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Information on EC 2.7.7.85 - diadenylate cyclase and Organism(s) Bacillus subtilis and UniProt Accession P37573
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2.7.7.85 diadenylate cyclaseIUBMB Comments
Cyclic di-3',5'-adenylate is a bioactive molecule produced by some bacteria and archaea, which may function as a secondary signalling molecule .
The intracellular bacterial pathogen Listeria monocytogenes secretes it into the host's cytosol, where it triggers a cytosolic pathway of innate immunity .
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Word Map
- 2.7.7.85
- monophosphate
- phosphodiesterases
- cyclases
- gdpp
- monocytogenes
-
listeria
- papa
- c-di-gmp
-
sporulation
-
di-adenosine
- cdar
- glmm
-
osmoregulation
-
holliday
-
phosphoglucosamine
-
sporulation-specific
- drug development
The taxonomic range for the selected organisms is: Bacillus subtilis
The expected taxonomic range for this enzyme is: Bacteria, Archaea
The expected taxonomic range for this enzyme is: Bacteria, Archaea
Synonyms
diadenylate cyclase, dna integrity scanning protein, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
CdaA
CdaS
Cyclic di-AMP synthase
cyclic-di-AMP synthase
-
-
-
-
Dac
dacA
disA
dacA
-
-
-
-
disA
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
ATP:ATP adenylyltransferase (cyclizing)
Cyclic di-3',5'-adenylate is a bioactive molecule produced by some bacteria and archaea, which may function as a secondary signalling molecule [1].
The intracellular bacterial pathogen Listeria monocytogenes secretes it into the host's cytosol, where it triggers a cytosolic pathway of innate immunity [2].
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
2 ATP
2 diphosphate + cyclic di-3',5'-adenylate
-
-
-
?
2 ATP
2 diphosphate + cyclic di-3',5'-adenylate
-
-
-
?
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
2 ATP
2 diphosphate + cyclic di-3',5'-adenylate
-
-
-
?
2 ATP
2 diphosphate + cyclic di-3',5'-adenylate
-
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
GlmM
binds directly to enzyme CdaA in the CdaA-CdaR-GlmM protein complex
-
theaflavin-3'-gallate
-
specifically inhibits DisA but not phosphodiesterase YybT
theaflavin-3,3'-digallate
-
specifically inhibits DisA but not phosphodiesterase YybT
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
CdaR
binds directly to enzyme CdaA in the CdaA-CdaR-GlmM protein complex
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
most bacteria possess only one diadenylate cyclase, either CdaA or DisA. In contrast, the spore-forming Gram-positive model organism Bacillus subtilis has the three enzymes, DisA, CdaA, and CdaS. The presence of three diadenylate cyclases is limited to members of the spore-forming genus Bacillus
malfunction
none of the corresponding genes is essential, but a strain lacking both DisA and CdaA is not viable under standard laboratory conditions
metabolism
CdaS is unable to replace the other enzymes since it is expressed only late during sporulation in the forespore but not in growing cells
physiological function
in the diadenylate cyclases, one type of catalytic domain, the diadenylate cyclase (DAC) domain, is coupled to various other domains that control the localization, the protein-protein interactions, and the regulation of the enzymes. None of the corresponding genes is essential
evolution
most bacteria possess only one diadenylate cyclase, either CdaA or DisA. In contrast, the spore-forming Gram-positive model organism Bacillus subtilis has the three enzymes, DisA, CdaA, and CdaS. The presence of three diadenylate cyclases is limited to members of the spore-forming genus Bacillus
malfunction
none of the corresponding genes is essential, but a strain lacking both DisA and CdaA is not viable under standard laboratory conditions
metabolism
physiological function
additional information
metabolism
CdaS is unable to replace the other enzymes since it is expressed only late during sporulation in the forespore but not in growing cells
metabolism
regulation of diadenylate cyclase activity in bacteria, replenishing the cyclic-di-AMP pool, overview. The intracellular pool of c-di-AMP is maintained by the activities of diadenylate cyclase (DAC) and phosphodiesterase (PDE) enzymes, as well as possibly via c-di-AMP export. Transient regulation of DAC enzyme in the CdaA-CdaR-GlmM protein complex
physiological function
-
the signaling nucleotide cyclic di-3',5'-adenylate is essential for the viability of Bacillus subtilis. However, excess cyclic di-3',5'-adenylate also harms the cells. The activity of the cyclases is subject to regulation. The activity of the diadenylate cyclases is controlled by distinct molecular mechanisms. Isoenzyme CdaA is stimulated by a regulatory interaction with the CdaR protein. In contrast, the activity of CdaS seems to be intrinsically restricted, and a single amino acid substitution is sufficient to drastically increase the activity of the enzyme
physiological function
