substrate specificity, and as a result has no known natural inhibitors in the body.<ref>{{cite journal |last1=Lorthiois |first1=E |last2=Anderson |first2=K |last3=Vulpetti |first3=A |last4=Rogel |first4=O |last5=Cumin |first5=F |last6=Ostermann |first6=N |last7=Steinbacher |first7=S |last8=Mac Sweeney |first8=A |last9=Delgado |first9=O |last10=Liao |first10=SM |last11=Randl |first11=S |last12=Rüdisser |first12=S |last13=Dussauge |first13=S |last14=Fettis |first14=K |last15=Kieffer |first15=L |last16=de Erkenez |first16=A |last17=Yang |first17=L |last18=Hartwieg |first18=C |last19=Argikar |first19=UA |last20=La Bonte |first20=LR |last21=Newton |first21=R |last22=Kansara |first22=V |last23=Flohr |first23=S |last24=Hommel |first24=U |last25=Jaffee |first25=B |last26=Maibaum |first26=J |title=Discovery of Highly Potent and Selective Small-Molecule Reversible Factor D Inhibitors Demonstrating Alternative Complement Pathway Inhibition in Vivo. |journal=Journal of Medicinal Chemistry |date=13 July 2017 |volume=60 |issue=13 |pages=5717–5735 |doi=10.1021/acs.jmedchem.7b00425 |pmid=28621538}}</ref> 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&nbsp;mg/L of blood in healthy humans. The synthesis rate of Factor is approximately 1.33&nbsp;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.<ref>{{cite journal |last1=Dobó |first1=J |last2=Kocsis |first2=A |last3=Gál |first3=P |title=Be on Target: Strategies of Targeting Alternative and Lectin Pathway Components in Complement-Mediated Diseases. |journal=Frontiers in Immunology |date=2018 |volume=9 |pages=1851 |doi=10.3389/fimmu.2018.01851 |pmid=30135690|pmc=6092519 |doi-access=free }}</ref> 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.<ref>{{cite journal |last1=Volanakis |first1=JE |last2=Barnum |first2=SR |last3=Giddens |first3=M |last4=Galla |first4=JH |title=Renal filtration and catabolism of complement protein D. |journal=The New England Journal of Medicine |date=14 February 1985 |volume=312 |issue=7 |pages=395–9 |doi=10.1056/NEJM198502143120702 |pmid=3844050}}</ref><ref>{{cite journal |last1=Pascual |first1=M |last2=Steiger |first2=G |last3=Estreicher |first3=J |last4=Macon |first4=K |last5=Volanakis |first5=JE |last6=Schifferli |first6=JA |title=Metabolism of complement factor D in renal failure. |journal=Kidney International |date=October 1988 |volume=34 |issue=4 |pages=529–36 |doi=10.1038/ki.1988.214 |pmid=3199673|doi-access=free }}</ref>

== Role in Diseases ==

A point mutation resulting in the replacement of a serine codon (Ser<sup>42</sup> 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.<ref>{{cite journal |last1=Biesma |first1=DH |last2=Hannema |first2=AJ |last3=van Velzen-Blad |first3=H |last4=Mulder |first4=L |last5=van Zwieten |first5=R |last6=Kluijt |first6=I |last7=Roos |first7=D |title=A family with complement factor D deficiency. |journal=The Journal of Clinical Investigation |date=July 2001 |volume=108 |issue=2 |pages=233–40 |doi=10.1172/JCI12023 |pmid=11457876|pmc=203023 }}</ref> 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.<ref>{{cite journal |last1=Hiemstra |first1=PS |last2=Langeler |first2=E |last3=Compier |first3=B |last4=Keepers |first4=Y |last5=Leijh |first5=PC |last6=van den Barselaar |first6=MT |last7=Overbosch |first7=D |last8=Daha |first8=MR |title=Complete and partial deficiencies of complement factor D in a Dutch family. |journal=The Journal of Clinical Investigation |date=December 1989 |volume=84 |issue=6 |pages=1957–61 |doi=10.1172/JCI114384 |pmid=2687330|pmc=304077 }}</ref>

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.<ref>{{cite journal |last1=Yuan |first1=X |last2=Gavriilaki |first2=E |last3=Thanassi |first3=JA |last4=Yang |first4=G |last5=Baines |first5=AC |last6=Podos |first6=SD |last7=Huang |first7=Y |last8=Huang |first8=M |last9=Brodsky |first9=RA |title=Small-molecule factor D inhibitors selectively block the alternative pathway of complement in paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. |journal=Haematologica |date=March 2017 |volume=102 |issue=3 |pages=466–475 |doi=10.3324/haematol.2016.153312 |pmid=27810992|pmc=5394948 }}</ref><ref>{{cite journal |last1=Risitano |first1=AM |title=Anti-Complement Treatment in Paroxysmal Nocturnal Hemoglobinuria: Where we Stand and Where we are Going. |journal=Translational Medicine @ UniSa |date=January 2014 |volume=8 |pages=43–52 |pmid=24778997|pmc=4000462 }}</ref>

== References ==
{{Reflist}}

==External links==
* {{MeshName|Complement+Factor+D}}

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{{Complement system}}
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[[Category:Complement system]]
[[Category:EC 3.4.21]]