DB code: D00429

RLCP classification	1.13.30000.10 : Hydrolysis
CATH domain	2.40.10.10 : Thrombin, subunit H	Catalytic domain
CATH domain	2.40.10.10 : Thrombin, subunit H	Catalytic domain
E.C.	3.4.21.46
CSA
M-CSA
MACiE

CATH domain	Related DB codes (homologues)
2.40.10.10 : Thrombin, subunit H	M00139 D00214 M00167 D00426 M00133 D00428 D00430 D00431 D00432 D00433 D00434 D00435 M00227 M00209 D00194 D00197 D00211 D00212 D00216 M00212 D00224 D00497 M00217 M00216 D00528 D00848 D00850 D00851 D00852 D00855 M00152 M00155 M00157 M00181 M00315 M00316 M00317 M00348 M00349 T00074 T00410 T00411

Uniprot Enzyme Name
UniprotKB	Protein name	Synonyms	RefSeq	MEROPS	Pfam
P00746	Complement factor D	EC 3.4.21.46 C3 convertase activator Properdin factor D Adipsin	NP_001919.2 (Protein) NM_001928.2 (DNA/RNA sequence)	S01.191 (Serine)	PF00089 (Trypsin) [Graphical View]

KEGG enzyme name
complement factor D C3 proactivator convertase properdin factor D esterase factor D factor D (complement)

UniprotKB: Accession Number	Entry name	Activity	Subunit	Subcellular location	Cofactor
P00746	CFAD_HUMAN	Selective cleavage of Arg-\|-Lys bond in complement factor B when in complex with complement subcomponent C3b or with cobra venom factor.		Secreted.

KEGG Pathways
Map code	Pathways	E.C.

Compound table
	Substrates				Products	Intermediates
KEGG-id	L00079	L00090	L00081	C00001	L00089	I00087	I00085	I00086
E.C.
Compound	Complement component C3b	Cobra venom factor	Complement factor B	H2O	C3 convertase (EzCatDB M00317)	Peptidyl-Ser-tetrahedral-intermediate (with previous peptide)	Acyl-enzyme(Peptidyl-Ser-acyl group)	Peptidyl-Ser-tetrahedral-intermediate
Type	peptide/protein	peptide/protein	peptide/protein	H2O	peptide/protein
ChEBI				15377 15377
PubChem				22247451 962 22247451 962

1bioA01	Unbound	Unbound	Unbound		Unbound	Unbound	Intermediate-analogue:SOA	Unbound
1dfpA01	Unbound	Unbound	Unbound		Unbound	Transition-state-analogue:DFP	Unbound	Unbound
1dfpB01	Unbound	Unbound	Unbound		Unbound	Transition-state-analogue:DFP	Unbound	Unbound
1dicA01	Unbound	Unbound	Unbound		Unbound	Unbound	Intermediate-analogue:DIC-__O	Unbound
1dstA01	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound	Unbound
1dsuA01	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound	Unbound
1dsuB01	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound	Unbound
1fdpA01	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound	Unbound
1fdpB01	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound	Unbound
1fdpC01	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound	Unbound
1fdpD01	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound	Unbound
1hfdA01	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound	Unbound
1bioA02	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound	Unbound
1dfpA02	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound	Unbound
1dfpB02	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound	Unbound
1dicA02	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound	Unbound
1dstA02	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound	Unbound
1dsuA02	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound	Unbound
1dsuB02	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound	Unbound
1fdpA02	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound	Unbound
1fdpB02	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound	Unbound
1fdpC02	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound	Unbound
1fdpD02	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound	Unbound
1hfdA02	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound	Unbound

Reference for Active-site residues
resource	references	E.C.

