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Information on EC 2.7.11.11 - cAMP-dependent protein kinase

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EC Tree
IUBMB Comments
This eukaryotic enzyme recognizes the sequence -Arg-Arg-X-Ser*/Thr*-Hpo, where * indicates the phosphorylated residue and Hpo indicates a hydrophobic residue.The inactive holoenzyme is a heterotetramer composed of two regulatory (R) subunits and two catalytic (C) subunits. Each R subunit occludes the active site of a C subunit and contains two binding sites for 3',5'-cyclic-AMP (cAMP). Binding of cAMP activates the enzyme by causing conformational changes that release two free monomeric C subunits from a dimer of the R subunits, i.e. R2C2 + 4 cAMP = R2(cAMP)4 + 2 C. Activity requires phosphorylation of a conserved Thr in the activation loop (T-loop) sequence (Thr198 in human Calpha; Thr224 in budding yeast Tpk2), installed by auto-phosphorylation or by the 3-phosphoinositide-dependent protein kinase-1 (PDPK1). Certain R2C2 combinations can be localized to particular subcellular regions by their association with diverse species of 'A Kinase-Anchoring Proteins' (AKAPs). The enzyme has been characterized from many organisms. Humans have three C units (Calpha, Cbeta, and Cgamma) encoded by the paralogous genes PRKACA, PRKACB and PRKACG, respectively, and four R subunits (R1alpha, RIbeta, RIIalpha and RIIbeta), encoded by PKRAR1A, PKRAR1B, PKRAR2A and PKRAR2B, respectively. Yeast (Saccharomyces cerevisiae) has three C subunits (Tpk1, Tpk2, and Tpk3) encoded by the paralogous genes TPK1, TPK2 and TPK3, respectively, and a single R subunit (Bcy1) encoded by the BCY1 gene. Some validated substrates of the enzyme include cAMP-response element-binding protein (CREB), phosphorylase kinase alpha subunit (PHKA), and tyrosine 3-monooxygenase (TH) in mammals; Adr1, Whi3, Nej1, and Pyk1 in yeast.
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UNIPROT: P17612
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Word Map
The expected taxonomic range for this enzyme is: Eukaryota, Archaea, Bacteria
Reaction Schemes
+
a [protein]-(L-serine/L-threonine)
=
+
a [protein]-(L-serine/L-threonine) phosphate
Synonyms
camp-dependent protein kinase, a kinase, cyclic amp-dependent protein kinase, camp-pka, camp/protein kinase a, capk, prkaca, camp dependent protein kinase, camp-dependent pka, cyclic amp-dependent protein kinase a, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
3',5'-cyclic adenosine monophosphate-dependent protein kinase
-
cAMP-dependent protein kinase
-
cAMP-dependent protein kinase, alpha-catalytic subunit
-
PKA-Calpha
-
PKACalpha
-
PRKACA
catalytic subunit
protein kinase A
-
A kinase
-
-
-
-
ATP:protein phosphotransferase (cAMP-dependent)
-
-
-
-
cAMP-dependent protein kinase
-
-
-
-
PK-25
-
-
-
-
PKA
-
-
-
-
PKA C-alpha
-
-
-
-
PKA C-beta
-
-
-
-
PKA C-gamma
-
-
-
-
PKA catalytic (C) subunit
-
-
-
-
protein kinase A
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
ATP:protein Ser/Thr-phosphotransferase (3',5'-cAMP-dependent)
This eukaryotic enzyme recognizes the sequence -Arg-Arg-X-Ser*/Thr*-Hpo, where * indicates the phosphorylated residue and Hpo indicates a hydrophobic residue.The inactive holoenzyme is a heterotetramer composed of two regulatory (R) subunits and two catalytic (C) subunits. Each R subunit occludes the active site of a C subunit and contains two binding sites for 3',5'-cyclic-AMP (cAMP). Binding of cAMP activates the enzyme by causing conformational changes that release two free monomeric C subunits from a dimer of the R subunits, i.e. R2C2 + 4 cAMP = R2(cAMP)4 + 2 C. Activity requires phosphorylation of a conserved Thr in the activation loop (T-loop) sequence (Thr198 in human Calpha; Thr224 in budding yeast Tpk2), installed by auto-phosphorylation or by the 3-phosphoinositide-dependent protein kinase-1 (PDPK1). Certain R2C2 combinations can be localized to particular subcellular regions by their association with diverse species of 'A Kinase-Anchoring Proteins' (AKAPs). The enzyme has been characterized from many organisms. Humans have three C units (Calpha, Cbeta, and Cgamma) encoded by the paralogous genes PRKACA, PRKACB and PRKACG, respectively, and four R subunits (R1alpha, RIbeta, RIIalpha and RIIbeta), encoded by PKRAR1A, PKRAR1B, PKRAR2A and PKRAR2B, respectively. Yeast (Saccharomyces cerevisiae) has three C subunits (Tpk1, Tpk2, and Tpk3) encoded by the paralogous genes TPK1, TPK2 and TPK3, respectively, and a single R subunit (Bcy1) encoded by the BCY1 gene. Some validated substrates of the enzyme include cAMP-response element-binding protein (CREB), phosphorylase kinase alpha subunit (PHKA), and tyrosine 3-monooxygenase (TH) in mammals; Adr1, Whi3, Nej1, and Pyk1 in yeast.
