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Information on EC 2.7.11.11 - cAMP-dependent protein kinase and Organism(s) Plasmodium falciparum and UniProt Accession Q7K6A0
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2.7.11.11 cAMP-dependent protein kinaseIUBMB 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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Word Map
- 2.7.11.11
- cyclase
- forskolin
- agonist
- adenylate
- phosphodiesterase
- cardiac
-
adenylyl
- phosphoprotein
- isoproterenol
- synaptic
-
holoenzyme
- cgmp
-
phorbol
-
dibutyryl
- a-kinase
- prostaglandin
- calmodulin
-
cgmp-dependent
-
beta-adrenergic
- creb
- phosphopeptide
-
desensitization
-
akaps
- autophosphorylation
-
camp-mediated
-
gamma-32patp
- pki
- rp-camps
-
pka-dependent
-
camp-responsive
-
sarcoplasmic
-
l-type
- phospholamban
-
8-br-camp
- 8-bromo-camp
-
calmodulin-dependent
-
pka-mediated
-
camp-independent
-
patch-clamp
- 3',5'-monophosphate
- ibmx
-
camp-induced
- 3-isobutyl-1-methylxanthine
- isoprenaline
-
camp-regulated
-
camp-stimulated
- dibutyryl-camp
-
phosphorylatable
- rolipram
-
phospholipid-dependent
- medicine
- drug development
The taxonomic range for the selected organisms is: Plasmodium falciparum
The expected taxonomic range for this enzyme is: Eukaryota, Archaea, Bacteria
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
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
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
PKA
-
-
-
-
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
142008-29-5
-
142008-29-5
cAMP-dependent protein kinase
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + apical membrane antigen 1
ADP + phosphorylated apical membrane antigen 1
-
-
-
?
additional information
?
-
the PKA catalytic subunit a serine/threonine kinase, that can phosphorylate many substrates, such as additional protein kinases and transcription factors
-
-
?
additional information
?
-
the PKA catalytic subunit a serine/threonine kinase, that can phosphorylate many substrates, such as additional protein kinases and transcription factors
-
-
?
additional information
?
-
-
the PKA catalytic subunit a serine/threonine kinase, that can phosphorylate many substrates, such as additional protein kinases and transcription factors
-
-
?
additional information
?
-
the PKA catalytic subunit a serine/threonine kinase, that can phosphorylate many substrates, such as additional protein kinases and transcription factors
-
-
?
additional information
?
-
the PKA catalytic subunit a serine/threonine kinase, that can phosphorylate many substrates, such as additional protein kinases and transcription factors
-
-
?
additional information
?
-
-
the PKA catalytic subunit a serine/threonine kinase, that can phosphorylate many substrates, such as additional protein kinases and transcription factors
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + apical membrane antigen 1
ADP + phosphorylated apical membrane antigen 1
-
-
-
?
additional information
?
-
the PKA catalytic subunit a serine/threonine kinase, that can phosphorylate many substrates, such as additional protein kinases and transcription factors
-
-
?
additional information
?
-
the PKA catalytic subunit a serine/threonine kinase, that can phosphorylate many substrates, such as additional protein kinases and transcription factors
-
-
?
additional information
?
-
-
the PKA catalytic subunit a serine/threonine kinase, that can phosphorylate many substrates, such as additional protein kinases and transcription factors
-
-
?
additional information
?
-
the PKA catalytic subunit a serine/threonine kinase, that can phosphorylate many substrates, such as additional protein kinases and transcription factors
-
-
?
additional information
?
-
the PKA catalytic subunit a serine/threonine kinase, that can phosphorylate many substrates, such as additional protein kinases and transcription factors
-
-
?
additional information
?
