WordNet

a poisonous substance produced during the metabolism and growth of certain microorganisms and some higher plant and animal species

PrepTutorEJDIC

(特にバクテリアの)毒素

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/03/30 18:12:58」(JST)

wiki en

Adenylate cyclase (EC 4.6.1.1, also commonly known as adenylyl cyclase) is an enzyme with key regulatory roles in essentially all cells. It is the most polyphyletic known enzyme: six distinct classes have been described, all catalyzing the same reaction but representing unrelated gene families with no known sequence or structural homology. The best known AC class is class III or AC-III (Roman numerals are used for classes). AC-III occurs widely in eukaryotes and has important roles in many human tissues.

All classes of AC catalyze the conversion of ATP to 3',5'-cyclic AMP (cAMP) and pyrophosphate. Divalent cations (usually Mg) are generally required and appear to be closely involved in the enzymatic mechanism. The cAMP produced by AC then serves as a regulatory signal via specific cAMP-binding proteins, either transcription factors or other enzymes (e.g., cAMP-dependent kinases).

Adenylate Cyclase catalyzes the conversion of ATP to 3',5'-cyclic AMP

Class I AC[edit]

Class I AC's occur in many bacteria including E. coli. This was the first class of AC to be characterized. It was observed that E. coli deprived of glucose produce cAMP that serves as an internal signal to activate expression of genes for importing and metabolizing other sugars. cAMP exerts this effect by binding the transcription factor CRP, also known as CAP. Class I AC's are large cytosolic enzymes (~100 kDa) with a large regulatory domain (~50 kDa) that indirectly senses glucose levels. As of 2012, no crystal structure is available for class I AC.

Class II AC[edit]

These AC's are toxins secreted by pathogenic bacteria such as Bacillus anthracis and Bordetella pertussis during infection. These bacteria also secrete proteins that enable the AC-II to enter host cells, where the exogenous AC activity undermines normal cellular processes. The genes for Class II AC's are known as cyaA. Several crystal structures are known for AC-II enzymes.

Class III AC[edit]

These AC's are the most familiar based on extensive study due to their important roles in human health. They are also found in some bacteria, notably Mycobacterium tuberculosis where they appear to have a key role in pathogenesis. Most AC-III's are integral membrane proteins involved in transducing extracellular signals into intracellular responses. A Nobel Prize was awarded to Earl Sutherland in 1971 for discovering the key role of AC-III in human liver, where adrenaline indirectly stimulates AC to mobilize stored energy in the "fight or flight" response. The effect of adrenaline is via a G protein signaling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell (cytoplasm). The outside signal (in this case, adrenaline) binds to a receptor, which transmits a signal to the G protein, which transmits a signal to adenylate cyclase, which transmits a signal by converting adenosine triphosphate to cyclic adenosine monophosphate (cAMP). cAMP is known as a second messenger.^[1]

cAMP (cyclic adenosine monophosphate) is an important molecule in eukaryotic signal transduction, a so-called second messenger. Adenylate cyclases are often activated or inhibited by G proteins, which are coupled to membrane receptors and thus can respond to hormonal or other stimuli. Following activation of adenylate cyclase, the resulting cAMP acts as a second messenger by interacting with and regulating other proteins such as protein kinase A and cyclic nucleotide-gated ion channels.

Photoactivatable adenylate cyclase (PAC) was discovered in E. gracilis and can be expressed in other organisms through genetic manipulation. Shining blue light on a cell containing PAC activates it and abruptly increases the rate of conversion of ATP to cAMP. This is a useful technique for researchers in neuroscience because it allows them to quickly increase the intracellular cAMP levels in particular neurons, and to study the effect of that increase in neural activity on the behavior of the organism. For example, PAC expression in certain neurons has been shown to alter the grooming behavior in fruit flies exposed to blue light.^[2] Channelrhodopsin-2 is also used in a similar fashion.

AC-III structure[edit]

Structure of adenylate cyclase

Most class III adenylyl cyclases are transmembrane proteins with 12 transmembrane segments. The protein is organized with 6 transmembrane segments, then the C1 cytoplasmic domain, then another 6 membrane segments, and then a second cytoplasmic domain called C2. The important parts for function are the N-terminus and the C1 and C2 regions. The C1a and C2a subdomains are homologous and form an intramolecular 'dimer' that forms the active site. In Mycobacterium tuberculosis, the AC-III polypeptide is only half as long, comprising one 6-transmembrane domain followed by a cytoplasmic domain, but two of these form a functional homodimer that resembles the mammalian architecture.