CAS REGISTRY NUMBER
COMMENTARY hide
142008-29-5
-
142008-29-5
cAMP-dependent protein kinase
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
ATP + AID protein
ADP + phosphorylated AID protein
show the reaction diagram
-
-
-
?
ATP + bAD protein
ADP + phosphorylated bAD protein
show the reaction diagram
-
-
-
?
ATP + calpain 2
ADP + phosphorylated calpain 2
show the reaction diagram
-
-
-
?
ATP + CFTR protein
ADP + phosphorylated CFTR protein
show the reaction diagram
-
-
-
?
ATP + CREb protein
ADP + phosphorylated CREb protein
show the reaction diagram
-
-
-
?
ATP + GRK2 protein
ADP + phosphorylated GRK2 protein
show the reaction diagram
-
-
-
?
ATP + GSK3 protein
ADP + phosphorylated GSK3 protein
show the reaction diagram
-
-
-
?
ATP + HSL protein
ADP + phosphorylated HSL protein
show the reaction diagram
-
-
-
?
ATP + KCNN2 protein
ADP + phosphorylated KCNN2 protein
show the reaction diagram
-
-
-
?
ATP + Kemptide
ADP + phosphorylated Kemptide
show the reaction diagram
-
-
-
?
ATP + NFAT2 protein
ADP + phosphorylated NFAT2 protein
show the reaction diagram
-
-
-
?
ATP + VASP protein
ADP + phosphorylated VASP protein
show the reaction diagram
-
-
-
?
additional information
?
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
ATP + AID protein
ADP + phosphorylated AID protein
show the reaction diagram
-
-
-
?
ATP + bAD protein
ADP + phosphorylated bAD protein
show the reaction diagram
-
-
-
?
ATP + calpain 2
ADP + phosphorylated calpain 2
show the reaction diagram
-
-
-
?
ATP + CFTR protein
ADP + phosphorylated CFTR protein
show the reaction diagram
-
-
-
?
ATP + CREb protein
ADP + phosphorylated CREb protein
show the reaction diagram
-
-
-
?
ATP + GRK2 protein
ADP + phosphorylated GRK2 protein
show the reaction diagram
-
-
-
?
ATP + GSK3 protein
ADP + phosphorylated GSK3 protein
show the reaction diagram
-
-
-
?
ATP + HSL protein
ADP + phosphorylated HSL protein
show the reaction diagram
-
-
-
?
ATP + KCNN2 protein
ADP + phosphorylated KCNN2 protein
show the reaction diagram
-
-
-
?
ATP + Kemptide
ADP + phosphorylated Kemptide
show the reaction diagram
-
-
-
?
ATP + NFAT2 protein
ADP + phosphorylated NFAT2 protein
show the reaction diagram
-
-
-
?
ATP + VASP protein
ADP + phosphorylated VASP protein
show the reaction diagram
-
-
-
?
additional information
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
cAMP-dependent protein kinase inhibitor(5-24)
peptide substrate-competitive inhibitor
-
N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide
i.e. H89, ATP-competitive inhibitor
-
N2-(6-([N2-(9-(4-[7-(2-ethoxy-2-oxoethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperazin-1-yl)-9-oxononanoyl)-D-arginyl]amino)hexanoyl)-D-argininamide
i.e. ARC-2116, very weak bisubstrate inhibitor of PKAcalpha
-
N2-(6-[(N-(9-oxo-9-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl]nonanoyl)-D-alanyl)amino]hexanoyl)-D-arginyl-D-arginyl-D-arginyl-D-arginyl-D-arginyl-D-argininamide
i.e. ARC-2123, photocaging of the tight-binding bisubstrate inhibitor of cAMP-dependent protein kinase (PKA) with a nitrodibenzofuran-based group fully abolishes its inhibitory potency
-
N2-(6-[(N2-(9-oxo-9-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl]nonanoyl)-D-arginyl)amino]hexanoyl)-D-argininamide
i.e. ARC-1408 , photocaging of the tight-binding bisubstrate inhibitor of cAMP-dependent protein kinase (PKA) with a nitrodibenzofuran-based group fully abolishes its inhibitory potency
-
N2-(6-[(N6-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]-N2-(9-oxo-9-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl]nonanoyl)-D-lysyl)amino]hexanoyl)-D-argininamide
i.e. ARC-2115, photocaging of the tight-binding bisubstrate inhibitor of cAMP-dependent protein kinase (PKA) with a nitrodibenzofuran-based group fully abolishes its inhibitory potency
-
N2-(9-oxo-9-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl]nonanoyl)-D-arginyl-D-arginyl-D-arginyl-D-arginyl-D-arginyl-D-arginyl-D-lysinamide
i.e. ARC-1411, photocaging of the tight-binding bisubstrate inhibitor of cAMP-dependent protein kinase (PKA) with a nitrodibenzofuran-based group fully abolishes its inhibitory potency
-
N2-[6-((N-[9-(4-(7-[(3-nitrodibenzo[b,d]furan-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-9-oxononanoyl]-D-alanyl)amino)hexanoyl]-D-arginyl-D-arginyl-D-arginyl-D-arginyl-D-arginyl-D-argininamide
i.e. ARC-2113, very weak bisubstrate inhibitor of PKAcalpha
-
N6-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]-N2-(6-[(N2-(9-oxo-9-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl]nonanoyl)-D-arginyl)amino]hexanoyl)-D-lysinamide