Active-site residues
PDB	Catalytic residues	Cofactor-binding residues	Modified residues	Main-chain involved in catalysis	Comment

1bioA01	SER 195			GLY 193;SER 195
1dfpA01	SER 195			GLY 193;SER 195
1dfpB01	SER 195			GLY 193;SER 195
1dicA01	SER 195			GLY 193;SER 195
1dstA01	SER 195			GLY 193;SER 195	mutant T214S, S215W
1dsuA01	SER 195			GLY 193;SER 195
1dsuB01	SER 195			GLY 193;SER 195
1fdpA01	SER 195			GLY 193;SER 195	invisible 144-151
1fdpB01	SER 195			GLY 193;SER 195	invisible 143-151, 187-192, 217-222
1fdpC01	SER 195			;SER 195	invisible 144-152, 187-193, 216-222
1fdpD01	SER 195			;SER 195	invisible 144-151, 187-193, 217-223
1hfdA01	SER 195			GLY 193;SER 195
1bioA02	HIS 57;ASP 102
1dfpA02	HIS 57;ASP 102
1dfpB02	HIS 57;ASP 102
1dicA02	HIS 57;ASP 102
1dstA02	HIS 57;ASP 102				mutant S94Y
1dsuA02	HIS 57;ASP 102
1dsuB02	HIS 57;ASP 102
1fdpA02	HIS 57;ASP 102
1fdpB02	HIS 57;ASP 102
1fdpC02	HIS 57;ASP 102
1fdpD02	HIS 57;ASP 102
1hfdA02	HIS 57;ASP 102

References for Catalytic Mechanism
References	Sections	No. of steps in catalysis
[9]	p.556-558
[12]

References
[1]
Resource
Comments
Medline ID
PubMed ID	2023254
Journal	J Mol Biol
Year	1991
Volume	219
Pages	1-3
Authors	Narayana SV, Kilpatrick JM, el-Kabbani O, Babu YS, Bugg CE, Volanakis JE, DeLucas LJ
Title	Crystallization and preliminary X-ray investigation of factor D of human complement.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID	8216203
Journal	Biochem J
Year	1993
Volume	295
Pages	109-14
Authors	Perkins SJ, Smith KF
Title	Identity of the putative serine-proteinase fold in proteins of the complement system with nine relevant crystal structures.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID	8216242
Journal	Biochem J
Year	1993
Volume	295
Pages	87-99
Authors	Perkins SJ, Smith KF, Kilpatrick JM, Volanakis JE, Sim RB
Title	Modelling of the serine-proteinase fold by X-ray and neutron scattering and sedimentation analyses: occurrence of the fold in factor D of the complement system.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID	7981199
Journal	Biochemistry
Year	1994
Volume	33
Pages	14393-9
Authors	Kim S, Narayana SV, Volanakis JE
Title	Mutational analysis of the substrate binding site of human complement factor D.
Related PDB
Related UniProtKB
[5]
Resource
Comments	X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS).
Medline ID	94118317
PubMed ID	8289289
Journal	J Mol Biol
Year	1994
Volume	235
Pages	695-708
Authors	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.
Related PDB	1dsu
Related UniProtKB	P00746
[6]
Resource
Comments
Medline ID
PubMed ID	8289314
Journal	J Mol Biol
Year	1994
Volume	235
Pages	1144-6
Authors	Narayana SV, Yamauchi Y, Macon KJ, Moore D, DeLucas LJ, Volanakis JE
Title	Preliminary crystallographic studies on human complement pro-factor D.
Related PDB
Related UniProtKB
[7]
Resource
Comments	X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS).
Medline ID	96025834
PubMed ID	7592653
Journal	J Biol Chem
Year	1995
Volume	270
Pages	24399-405
Authors	Kim S, Narayana SV, Volanakis JE
Title	Crystal structure of a complement factor D mutant expressing enhanced catalytic activity.
Related PDB	1dst
Related UniProtKB	P00746
[8]
Resource
Comments
Medline ID
PubMed ID	7751649
Journal	J Immunol
Year	1995
Volume	154
Pages	6073-9
Authors	Kim S, Narayana SV, Volanakis JE
Title	Catalytic role of a surface loop of the complement serine protease factor D.
Related PDB
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID	8845746
Journal	Protein Sci
Year	1996
Volume	5
Pages	553-64
Authors	Volanakis JE, Narayana SV
Title	Complement factor D, a novel serine protease.
Related PDB
Related UniProtKB
[10]
Resource
Comments	X-ray crystallography
Medline ID
PubMed ID
Journal	Acta Crystallogr D Biol Crystallogr
Year	1997
Volume	53
Pages	143-150
Authors	Cole LB, Chu N, Kilpatrick JM, Volanakis JE, Narayana SV, Babu YS
Title	Structure of Diisopropyl Fluorophosphate-Inhibited Factor D.
Related PDB	1dfp
Related UniProtKB
[11]
Resource
Comments	X-ray crystallography
Medline ID
PubMed ID	9757085
Journal	Acta Crystallogr D Biol Crystallogr
Year	1998
Volume	54
Pages	711-7
Authors	Cole LB, Kilpatrick JM, Chu N, Babu YS
Title	Structure of 3,4-dichloroisocoumarin-inhibited factor D.
Related PDB	1dic
Related UniProtKB
[12]
Resource
Comments	X-ray crystallography
Medline ID
PubMed ID	9753554
Journal	J Mol Biol
Year	1998
Volume	282
Pages	1061-81
Authors	Jing H, Babu YS, Moore D, Kilpatrick JM, Liu XY, Volanakis JE, Narayana 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.
Related PDB	1bio 1hfd
Related UniProtKB
[13]
Resource
Comments
Medline ID
PubMed ID	10052957
Journal	Biochemistry
Year	1999
Volume	38
Pages	2849-59
Authors	Taylor FR, Bixler SA, Budman JI, Wen D, Karpusas M, Ryan ST, Jaworski GJ, Safari-Fard A, Pollard S, Whitty A
Title	Induced fit activation mechanism of the exceptionally specific serine protease, complement factor D.
Related PDB
Related UniProtKB
[14]
Resource
Comments	X-ray crystallography
Medline ID
PubMed ID	10022823
Journal	EMBO J
Year	1999
Volume	18
Pages	804-14
Authors	Jing H, Macon KJ, Moore D, DeLucas LJ, Volanakis JE, Narayana SV
Title	Structural basis of profactor D activation: from a highly flexible zymogen to a novel self-inhibited serine protease, complement factor D.
Related PDB	1fdp
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID	11414354
Journal	Immunol Rev
Year	2001
Volume	180
Pages	123-35
Authors	Xu Y, Narayana SV, Volanakis JE
Title	Structural biology of the alternative pathway convertase.
Related PDB
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID	12080056
Journal	J Biol Chem
Year	2002
Volume	277
Pages	33068-74
Authors	Turner RB, Liu L, Sazonova IY, Reed GL
Title	Structural elements that govern the substrate specificity of the clot-dissolving enzyme plasmin.
Related PDB
Related UniProtKB