Types of AC-III[edit]

There are ten known isoforms of adenylate cyclases in mammals:

ADCY1
ADCY2
ADCY3
ADCY4
ADCY5
ADCY6
ADCY7
ADCY8
ADCY9
ADCY10

These are also sometimes called simply AC1, AC2, etc., and, somewhat confusingly, sometimes Roman numerals are used for these isoforms that all belong to the overall AC class III. They differ mainly in how they are regulated, and are differentially expressed in various tissues throughout mammalian development.

AC-III regulation[edit]

Adenylate cyclase is dually regulated by G proteins (Gs stimulating activity and Gi inhibiting it), and by forskolin, as well as other isoform-specific effectors:

Isoforms III, V and VIII are also stimulated by Ca²⁺/calmodulin.
Isoforms I and VI are inhibited by Ca²⁺ in a calmodulin-independent manner.
Isoforms II, IV and IX are stimulated by beta gamma subunits of the G protein.
Isoforms I, V and VI are most clearly inhibited by Gi, while other isoforms show less dual regulation by the inhibitory G protein.
Soluble AC (sAC) is not a transmembrane form and is not regulated by G proteins or forskolin, inste ad acts as a bicarbonate/pH sensor. sAC is present within mitochondria.^[3]

In neurons, calcium-sensitive adenylate cyclases are located next to calcium ion channels for faster reaction to Ca²⁺ influx; they are suspected of playing an important role in learning processes. This is supported by the fact that adenylate cyclases are coincidence detectors, meaning that they are activated only by several different signals occurring together. In peripheral cells and tissues adenylate cyclases appear to form molecular complexes with specific receptors and other signaling proteins in an isoform-specific manner.

Class IV[edit]

AC-IV was first reported in the bacterium Aeromonas hydrophila, and the structure of the AC-IV from Yersinia pestis has been reported. These are the smallest of the AC enzyme classes; the AC-IV from Yersinia is a dimer of 19 kDa subunits with no known regulatory components.

Class V and VI[edit]

These forms of AC have been reported in specific bacteria (Prevotella ruminicola and Rhizobium etti, respectively) and have not been extensively characterized.

Additional images[edit]

Beta adrenergic receptor kinase pathway

References[edit]

^ Reece J, Campbell N (2002). Biology. San Francisco: Benjamin Cummings. p. 207. ISBN 0-8053-6624-5.
^ Schröder-Lang S, Schwärzel M, Seifert R, Strünker T, Kateriya S, Looser J, Watanabe M, Kaupp UB, Hegemann P, Nagel G (January 2007). "Fast manipulation of cellular cAMP level by light in vivo". Nat. Methods 4 (1): 39–42. doi:10.1038/nmeth975. PMID 17128267.
^ Acin-Perez R, Salazar E, Kamenetsky M, Buck J, Levin LR, Manfredi G (March 2009). "Cyclic AMP produced inside mitochondria regulates oxidative phosphorylation". Cell Metab. 9 (3): 265–76. doi:10.1016/j.cmet.2009.01.012. PMC 2684673. PMID 19254571.

External links[edit]

Adenylate cyclase at the US National Library of Medicine Medical Subject Headings (MeSH)
Interactive 3D views of Adenylate cyclase at Proteopedia Adenylyl_cyclase

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 百日咳菌感染症：疫学、微生物学、および病因 bordetella pertussis infection epidemiology microbiology and pathogenesis
2. 思春期および成人における百日咳菌感染症：臨床症状および診断 bordetella pertussis infection in adolescents and adults clinical manifestations and diagnosis
3. ペプチドホルモンのシグナル伝達および調節 peptide hormone signal transduction and regulation
4. 甲状腺結節および非髄様甲状腺癌におけるオンコジーンおよび腫瘍抑制遺伝子 oncogenes and tumor suppressor genes in thyroid nodules and nonmedullary thyroid cancer
5. 病原性大腸菌 pathogenic escherichia coli

English Journal

Adenylate cyclase toxin-hemolysin relevance for pertussis vaccines.