i.e. ARC-2114, photocaging of the tight-binding bisubstrate inhibitor of cAMP-dependent protein kinase (PKA) with a nitrodibenzofuran-based group fully abolishes its inhibitory potency
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0169 - 0.0276
ATP
0.00974 - 0.0609
Kemptide
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2.15 - 6.03
ATP
7.5 - 14.5
Kemptide
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
77.9 - 356.8
ATP
123.2 - 1488.7
Kemptide
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0000037 - 0.00125
cAMP-dependent protein kinase inhibitor(5-24)
-
0.0000255 - 0.000278
N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0000074 - 0.00187
cAMP-dependent protein kinase inhibitor(5-24)
-
0.0000606 - 0.0000633
N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
SwissProt
Manually annotated by BRENDA team
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
of patients with adrenocorticotropic hormone-independent Cushing's syndrome
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
exploration and elucidation of the evolution of the alternative 5' exons and the splicing pattern giving rise to the numerous PKA catalytic subunit isoforms. Alignment of the segments encoded by Calpha1- and Cbeta1-specific 5'exons
physiological function
the cAMP-dependent protein kinase downregulates glucose-6-phosphatase expression through retinoic acid related orphan receptor alpha (RORalpha) and steroid receptor coactivator 2 (SRC-2) coactivator transcriptional activity
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
KAPCA_HUMAN
351
0
40590
Swiss-Prot
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
unmyristylated Calpha2 may be essential for fertility in the male
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
L205R
the mutation affects the kinetics of both Kemptide and ATP as substrates, decreasing the catalytic efficiency (kcat/KM) for each substrate by 12-fold and 4.5-fold, respectively. The L205R mutation has no effect on the potency of the inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89), but causes a more than 250-fold loss in potency for cAMP-dependent protein kinase inhibitor(5-24)
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Agustin, J.T.; Wilkerson, C.G.; Witman, G.B.
The unique catalytic subunit of sperm cAMP-dependent protein kinase is the product of an alternative Calpha mRNA expressed specifically in spermatogenic cells
Mol. Biol. Cell
11
3031-3044
2000
Homo sapiens (P17612), Homo sapiens
Manually annotated by BRENDA team
Desseyn, J.L.; Burton, K.A.; McKnight, G.S.
Expression of a nonmyristylated variant of the catalytic subunit of protein kinase A during male germ-cell development
Proc. Natl. Acad. Sci. USA
97
6433-6438
2000
Homo sapiens (P17612)
Manually annotated by BRENDA team
Maldonado, F.; Hanks, S.K.
A cDNA clone encoding human cAMP-dependent protein kinase catalytic subunit C alpha
Nucleic Acids Res.
16
8189-8190
1988
Homo sapiens (P17612), Homo sapiens
Manually annotated by BRENDA team
Huang, S.; Li, Q.; Alberts, I.; Li, X.
PRKX, a novel cAMP-dependent protein kinase member, plays an important role in development
J. Cell. Biochem.
117
566-573
2016
Homo sapiens (P17612), Homo sapiens
Manually annotated by BRENDA team
Sormus, T.; Lavogina, D.; Enkvist, E.; Uri, A.; Viht, K.
Efficient photocaging of a tight-binding bisubstrate inhibitor of cAMP-dependent protein kinase
Chem. Commun. (Camb.)
55
11147-11150
2019
Homo sapiens (P17612)
Manually annotated by BRENDA team
Luzi, N.M.; Lyons, C.E.; Peterson, D.L.; Ellis, K.C.
Kinetics and inhibition studies of the L205R mutant of cAMP-dependent protein kinase involved in Cushings syndrome
FEBS open bio
8
606-613
2018
Homo sapiens (P17612), Homo sapiens
Manually annotated by BRENDA team
Madsen, A.; Bjune, J.; Bjorkhaug, L.; Mellgren, G.; Sagen, J.
The cAMP-dependent protein kinase downregulates glucose-6-phosphatase expression through RORalpha and SRC-2 coactivator transcriptional activity
Mol. Cell. Endocrinol.
419
92-101
2016
Homo sapiens (P17612)
Manually annotated by BRENDA team
Soberg, K.; Moen, L.V.; Skalhegg, B.S.; Laerdahl, J.K.
Evolution of the cAMP-dependent protein kinase (PKA) catalytic subunit isoforms
PLoS ONE
12
e0181091
2017
Alligator mississippiensis, Gallus gallus, Anolis carolinensis, Callorhinchus milii, Aquila chrysaetos, Mus musculus (P05132), Mus musculus (P68181), Homo sapiens (P17612), Homo sapiens (P22694)
Manually annotated by BRENDA team