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| Names | |
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| IUPAC name Adenosine 3′,5′-(hydrogen phosphate) | |
| Systematic IUPAC name (4aR,6R,7R,7aS)-6-(6-Amino-9H-purin-9-yl)-2,7-dihydroxytetrahydro-2H,4H-2λ5-furo[3,2-d][1,3,2]dioxaphosphinin-2-one | |
| Identifiers | |
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3D model (JSmol) | |
| ChEBI | |
| ChEMBL | |
| ChemSpider |
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| DrugBank |
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| ECHA InfoCard | 100.000.448 |
| KEGG |
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| MeSH | Cyclic+AMP |
| UNII | |
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| Properties | |
| C10H11N5O6P | |
| Molar mass | 329.206 g/mol |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Cyclic adenosine monophosphate (cAMP,cyclic AMP, or3',5'-cyclicadenosine monophosphate) is asecond messenger, or cellular signal occurring within cells, that is important in many biological processes. cAMP is a derivative ofadenosine triphosphate (ATP) and used for intracellularsignal transduction in many different organisms, conveying thecAMP-dependent pathway.
Earl Sutherland ofVanderbilt University won aNobel Prize in Physiology or Medicine in 1971 "for his discoveries concerning the mechanisms of the action of hormones", especially epinephrine, viasecond messengers (such as cyclic adenosine monophosphate, cyclic AMP).
The synthesis of cAMP is stimulated by trophic hormones that bind to receptors on the cell surface. cAMP levels reach maximal levels within minutes and decrease gradually over an hour in cultured cells.[1] CyclicAMP is synthesized fromATP byadenylate cyclase located on the inner side of the plasma membrane and anchored at various locations in the interior of the cell.[2] Adenylate cyclase isactivated by a range of signaling molecules through the activation of adenylate cyclase stimulatory G (Gs)-protein-coupled receptors. Adenylate cyclase isinhibited by agonists of adenylate cyclase inhibitory G (Gi)-protein-coupled receptors. Liver adenylate cyclase responds more strongly to glucagon, and muscle adenylate cyclase responds more strongly to adrenaline.
cAMP decomposition intoAMP is catalyzed by the enzymephosphodiesterase.
cAMP is asecond messenger, used for intracellular signal transduction, such astransferring into cells the effects ofhormones likeglucagon andadrenaline, which cannot pass through the plasma membrane. It is also involved in the activation ofprotein kinases. In addition, cAMPbinds to and regulates the function ofion channels such as theHCN channels and a few othercyclic nucleotide-binding proteins such asEpac1 andRAPGEF2.
cAMP is associated with kinases function in several biochemical processes, including the regulation ofglycogen,sugar, andlipidmetabolism.[3]
In eukaryotes, cyclic AMP works by activating protein kinase A (PKA, orcAMP-dependent protein kinase). PKA is normally inactive as a tetramericholoenzyme, consisting of twocatalytic and two regulatory units (C2R2), with the regulatory units blocking the catalytic centers of the catalytic units.
Cyclic AMP binds to specific locations on the regulatory units of the protein kinase, and causes dissociation between the regulatory and catalytic subunits, thus enabling those catalytic units tophosphorylate substrate proteins.
The active subunits catalyze the transfer of phosphate from ATP to specificserine orthreonine residues of protein substrates. The phosphorylated proteins may act directly on the cell's ion channels, or may become activated or inhibited enzymes. Protein kinase A can also phosphorylate specific proteins that bind to promoter regions of DNA, causing increases in transcription. Not all protein kinases respond to cAMP. Several classes ofprotein kinases, including protein kinase C, are not cAMP-dependent.
Further effects mainly depend oncAMP-dependent protein kinase, which vary based on the type of cell.
Still, there are some minor PKA-independent functions of cAMP, e.g., activation ofcalcium channels, providing a minor pathway by whichgrowth hormone-releasing hormone causes a release ofgrowth hormone.
However, the view that the majority of the effects of cAMP are controlled by PKA is an outdated one. In 1998 a family of cAMP-sensitive proteins withguanine nucleotide exchange factor (GEF) activity was discovered. These are termed Exchange proteins activated by cAMP (Epac) and the family comprisesEpac1 andEpac2.[4] The mechanism of activation is similar to that of PKA: the GEF domain is usually masked by the N-terminal region containing the cAMP binding domain. When cAMP binds, the domain dissociates and exposes the now-active GEF domain, allowing Epac to activate small Ras-like GTPase proteins, such asRap1.
In the speciesDictyostelium discoideum, cAMP acts outside the cell as a secreted signal. Thechemotactic aggregation of cells is organized by periodic waves of cAMP that propagate between cells over distances as large as several centimetres. The waves are the result of a regulated production and secretion of extracellular cAMP and a spontaneous biological oscillator that initiates the waves at centers of territories.[5]
Inbacteria, the level of cAMP varies depending on the medium used for growth. In particular, cAMP is low when glucose is the carbon source. This occurs through inhibition of the cAMP-producing enzyme,adenylate cyclase, as a side-effect of glucose transport into the cell. The transcription factorcAMP receptor protein (CRP) also calledCAP (catabolite gene activator protein) forms a complex with cAMP and thereby is activated to bind to DNA. CRP-cAMP increases expression of a large number of genes, including some encodingenzymes that can supply energy independent of glucose.
cAMP, for example, is involved in the positive regulation of thelac operon. In an environment with a low glucose concentration, cAMP accumulates and binds to the allosteric site on CRP (cAMP receptor protein), a transcription activator protein. The protein assumes its active shape and binds to a specific site upstream of the lac promoter, making it easier for RNA polymerase to bind to the adjacent promoter to start transcription of the lac operon, increasing the rate of lac operon transcription. With a high glucose concentration, the cAMP concentration decreases, and the CRP disengages from the lac operon.
Since cyclic AMP is a second messenger and plays vital role in cell signalling, it has been implicated in various disorders but not restricted to the roles given below:
Some research has suggested that a deregulation of cAMP pathways and an aberrant activation of cAMP-controlled genes is linked to the growth of some cancers.[6][7][8]
Research suggests that cAMP affects the function of higher-order thinking in theprefrontal cortex through its regulation of ion channels calledhyperpolarization-activated cyclic nucleotide-gated channels (HCN). HCN channels will open when exposed to cAMP. Once the HCN channel is open, the electrical activity within the neuron is disrupted and the cell becomes less responsive. This interferes with the function of theprefrontal cortex in working memory tasks. Inhibition of cAMP has been observed to improve spatial working memory.[9][10]
cAMP is involved in activation of trigeminocervical system leading to neurogenic inflammation and causing migraine.[11]
Disrupted functioning of cAMP has been noted as one of the mechanisms of several bacterial exotoxins.
They can be subgrouped into two distinct categories:[12]
Forskolin is commonly used as a tool in biochemistry to raise levels of cAMP in the study and research ofcell physiology.[16]