-
-
the PKA catalytic subunit a serine/threonine kinase, that can phosphorylate many substrates, such as additional protein kinases and transcription factors
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ATP
residues of the PfPKA catalytic subunit G40, G42, and G45 are involved in ATP fixation, E82 in ATP stabiization, D175 in orienting the phosphate of ATP
ATP
residues of the PfPKA catalytic subunit G40, G42, and G45 are involved in ATP fixation, E82 in ATP stabiization, D175 in orienting the phosphate of ATP
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
H89
inhibits PfPKA catalytic subunit activity in vitro, leads to parasite growth arrest and morphological alteration
protein kinase inhibitor
PKI, a natural endogenous inhibitor
-
H89
inhibits PfPKA catalytic subunit activity in vitro, leads to parasite growth arrest and morphological alteration
protein kinase inhibitor
PKI, a natural endogenous inhibitor
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
cAMP
binding of 2 cAMP molecules to each regulatory subunit alters its affinity for the catalytic subunit, resulting in release of the active catalytic subunit
cAMP
binding of 2 cAMP molecules to each regulatory subunit alters its affinity for the catalytic subunit, resulting in release of the active catalytic subunit
cAMP
the regulatory subunit of Plasmodium falciparum protein kinase A (PfPKA-R) holds the kinase's catalytic subunit (C) in an inactive state by exerting an allosteric inhibitory effect. When two cAMP molecules bind to PKA-R, they stabilize a structural conformation that facilitates its dissociation, freeing PKA-C to phosphorylate downstream substrates such as apical membrane antigen 1
pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
additional information
in cytosolic extracts of both the asexual and sexual stages of the parasite, catalytic and regulatory subunits of PfPKA are expressed weakly during the ring and trophozoite stages compared to the schizont stage, and pfpkac mRNA levels are lower in gametocytes and gametes
additional information
in cytosolic extracts of both the asexual and sexual stages of the parasite, catalytic and regulatory subunits of PfPKA are expressed weakly during the ring and trophozoite stages compared to the schizont stage, and pfpkac mRNA levels are lower in gametocytes and gametes
additional information
-
in cytosolic extracts of both the asexual and sexual stages of the parasite, catalytic and regulatory subunits of PfPKA are expressed weakly during the ring and trophozoite stages compared to the schizont stage, and pfpkac mRNA levels are lower in gametocytes and gametes
additional information
in cytosolic extracts of both the asexual and sexual stages of the parasite, catalytic and regulatory subunits of PfPKA are expressed weakly during the ring and trophozoite stages compared to the schizont stage, and pfpkac mRNA levels are lower in gametocytes and gametes
additional information
in cytosolic extracts of both the asexual and sexual stages of the parasite, catalytic and regulatory subunits of PfPKA are expressed weakly during the ring and trophozoite stages compared to the schizont stage, and pfpkac mRNA levels are lower in gametocytes and gametes
additional information
-
in cytosolic extracts of both the asexual and sexual stages of the parasite, catalytic and regulatory subunits of PfPKA are expressed weakly during the ring and trophozoite stages compared to the schizont stage, and pfpkac mRNA levels are lower in gametocytes and gametes
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
downregulation of gene pfpkac mRNA using gene silencing leads to morphological changes in schizont stages and cell cycle arrest, and is also associated with a compensatory decrease in pfpkar mRNA levels, suggesting a transcriptional self-regulation of the PfPKA signalling network
metabolism
the cAMP/PfPKA signalling pathway is essential for parasite growth and survival, mechanism and regulation, model of cAMP/PKA signalling pathway in Plasmodium falciparum, and of signalling events including PfPKA catalytic subunit during the Plasmodium falciparum life cycle, overview. The cAMP pathway regulates sporozoite motility and hepatic cell invasion by Plasmodium falciparum sporozoites. Putative role for PfPKA in the induction of gametocytogenesis, in erythrocyte invasion by merozoites, and in the regulation of mitochondrial protein traffic. Highly complex relationship between cAMP/PfPKA and calcium pathways in the asexual life cycle, with a key role of PfPKA in anion transport across the erythrocyte membrane, overview
physiological function
Plasmodium falciparum cAMP-dependent protein kinase plays an important role in the parasite's life cycle. The parasites appear to have tightly controlled mechanisms for selfregulating PfPKA levels to maintain appropriate PKA signalling
evolution
cAMP-dependent protein kinases are a major regulator of signal transduction that arose prior to the origin of multicellularity in eukaryotes. In mammalian protein kinase A (PKAs), the two binding sites of the regulatpory R subunits display positive cooperativity upon cAMP binding. The C-terminal CBD2, or B site, is always exposed and immediately available for nucleotide binding. When this site is occupied, it stabilizes structural changes within CBD1 that drastically increase its affinity for cAMP and promote subunit dissociation and hence activation. The regulatory subunit of Plasmodium falciparum protein kinase A (PfPKA-R) utilizes a similar two-state cooperative binding mechanism that provides an enthalpically driven interaction with nanomolar affinity for cAMP, as in vertebrates
malfunction
metabolism
