Information on EC 3.4.21.43 - classical-complement-pathway C3/C5 convertase

Word Map on EC 3.4.21.43
Please wait a moment until all data is loaded. This message will disappear when all data is loaded.
Specify your search results
Select one or more organisms in this record:
Show additional data
Do not include text mining results
Include (text mining) results (more...)
Include results (AMENDA + additional results, but less precise; more...)

The enzyme appears in viruses and cellular organisms

EC NUMBER
COMMENTARY hide
3.4.21.43
-
RECOMMENDED NAME
GeneOntology No.
classical-complement-pathway C3/C5 convertase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
Selective cleavage of Arg-/-Ser bond in complement component C3 alpha-chain to form C3a and C3b, and Arg-/- bond in complement component C5 alpha-chain to form C5a and C5b
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
hydrolysis of peptide bond
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY hide
56626-15-4
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
-
inhibition of C3 convertase activity by hepatitis C virus as an additional lesion in the regulation of complement components. Inhibition of C3 convertase activity and C3b deposition onto bacterial membrane by hepatitis C virus, impairment of both C3 convertase and Factor I activity, overview
metabolism
physiological function
additional information
-
the classical C5 convertase requires factor D, factor B, and properdin for activation and complex assembly
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
C3 zymogen + H2O
C3b + C3a
show the reaction diagram
C5 zymogen + H2O
C5b + C5a
show the reaction diagram
complement component C3 + H2O
?
show the reaction diagram
-
classical pathway of the complement system
-
-
-
complement component C3 + H2O
complement component C3a + complement component C3b
show the reaction diagram
complement component C3 + H2O
component C3b + anaphylatoxin C3a
show the reaction diagram
-
-
iC3b is generated by Factor I after formation of C3b. iC3b is a proteolytically inactive form of C3b that retains the ability to opsonize microbes, but cannot participate in convertase function
-
?
complement component C5 + H2O
?
show the reaction diagram
-
activity of enzyme bound to component C3b
-
-
?
complement component C5 + H2O
complement component C5a + complement component C5b
show the reaction diagram
complement componentC3 + H2O
complement component C3a + complement component C3b
show the reaction diagram
additional information
?
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
C3 zymogen + H2O
C3b + C3a
show the reaction diagram
-
activation
-
-
?
C5 zymogen + H2O
C5b + C5a
show the reaction diagram
-
activation
-
-
?
complement component C3 + H2O
?
show the reaction diagram
-
classical pathway of the complement system
-
-
-
complement component C3 + H2O
complement component C3a + complement component C3b
show the reaction diagram
complement component C3 + H2O
component C3b + anaphylatoxin C3a
show the reaction diagram
-
-
iC3b is generated by Factor I after formation of C3b. iC3b is a proteolytically inactive form of C3b that retains the ability to opsonize microbes, but cannot participate in convertase function
-
?
complement component C5 + H2O
complement component C5a + complement component C5b
show the reaction diagram
complement componentC3 + H2O
complement component C3a + complement component C3b
show the reaction diagram
additional information
?