enzyme forms a complex with the regulatory protein CdaR and the glucosamine-6-phosphate mutase GlmM. cCaA, cdaR, and GlmM form a gene cluster that is conserved throughout the firmicutes. Data suggest that GlmM and GlmS are involved in the control of cyclic di-AMP synthesis. They convert glutamine and fructose-6-phosphate to glutamate and glucosamine-1-phosphate. Cyclic di-AMP synthesis is enhanced if the cells are grown in the presence of glutamate compared to that in glutamine-grown cells
physiological function
a broadly conserved second messenger is cyclic-di-AMP (c-di-AMP) which regulates a range of processes including cell wall homeostasis, potassium uptake, DNA repair, fatty acid synthesis, biofilm formation and central metabolism in bacteria. Regulators of the membrane-bound enzyme CdaA are the membrane-bound CdaR and the phosphoglucosamine mutase GlmM which both bind directly to the DAC
physiological function
in the diadenylate cyclases, one type of catalytic domain, the diadenylate cyclase (DAC) domain, is coupled to various other domains that control the localization, the protein-protein interactions, and the regulation of the enzymes. None of the corresponding genes is essential
physiological function
in the diadenylate cyclases, one type of catalytic domain, the diadenylate cyclase (DAC) domain, is coupled to various other domains that control the localization, the protein-protein interactions, and the regulation of the enzymes. None of the corresponding genes is essential. CdaS is unable to replace the other enzymes since it is expressed only late during sporulation in the forespore but not in growing cells
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
homodimer
the dimer-forming CdaA contains three transmembrane domains with the DAC domain (Dis_N Pfam PF02457) located intracellularly, while CdaR contains one transmembrane domain and several YbbR domains (Pfam PF07949) predicted to be located extracellularly
additional information
the DAC enzyme is organized in the CdaA-CdaR-GlmM protein complex
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
very low expression of CdaS as the single diadenylate cyclase results in the appearance of spontaneous suppressor mutations. Several of these mutations in the cdaS gene affect the N-terminal domain of CdaS. The corresponding CdaS mutant proteins exhibit a significantly increased enzymatic activity. Deletion of the first or both N-terminal domain alpha-helices results also in strongly increased activity. The mutations and the deletions of the N-terminal domain result in conformational changes that lead to highly increased enzymatic activity. Although the full-length CdaS protein forms hexamers, a truncated version with a deletion of the first N-terminal helix formed dimers with high enzyme activity
additional information
-
very low expression of CdaS as the single diadenylate cyclase results in the appearance of spontaneous suppressor mutations. Several of these mutations in the cdaS gene affect the N-terminal domain of CdaS. The corresponding CdaS mutant proteins exhibit a significantly increased enzymatic activity. Deletion of the first or both N-terminal domain alpha-helices results also in strongly increased activity. The mutations and the deletions of the N-terminal domain result in conformational changes that lead to highly increased enzymatic activity. Although the full-length CdaS protein forms hexamers, a truncated version with a deletion of the first N-terminal helix formed dimers with high enzyme activity
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
cdaA and cdaS genes are cloned into the expression vector pET28a, expression in Escherichia coli
-
gene cdaA, genetic organization of CdaA, CdaR, and GlmM encoding genes
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Mehne, F.M.; Gunka, K.; Eilers, H.; Herzberg, C.; Kaever, V.; Stuelke, J.
Cyclic di-AMP homeostasis in Bacillus subtilis: both lack and high level accumulation of the nucleotide are detrimental for cell growth
J. Biol. Chem.
288
2004-2017
2013
Bacillus subtilis, Bacillus subtilis 168
Witte, G.; Hartung, S.; Buettner, K.; Hopfner, K.P.
Structural biochemistry of a bacterial checkpoint protein reveals diadenylate cyclase activity regulated by DNA recombination intermediates
Mol. Cell
30
167-178
2008
Bacillus subtilis (P37573), Bacillus subtilis, Thermotoga maritima (Q9WY43)
Gundlach, J.; Mehne, F.M.; Herzberg, C.; Kampf, J.; Valerius, O.; Kaever, V.; Stuelke, J.
An essential poison: synthesis and degradation of cyclic di-AMP in Bacillus subtilis
J. Bacteriol.
197
3265-3274
2015
Bacillus subtilis (Q45589), Bacillus subtilis, Bacillus subtilis 168 (Q45589)
Mehne, F.M.; Schroeder-Tittmann, K.; Eijlander, R.T.; Herzberg, C.; Hewitt, L.; Kaever, V.; Lewis, R.J.; Kuipers, O.P.; Tittmann, K.; Stuelke, J.
Control of the diadenylate cyclase CdaS in Bacillus subtilis: an autoinhibitory domain limits cyclic di-AMP production
J. Biol. Chem.
289
21098-21107
2014
Bacillus subtilis (O31854), Bacillus subtilis, Bacillus subtilis 168 (O31854)
Opoku-Temeng, C.; Sintim, H.O.
Inhibition of cyclic diadenylate cyclase, DisA, by polyphenols
Sci. Rep.
6
25445
2016
Bacillus subtilis
Pham, T.H.; Liang, Z.X.; Marcellin, E.; Turner, M.S.