Sebo P1, Osicka R, Masin J.
Expert review of vaccines.Expert Rev Vaccines.2014 Oct;13(10):1215-27. doi: 10.1586/14760584.2014.944900. Epub 2014 Aug 4.
The adenylate cyclase toxin-hemolysin (ACT, AC-Hly or CyaA) is a key virulence factor of Bordetella pertussis. It targets bactericidal activities of phagocytes, such as oxidative burst and complement- or antibody-mediated opsonophagocytic killing of bacteria. Through cAMP signaling, CyaA also skews
PMID 25090574

Mutation in the β-hairpin of the Bordetella pertussis adenylate cyclase toxin modulates N-lobe conformation in calmodulin.

Springer TI1, Goebel E1, Hariraju D1, Finley NL2.
Biochemical and biophysical research communications.Biochem Biophys Res Commun.2014 Sep 20. pii: S0006-291X(14)01664-7. doi: 10.1016/j.bbrc.2014.09.048. [Epub ahead of print]
Bordetella pertussis, causative agent of whooping cough, produces an adenylate cyclase toxin (CyaA) that is an important virulence factor. In the host cell, the adenylate cyclase domain of CyaA (CyaA-ACD) is activated upon association with calmodulin (CaM), an EF-hand protein comprised of N- and C-l
PMID 25251320

Calcium, acylation and molecular confinement favor folding of Bordetella pertussis adenylate cyclase CyaA toxin into a monomeric and cytotoxic form.

Karst JC1, Ntsogo Enguéné VY1, Cannella SE1, Subrini O1, Hessel A1, Debard S2, Ladant D1, Chenal A3.
The Journal of biological chemistry.J Biol Chem.2014 Sep 17. pii: jbc.M114.580852. [Epub ahead of print]
The adenylate cyclase (CyaA) toxin, a multidomain protein of 1706 amino-acids, is one of the major virulence factors produced by Bordetella pertussis, the causative agent of whooping cough. CyaA is able to invade eukaryotic target cells in which it produces high levels of cAMP thus altering the cell
PMID 25231985

Japanese Journal

Aromatic D-amino acids act as chemoattractant factors for human leukocytes through a G protein-coupled receptor, GPR109B

Irukayama-Tomobe Yoko,Tanaka Hirokazu,Yokomizo Takehiro,Hashidate-Yoshida Tomomi,Yanagisawa Masashi,Sakurai Takeshi
Proceedings of the National Academy of Sciences of the United States of America 106(10), 3930-3934, 2009-03-10
… In this study, we found that certain aromatic D-amino acids, including D-phenylalanine, D-tryptophan, and the metabolite of the latter, D-kynurenine, decreased the activity of adenylate cyclase in cells transfected with GPR109B cDNA through activation of pertussis toxin (PTX)-sensitive G proteins. …
NAID 120001256673

Non-GMI Ganglioside-Targeting Bacterial Toxins and Derivatives with Mucosal Adjuvant Activity

Duverger Alexandra,Kobayashi Ryoki,Fukuiwa Tatsuya,Fujihashi Keiko,Tome Daniel,Fujihashi Kohtaro,McGhee Jerry R.,Boyaka Prosper N.
International Journal of Oral-Medical Sciences 4(2), 53-60, 2005
… Studies using the enterotoxin cholera toxin and the related heat-labile toxin I of Escherichia coli as adjuvants have established that effective immunity can be provided in mucosal tissues and the general blood stream by vaccines administered by the oral or nasal route. … The CTA1-DD adjuvant, which acts by B-cell targeting of the enzymatically active cholera toxin A subunit, represents one of the strategies to induce immunity by nasal immunization without targeting central nervous system tissues. …
NAID 130000652924

Adenylate cyclase toxin from Bordetella pertussis synergized with lipopolysaccharide to promote innate interleukin-10 production and enhanced the induction of Th2 and regulatory T cells

ROSS P. J.
Infect. Immun. 72, 1568-1579, 2004
NAID 30020832020

Related Pictures

★リンクテーブル★

リンク元	「アデニル酸シクラーゼ毒素」
関連記事	「adenylate」「cyclase」「adenylate cyclase」

「アデニル酸シクラーゼ毒素」

Search
PMC	articles
PubMed	articles
NCBI	proteins

Adenylate cyclase
Identifiers
EC number	4.6.1.1
CAS number	9012-42-4
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
Search
PMC	articles
PubMed	articles
NCBI	proteins