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Iodine
-
stabilization
Li+
-
binds to complement component C2A
Mn2+
-
binds to complement component C2A
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
C1 inhibitor
-
blocks the the classical pathway
-
C4b-binding protein
-
regulates assembly and decay of the classical pathway C3/C5 convertase 4times lower than the lectin pathway convertase
-
C4d antibody
-
blocks the the classical pathway
-
CN-
-
inhibits the aggregation of C4b and C2a and the activity of the active enzyme
complement receptor type 1-related protein y
-
i.e. Crry, a mouse-specific complement inhibitor, expressed in astrocytes, microglia, and neurons of murine brain, in vivo and in vitro inhibition of C3 convertase, overview
-
diisopropyl fluorophosphate
-
-
EDTA
-
inhibits interaction between C4b and C2b
extracellular complement-binding protein
-
Ecb, a potent complement inhibitor from Staphylococcus aureus, with strong antiinflammatory properties, inhibitory mechanism for blocking C3b-containing convertases, Efb-C and Ecb act on the bacterial surface, overview
-
extracellular fibrinogen-binding protein
-
Efb, a potent complement inhibitor from Staphylococcus aureus, with strong antiinflammatory properties, inhibitory mechanism for blocking C3b-containing convertases, Efb-C and Ecb act on the bacterial surface, overview
-
hepatitis virus C
-
inhibition of C3 convertase activity and C3b deposition onto bacterial membrane by hepatitis C virus, impairment of both C3 convertase and Factor I activity
-
mouse anti human factor B antibody
-
-
-
N-terminal long homologous repeat A of complement receptor type 1
-
responsible for dissociation of enzyme. Highest decay accelerating activity for mutant dimeric construct N-terminal long homologous repeat A (D109N/E116K)/N-terminal long homologous repeat A (D109N)
-
NH2-CD59-DAF-GPI
-
chimeric molecule, DAF: decay accelerating factor, GPI: glycosylphosphatidylinositol
-
NH2DAF-CD59-GPI
-
chimeric molecule, DAF: decay accelerating factor, GPI: glycosylphosphatidylinositol
-
OmCI
-
the inhibitor blocks C5 cleavage by interfering with convertase recognition far from C5a
-
Pra1
-
i. e. Candida albicans complement regulator acquiring surface protein 2 or pH-regulated Ag 1. In the direct surrounding of the pathogen, inhibitor binds to fluid-phase C3, blocks cleavage of C3 to C3a and C3b and inhibits complement activation via the alternative and classical pathways. In addition, the release of the anaphylatoxins C3a and C5a, as well as C3b/iC3b surface deposition, is reduced. By reducing C3b/iC3b levels at the yeast surface, Pra1 decreases complement-mediated adhesion, as well as uptake of Candida albicans by human macrophages
-
rosmarinic acid
-
inhibition of C5 convertase by binding to component C3b
SSL7
-
the inhibitor blocks C5 cleavage by interfering with convertase recognition far from C5a
-
staphylococcal complement inhibitor
-
SCIN, a potent complement inhibitor from Staphylococcus aureus, with strong antiinflammatory properties, inhibitory mechanism for blocking C3b-containing convertases, overview
-
thioredoxin 1
-
Trx-1, but not an active site mutated form, inhibits both C3 and C5 classical convertase formation, mechanism, overview. Trx-1 is capable of inhibiting all classical and alternative convertases but its effect is more pronounced in inhibition of alternative ones
additional information
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
beta-amyloid peptide
-
i.e. Abeta1-42, activates
-
C3b
-
both the soluble form of the enzyme, C4b,C2a and the surface-bound form of the enzyme EAC1,C4b,C2a exhibit a poor affinity for the substrate C5. Very high affinity C5 convertase is generated only when the low affinity C3/C5 convertases are allowed to deposit C3b by cleaving native C3
-
complement C2
-
provides catalytic activity for the C3 convertase C4bC2a
-
complement component C2b
-
essential for the interaction of C4b and C2a
-
complement component C3b
-
in inactive surface-fixed form essential for cleavage of C5
-
factor B
-
the classical C5 convertase requires factor D, factor B, and properdin for activation and complex assembly
-
factor D
-
the classical C5 convertase requires factor D, factor B, and properdin for activation and complex assembly
-
properdin
-
the classical C5 convertase requires factor D, factor B, and properdin for activation and complex assembly
-
zymosan
-
it is capable of activating the classical pathway as well as the alternative pathway, when the classical pathway is blocked, mechanism, overview
-
additional information
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0000011 - 0.0089
Complement component C5
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.015 - 0.047
Complement component C5
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.000005 - 0.000072
C4b-binding protein
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.3
-
assay at
7.4
-
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
74000
-
C4bC2a, 1 * 198000 + 1 * 74000, C2a is the catalytic subunit, but unable to catalyze the reaction alone
198000
-
C4bC2a, 1 * 198000 + 1 * 74000, C2a is the catalytic subunit, but unable to catalyze the reaction alone
280000
-
gel filtration
305000
-