Replenishing the cyclic-di-AMP pool regulation of diadenylate cyclase activity in bacteria
Curr. Genet.
62
731-738
2016
Bacillus amyloliquefaciens (A0A0D7XMK3), Bacillus anthracis (A0A2A8KZ47), Bacillus licheniformis (Q65P49), Bacillus licheniformis ATCC 14580 (Q65P49), Bacillus licheniformis DSM 13 (Q65P49), Bacillus licheniformis Gibson 46 (Q65P49), Bacillus licheniformis JCM 2505 (Q65P49), Bacillus licheniformis NBRC 12200 (Q65P49), Bacillus licheniformis NCIMB 9375 (Q65P49), Bacillus licheniformis NRRL NRS-1264 (Q65P49), Bacillus subtilis (Q45589), Bacillus subtilis 168 (Q45589), Clostridium botulinum (A0A0C2N691), Clostridium ljungdahlii (D8GIJ7), Clostridium ljungdahlii ATCC 55383 (D8GIJ7), Clostridium ljungdahlii DSM 13528 (D8GIJ7), Clostridium ljungdahlii PETC (D8GIJ7), Clostridium novyi (A0PXZ3), Clostridium novyi NT (A0PXZ3), Clostridium perfringens (A0A0H2YU52), Clostridium perfringens DSM 756 (A0A0H2YU52), Clostridium perfringens JCM 1290 (A0A0H2YU52), Clostridium perfringens NCIMB 6125 (A0A0H2YU52), Clostridium perfringens NCTC 8237 (A0A0H2YU52), Clostridium perfringens type A (A0A0H2YU52), Enterococcus faecalis (A0A2Z6BU13), Enterococcus faecalis ERV62 (A0A2Z6BU13), Geobacter sulfurreducens (Q74EU1), Geobacter sulfurreducens ATCC 51573 (Q74EU1), Geobacter sulfurreducens PCA (Q74EU1), Lacticaseibacillus rhamnosus (A0A2A5L6R6), Lacticaseibacillus rhamnosus ATCC 8530 (A0A2A5L6R6), Lactobacillus acidophilus (Q5FL37), Lactobacillus acidophilus ATCC 700396 (Q5FL37), Lactobacillus acidophilus N2 (Q5FL37), Lactobacillus acidophilus NCFM (Q5FL37), Lactobacillus acidophilus NCK56 (Q5FL37), Lactococcus cremoris (A2RIF7), Lactococcus cremoris (Q031P4), Lactococcus cremoris MG1363 (A2RIF7), Lactococcus cremoris Sk11 (Q031P4), Listeria monocytogenes EGD (Q8Y5E4), Listeria monocytogenes EGD ATCC BAA-679 (Q8Y5E4), Listeria monocytogenes EGD EGD-e (Q8Y5E4), Staphylococcus aureus (Q2FW92), Staphylococcus aureus NCTC 8325 (Q2FW92), Staphylococcus aureus PS 47 (Q2FW92), Streptococcus equi subsp. zooepidemicus (A0A2X3T317), Streptococcus mutans serotype c (Q8DTC4), Streptococcus mutans serotype c ATCC 700610 (Q8DTC4), Streptococcus mutans serotype c UA159 (Q8DTC4), Streptococcus pneumoniae (A0A0B7L730), Streptococcus pneumoniae ATCC 700669 (A0A0B7L730), Streptococcus pyogenes serotype M2 (Q1JH51), Streptococcus pyogenes serotype M2 MGAS10270 (Q1JH51), Tetragenococcus halophilus (G4L7W3), Tetragenococcus halophilus DSM 20338 (G4L7W3), Tetragenococcus halophilus JCM 20259 (G4L7W3), Tetragenococcus halophilus NBRC 12172 (G4L7W3), Tetragenococcus halophilus NCIMB 9735 (G4L7W3), Geobacter sulfurreducens DSM 12127 (Q74EU1)
Commichau, F.M.; Heidemann, J.L.; Ficner, R.; Stuelke, J.
Making and breaking of an essential poison the cyclases and phosphodiesterases that produce and degrade the essential second messenger cyclic di-AMP in bacteria
J. Bacteriol.
201
e00462-18
2019
Bacillus subtilis (A0A6M3Z9Z6), Bacillus subtilis (O31854), Bacillus subtilis (P37573), Bacillus subtilis 168 (A0A6M3Z9Z6), Bacillus subtilis 168 (O31854), Bacillus subtilis 168 (P37573), Listeria monocytogenes EGD (Q8Y5E4), Listeria monocytogenes EGD ATCC BAA-679 (Q8Y5E4), Listeria monocytogenes EGD EGD-e (Q8Y5E4), Mycoplasma pneumoniae (P75528), Mycoplasma pneumoniae ATCC 29342 (P75528), Mycoplasma pneumoniae M129 (P75528), Staphylococcus aureus (Q9RL70), Streptococcus pneumoniae (A0A0B7L730)
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