Comments
This enzyme belongs to the peptidase family-S1. Despite the catalytic triad, composed of Ser/His/Asp, its conformation is disrupted, showing lower activity (in terms of kcat), compared to that of trypsin (D00197 in EzCatDB), according to the literature [9]. This disruption of the active-site structure seems to be due to the residues, Ser94/Thr214/Ser215. The triple mutant of S94Y/T214S/S215W gives a similar conformation of the catalytic triad to that of trypsin (see [9]). This literature suggested that substrate-induced (C3b-induced) conformational changes, which can lead to the rearrangement of the catalytic-triad residues, might be necessary for the enzyme activation (see [9], [12] & [13]). Moreover, this enzyme activates factor B in the alternative pathway of complement system, generating C3-convertase that is complexed with C3b molecule (M00317 in EzCatDB).

Comments

This enzyme belongs to the peptidase family-S1.
Despite the catalytic triad, composed of Ser/His/Asp, its conformation is disrupted, showing lower activity (in terms of kcat), compared to that of trypsin (D00197 in EzCatDB), according to the literature [9]. This disruption of the active-site structure seems to be due to the residues, Ser94/Thr214/Ser215. The triple mutant of S94Y/T214S/S215W gives a similar conformation of the catalytic triad to that of trypsin (see [9]). This literature suggested that substrate-induced (C3b-induced) conformational changes, which can lead to the rearrangement of the catalytic-triad residues, might be necessary for the enzyme activation (see [9], [12] & [13]).
Moreover, this enzyme activates factor B in the alternative pathway of complement system, generating C3-convertase that is complexed with C3b molecule (M00317 in EzCatDB).

Created	Updated
2004-10-26	2012-08-24