the cAMP/PfPKA signalling pathway is essential for parasite growth and survival, mechanism and regulation, model of cAMP/PKA signalling pathway in Plasmodium falciparum, and of signalling events including PfPKA catalytic subunit during the Plasmodium falciparum life cycle, overview. The cAMP pathway regulates sporozoite motility and hepatic cell invasion by Plasmodium falciparum sporozoites. Putative role for PfPKA in the induction of gametocytogenesis, in erythrocyte invasion by merozoites, and in the regulation of mitochondrial protein traffic. Highly complex relationship between cAMP/PfPKA and calcium pathways in the asexual life cycle, with a key role of PfPKA in anion transport across the erythrocyte membrane, overview
physiological function
additional information
malfunction
downregulation of gene pfpkac mRNA using gene silencing leads to morphological changes in schizont stages and cell cycle arrest, and is also associated with a compensatory decrease in pfpkar mRNA levels, suggesting a transcriptional self-regulation of the PfPKA signalling network
malfunction
uncontrolled premature activation of cAMP-dependent protein kinase regulatory subunit (PfPKA-R) is disruptive to parasite survival
physiological function
Plasmodium falciparum cAMP-dependent protein kinase plays an important role in the parasite's life cycle. The parasites appear to have tightly controlled mechanisms for selfregulating PfPKA levels to maintain appropriate PKA signalling
physiological function
cAMP-dependent protein kinases are a major regulator of signal transduction
additional information
PKA has two regulatory subunits, which bind to and inhibit two catalytic subunits, domain organization and structure comparison with mammalian/human enzymes, overview. Sequence E221-C226-P227-P228-F229-Y23 and residue E161 of the PfPKA catalytic subunit are involved in substrate recognition, residues K63, D211, D157, N162, and E199 are required for catalysis
additional information
PKA has two regulatory subunits, which bind to and inhibit two catalytic subunits, domain organization and structure comparison with mammalian/human enzymes, overview. Sequence E221-C226-P227-P228-F229-Y23 and residue E161 of the PfPKA catalytic subunit are involved in substrate recognition, residues K63, D211, D157, N162, and E199 are required for catalysis
additional information
-
PKA has two regulatory subunits, which bind to and inhibit two catalytic subunits, domain organization and structure comparison with mammalian/human enzymes, overview. Sequence E221-C226-P227-P228-F229-Y23 and residue E161 of the PfPKA catalytic subunit are involved in substrate recognition, residues K63, D211, D157, N162, and E199 are required for catalysis
additional information
PKA has two regulatory subunits, which bind to and inhibit two catalytic subunits, domain organization and structure comparison with mammalian/human enzymes, overview. Sequence E221-C226-P227-P228-F229-Y23 and residue E161 of the PfPKA catalytic subunit are involved in substrate recognition, residues K63, D211, D157, N162, and E199 are required for catalysis
additional information
PKA has two regulatory subunits, which bind to and inhibit two catalytic subunits, domain organization and structure comparison with mammalian/human enzymes, overview. Sequence E221-C226-P227-P228-F229-Y23 and residue E161 of the PfPKA catalytic subunit are involved in substrate recognition, residues K63, D211, D157, N162, and E199 are required for catalysis
additional information
-
PKA has two regulatory subunits, which bind to and inhibit two catalytic subunits, domain organization and structure comparison with mammalian/human enzymes, overview. Sequence E221-C226-P227-P228-F229-Y23 and residue E161 of the PfPKA catalytic subunit are involved in substrate recognition, residues K63, D211, D157, N162, and E199 are required for catalysis
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
42200
alpha2beta2, 2 * 42200, about, catalytic subunit, + 2 * 50800, about, regulatory subunit, sequence calculation
50800
alpha2beta2, 2 * 42200, about, catalytic subunit, + 2 * 50800, about, regulatory subunit, sequence calculation
42200
alpha2beta2, 2 * 42200, about, catalytic subunit, + 2 * 50800, about, regulatory subunit, sequence calculation
50800
alpha2beta2, 2 * 42200, about, catalytic subunit, + 2 * 50800, about, regulatory subunit, sequence calculation
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
heterotetramer
alpha2beta2, 2 * 42200, about, catalytic subunit, + 2 * 50800, about, regulatory subunit, sequence calculation
heterotetramer
alpha2beta2, 2 * 42200, about, catalytic subunit, + 2 * 50800, about, regulatory subunit, sequence calculation
additional information
additional information
structure comparison with mammalian enzymes, overview
additional information
structure comparison with mammalian enzymes, overview
additional information
-
structure comparison with mammalian enzymes, overview
additional information
structure comparison with mammalian enzymes, overview
additional information
structure comparison with mammalian enzymes, overview
additional information
-
structure comparison with mammalian enzymes, overview
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene pfpkac encoding the catalytic subunit, phylogenetic analysis
gene pfpkar encoding the regulatory subunit, phylogenetic analysis and sequence comparison
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
the enzyme represents an attractive target for the development of anti-malarial drugs
drug development
the enzyme represents an attractive target for the development of anti-malarial drugs
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Wurtz, N.; Chapus, C.; Desplans, J.; Parzy, D.
cAMP-dependent protein kinase from Plasmodium falciparum: an update
Parasitology
138
1-25
2011
Plasmodium falciparum (Q7K6A0), Plasmodium falciparum (Q7KQK0), Plasmodium falciparum
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