calculation from sedimentation coefficient and diffusion constant
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
glycoprotein
-
C2 is a glycosylated modular protein consisting of three domains
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
crystal structures of the C3b homologue cobra venom factor CVF in complex with C5, and in complex with C5 and the inhibitor SSL7, both at 4.3 A resolution. The structures reveal a parallel two-point attachment between C5 and CVF, where the presence of SSL7 only slightly affects the C5-CVF interface, explaining the IgA dependence for SSL7-mediated inhibition of C5 cleavage. CVF functions as a relatively rigid binding scaffold inducing a conformational change in C5, which positions its cleavage site in proximity to the serine protease Bb
Mg2+-bound C2a, hanging drop vapor diffusion method, 22°C, 0.002 ml of 20 mg/ml protein solution is mixed with 0.002 ml of well solution containing 20% w/v polyethylene glycol 10000, 0.1 M HEPES, pH 7.5, and 0.0004 ml of 0.3 M glycyl-glycyl-glycine, 3-7 days, X-ray diffraction structure determination and analysis at 1.9-2.3 A resolution
-
N-terminal segment C2b, by the hanging-drop vapor-diffusion method, to 1.8 A resolution. Space group P31 with unit-cell parameters a=b= 60.09 A and c = 61.69 A. Conformational changes of C2, C2a and C2b during C3 convertase C4bC2a formation
-
pH STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.5 - 9
-
at pH 6.5 more stable than at pH 9
81406
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
24
-
half-life: 400 min
30
-
half-life: 180 min
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
complement component C2b accelerates dissociation
-
complex C4bC2a extremely unstable
-
decay-accelerating factor from guinea pig erythrocyte stroma accelerates decay
-
dilute iodine solution stabilizes
-
dissociation of the classical-complement-pathway C3/C5 convertase by the regulators decay-accelerating factor, DAF, complement receptor 1, CR1, factor H and C4-binding protein C4BP, controls the function of the enzyme. Decay acceleration mediated by DAF, C4BP and CR1 requires interaction of the alpha4/5 region of C2a with a CCO2/CCO3 site of DAF or structurally homologous sites of CR1 and C4BP
-
in the presence of C4b-binding protein C4BP the assembly of the classical pathway C3-convertase is prevented and its decay is accelerated. Positively charged amino acids at the interface between alpha-chain CCP1 and CCP2 of C4BP are required for regulation of the classical C3-convertase
-
the C3 convertase is stabilized by the binding of properdin
-
the enzyme has a very short half-life. Dissociation of the two noncovalently bound subunits proceeds with a half-life of 1-3 min at 37°C under physiological conditions, and this rate increases greatly if regulatory proteins are present. Numerous decay-accelerating proteins are present in plasma and on host cells that bind to the noncatalytic subunit C4b and increase the rate at which the catalytic subunit C2a is released into the medium. C2a loses its enzymatic activity and its ability to bind to C4b upon release. Although C4b is able to rebind C2 and reform the enzyme, the interaction with most decay-accelerating factors also leads to permanent proteolytic interaction of the cell-bound subunit C4b by a fluid-phase protease Factor I. Theses regulatory events limit cleavage of C3, reduce release of the anaphylatoxin C3a and control the formation of more efficient C5 convertase enzymes
-
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
0°C, 8 d, 40% loss of activity
-
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
complement C2, by gel filtration
-
complement proteins purified by gel filtration, to homogeneity
-
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expression of C2 in insect cells
-
full-length C2 cDNA cloned into the baculovirus expression vector pACgp67A and cotransfected with BD Baculogold Bright linearized baculovirus DNA into sf9 insect cells. High-titer stocks produced in sf9 insect cells and used to infect High Five insect cells for protein expression
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
C3a generation and C5a generation is decreased in mice deficient in factor B
-
expression of classical C3 convertase (C4b2a) is decreased in case of hepatitis C viral infection
-
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C241A
-
C2 mutation, behaves similarly to the wild-type enzyme with slightly elevated hemolytic activity
Q243G
-
C2 mutation reduces C4b2a sensitivity to decay-accelerating factor DAF to 2% of the wild-type, moderately reduces C4b2a sensitivity to complement receptor 1-A to 55% of the wild-type
Y327A
-
C2 mutation reduces C4b2a sensitivity to decay-accelerating factor DAF and to complement receptor 1-A to less than 1% of the wild-type
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
-
activation of complement via the lectin pathway may be a more prominent contributor to the pathology of inflammatory reactions as compared to activation of complement via the classical pathway
pharmacology
-
pharmacological complement inhibition at the C3 convertase level is a promising approach for attenuation of neuroinflammation and secondary neurodegeneration after head injury