EC |
2.7.11.11 |
Accepted name: |
cAMP-dependent protein kinase |
Reaction: |
ATP + a [protein]-(L-serine/L-threonine) = ADP + a [protein]-(L-serine/L-threonine) phosphate |
Glossary: |
3′,5′-cyclic-AMP = cAMP |
Other name(s): |
PKA; protein kinase A; PKA catalytic (C) subunit; A kinase; ATP:protein phosphotransferase (cAMP-dependent) |
Systematic name: |
ATP:protein Ser/Thr-phosphotransferase (3′,5′-cAMP-dependent) |
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 Cα; 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 (Cα, Cβ, and Cγ) encoded by the paralogous genes PRKACA, PRKACB and PRKACG, respectively, and four R subunits (R1α, RIβ, RIIα and RIIβ), 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 α subunit (PHKA), and tyrosine 3-monooxygenase (TH) in mammals; Adr1, Whi3, Nej1, and Pyk1 in yeast. |
Links to other databases: |
BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 142008-29-5 |
References: |
1. |
Krebs, E.G. The Albert Lasker Medical Awards. Role of the cyclic AMP-dependent protein kinase in signal transduction. JAMA 262 (1989) 1815–1818. [DOI] [PMID: 2550680] |
2. |
Technikova-Dobrova, Z., Sardanelli, A.M., Speranza, F., Scacco, S., Signorile, A., Lorusso, V. and Papa, S. Cyclic adenosine monophosphate-dependent phosphorylation of mammalian mitochondrial proteins: enzyme and substrate characterization and functional role. Biochemistry 40 (2001) 13941–13947. [DOI] [PMID: 11705384] |
3. |
Smith, F.D., Samelson, B.K. and Scott, J.D. Discovery of cellular substrates for protein kinase A using a peptide array screening protocol. Biochem. J. 438 (2011) 103–110. [DOI] [PMID: 21644927] |
4. |
Broach, J.R. Nutritional control of growth and development in yeast. Genetics 192 (2012) 73–105. [DOI] [PMID: 22964838] |
5. |
Embogama, D.M. and Pflum, M.K. K-BILDS: a kinase substrate discovery tool. Chembiochem 18 (2017) 136–141. [DOI] [PMID: 27860220] |
6. |
Taylor, S.S., Wu, J., Bruystens, J.GH., Del Rio, J.C., Lu, T.W., Kornev, A.P. and Ten Eyck, L.F. From structure to the dynamic regulation of a molecular switch: A journey over 3 decades. J. Biol. Chem. 296:100746 (2021). [DOI] [PMID: 33957122] |
7. |
Ramms, D.J., Raimondi, F., Arang, N., Herberg, F.W., Taylor, S.S. and Gutkind, J.S. Gαs-protein kinase A (PKA) pathway signalopathies: the emerging genetic landscape and therapeutic potential of human diseases driven by aberrant Gαs-PKA signaling. Pharmacol Rev 73 (2021) 155–197. [DOI] [PMID: 34663687] |
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[EC 2.7.11.11 created 2005 (EC 2.7.1.37 part-incorporated 2005), modified 2022] |
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EC |
3.1.4.53 |
Accepted name: |
3′,5′-cyclic-AMP phosphodiesterase |
Reaction: |
adenosine 3′,5′-cyclic phosphate + H2O = AMP |
Glossary: |
AMP = adenosine 5′-phosphate |
Other name(s): |
cAMP-specific phosphodiesterase; cAMP-specific PDE; PDE1; PDE2A; PDE2B; PDE4; PDE7; PDE8; PDEB1; PDEB2 |
Systematic name: |
3′,5′-cyclic-AMP 5′-nucleotidohydrolase |
Comments: |
Requires Mg2+ or Mn2+ for activity [2]. This enzyme is specific for 3′,5′-cAMP and does not hydrolyse other nucleoside 3′,5′-cyclic phosphates such as cGMP (cf. EC 3.1.4.17, 3,5-cyclic-nucleotide phosphodiesterase and EC 3.1.4.35, 3,5-cyclic-GMP phosphodiesterase). It is involved in modulation of the levels of cAMP, which is a mediator in the processes of cell transformation and proliferation [3]. |
Links to other databases: |
BRENDA, EXPASY, KEGG, MetaCyc, PDB |
References: |
1. |
Alonso, G.D., Schoijet, A.C., Torres, H.N. and Flawiá, M.M. TcPDE4, a novel membrane-associated cAMP-specific phosphodiesterase from Trypanosoma cruzi. Mol. Biochem. Parasitol. 145 (2006) 40–49. [DOI] [PMID: 16225937] |
2. |
Bader, S., Kortholt, A., Snippe, H. and Van Haastert, P.J. DdPDE4, a novel cAMP-specific phosphodiesterase at the surface of Dictyostelium cells. J. Biol. Chem. 281 (2006) 20018–20026. [DOI] [PMID: 16644729] |
3. |
Rascón, A., Soderling, S.H., Schaefer, J.B. and Beavo, J.A. Cloning and characterization of a cAMP-specific phosphodiesterase (TbPDE2B) from Trypanosoma brucei. Proc. Natl. Acad. Sci. USA 99 (2002) 4714–4719. [DOI] [PMID: 11930017] |
4. |
Johner, A., Kunz, S., Linder, M., Shakur, Y. and Seebeck, T. Cyclic nucleotide specific phosphodiesterases of Leishmania major. BMC Microbiol. 6:25 (2006). [DOI] [PMID: 16522215] |
5. |
Lugnier, C., Keravis, T., Le Bec, A., Pauvert, O., Proteau, S. and Rousseau, E. Characterization of cyclic nucleotide phosphodiesterase isoforms associated to isolated cardiac nuclei. Biochim. Biophys. Acta 1472 (1999) 431–446. [DOI] [PMID: 10564757] |
6. |
Imamura, R., Yamanaka, K., Ogura, T., Hiraga, S., Fujita, N., Ishihama, A. and Niki, H. Identification of the cpdA gene encoding cyclic 3′,5′-adenosine monophosphate phosphodiesterase in Escherichia coli. J. Biol. Chem. 271 (1996) 25423–25429. [DOI] [PMID: 8810311] |
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[EC 3.1.4.53 created 2008, modified 2011] |
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EC |
4.6.1.1 |
Accepted name: |
adenylate cyclase |
Reaction: |
ATP = 3′,5′-cyclic AMP + diphosphate |
Other name(s): |
adenylylcyclase; adenyl cyclase; 3′,5′-cyclic AMP synthetase; ATP diphosphate-lyase (cyclizing) |
Systematic name: |
ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming) |
Comments: |
Also acts on dATP to form 3′,5′-cyclic dAMP. Requires pyruvate. Activated by NAD+ in the presence of EC 2.4.2.31 NAD(P)+—arginine ADP-ribosyltransferase. |
Links to other databases: |
BRENDA, EXPASY, GTD, KEGG, MetaCyc, PDB, CAS registry number: 9012-42-4 |
References: |
1. |
Hirata, M. and Hayaishi, O. Adenyl cyclase of Brevibacterium liquefaciens. Biochim. Biophys Acta 149 (1967) 1–11. [DOI] [PMID: 4295782] |
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[EC 4.6.1.1 created 1972] |
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