Cyclic adenosine monophosphate

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Cyclic adenosine monophosphate
CAMP.svg
Cyclic-adenosine-monophosphate-from-xtal-3D-bs-17.png
Names
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
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.448 OOjs UI icon edit-ltr-progressive.svg
KEGG
MeSH Cyclic+AMP
PubChem CID
UNII
  • InChI=1S/C10H12N5O6P/c11-8-5-9(13-2-12-8)15(3-14-5)10-6(16)7-4(20-10)1-19-22(17,18)21-7/h2-4,6-7,10,16H,1H2,(H,17,18)(H2,11,12,13)/t4-,6-,7-,10-/m1/s1 Yes check.svgY
    Key: IVOMOUWHDPKRLL-KQYNXXCUSA-N Yes check.svgY
  • InChI=1/C10H12N5O6P/c11-8-5-9(13-2-12-8)15(3-14-5)10-6(16)7-4(20-10)1-19-22(17,18)21-7/h2-4,6-7,10,16H,1H2,(H,17,18)(H2,11,12,13)/t4-,6-,7-,10-/m1/s1
    Key: IVOMOUWHDPKRLL-KQYNXXCUBU
  • c1nc(c2c(n1)n(cn2)[C@H]3[C@@H]([C@H]4[C@H](O3)COP(=O)(O4)O)O)N
Properties
C10H11N5O6P
Molar mass 329.206 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)
cAMP represented in three ways CAMP.PNG
cAMP represented in three ways
Adenosine triphosphate ATP chemical structure.png
Adenosine triphosphate

Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate ) is a second messenger, or cellular signal occurring within cells, that is important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transduction in many different organisms, conveying the cAMP-dependent pathway.

Contents

History

Earl Sutherland of Vanderbilt University won a Nobel Prize in Physiology or Medicine in 1971 "for his discoveries concerning the mechanisms of the action of hormones", especially epinephrine, via second messengers (such as cyclic adenosine monophosphate, cyclic AMP).

Synthesis

Cyclic AMP is synthesized from ATP by adenylate cyclase located on the inner side of the plasma membrane and anchored at various locations in the interior of the cell. [1] Adenylate cyclase is activated by a range of signaling molecules through the activation of adenylate cyclase stimulatory G (Gs)-protein-coupled receptors. Adenylate cyclase is inhibited 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 into AMP is catalyzed by the enzyme phosphodiesterase.

Functions

cAMP is a second messenger, used for intracellular signal transduction, such as transferring into cells the effects of hormones like glucagon and adrenaline, which cannot pass through the plasma membrane. It is also involved in the activation of protein kinases. In addition, cAMP binds to and regulates the function of ion channels such as the HCN channels and a few other cyclic nucleotide-binding proteins such as Epac1 and RAPGEF2.

Role in eukaryotic cells

cAMP is associated with kinases function in several biochemical processes, including the regulation of glycogen, sugar, and lipid metabolism. [2]

In eukaryotes, cyclic AMP works by activating protein kinase A (PKA, or cAMP-dependent protein kinase). PKA is normally inactive as a tetrameric holoenzyme, consisting of two catalytic 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 to phosphorylate substrate proteins.

The active subunits catalyze the transfer of phosphate from ATP to specific serine or threonine 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 of protein kinases, including protein kinase C, are not cAMP-dependent.

Further effects mainly depend on cAMP-dependent protein kinase, which vary based on the type of cell.

Still, there are some minor PKA-independent functions of cAMP, e.g., activation of calcium channels, providing a minor pathway by which growth hormone-releasing hormone causes a release of growth 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 with guanine nucleotide exchange factor (GEF) activity was discovered. These are termed Exchange proteins activated by cAMP (Epac) and the family comprises Epac1 and Epac2. [3] 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 as Rap1.

Additional role of secreted cAMP in social amoebae

In the species Dictyostelium discoideum , cAMP acts outside the cell as a secreted signal. The chemotactic 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. [4]

Role in bacteria

In bacteria, 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 factor cAMP receptor protein (CRP) also called CAP (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 encoding enzymes that can supply energy independent of glucose.

cAMP, for example, is involved in the positive regulation of the lac 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.

Pathology

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:

Role in human carcinoma

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. [5] [6] [7]

Role in prefrontal cortex disorders

Recent research suggests that cAMP affects the function of higher-order thinking in the prefrontal cortex through its regulation of ion channels called hyperpolarization-activated cyclic nucleotide-gated channels (HCN). When cAMP stimulates the HCN, the channels open, This research, especially the cognitive deficits in age-related illnesses and ADHD, is of interest to researchers studying the brain. [8]

cAMP is involved in activation of trigeminocervical system leading to neurogenic inflammation and causing migraine. [9]

Role in infectious disease agents' pathogenesis

Disrupted functioning of cAMP has been noted as one of the mechanisms of several bacterial exotoxins.

They can be subgrouped into two distinct categories: [10]

  • Cholera toxin is an AB toxin that has five B subunints and one A subunit. The toxin acts by the following mechanism: First, the B subunit ring of the cholera toxin binds to GM1 gangliosides on the surface of target cells. If a cell lacks GM1 the toxin most likely binds to other types of glycans, such as Lewis Y and Lewis X, attached to proteins instead of lipids. [11] [12] [13] [10]

Uses

Forskolin is commonly used as a tool in biochemistry to raise levels of cAMP in the study and research of cell physiology. [14]

See also

Related Research Articles

<span class="mw-page-title-main">Adenylyl cyclase</span> Enzyme with key regulatory roles in most cells

Adenylate cyclase is an enzyme with systematic name ATP diphosphate-lyase . It catalyzes the following reaction:

<span class="mw-page-title-main">G protein-coupled receptor</span> Class of cell surface receptors coupled to G-protein-associated intracellular signaling

G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. They are coupled with G proteins. They pass through the cell membrane seven times in the form of six loops of amino acid residues, which is why they are sometimes referred to as seven-transmembrane receptors. Ligands can bind either to the extracellular N-terminus and loops or to the binding site within transmembrane helices. They are all activated by agonists, although a spontaneous auto-activation of an empty receptor has also been observed.

<span class="mw-page-title-main">G protein</span> Type of proteins

G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their activity is regulated by factors that control their ability to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). When they are bound to GTP, they are 'on', and, when they are bound to GDP, they are 'off'. G proteins belong to the larger group of enzymes called GTPases.

<span class="mw-page-title-main">Adenosine monophosphate</span> Chemical compound

Adenosine monophosphate (AMP), also known as 5'-adenylic acid, is a nucleotide. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine. It is an ester of phosphoric acid and the nucleoside adenosine. As a substituent it takes the form of the prefix adenylyl-.

<span class="mw-page-title-main">Cyclic nucleotide</span> Cyclic nucleic acid

A cyclic nucleotide (cNMP) is a single-phosphate nucleotide with a cyclic bond arrangement between the sugar and phosphate groups. Like other nucleotides, cyclic nucleotides are composed of three functional groups: a sugar, a nitrogenous base, and a single phosphate group. As can be seen in the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) images, the 'cyclic' portion consists of two bonds between the phosphate group and the 3' and 5' hydroxyl groups of the sugar, very often a ribose.

<span class="mw-page-title-main">Glucagon</span> Peptide hormone

Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose. It is produced from proglucagon, encoded by the GCG gene.

<span class="mw-page-title-main">Protein kinase A</span> Family of enzymes

In cell biology, protein kinase A (PKA) is a family of serine-threonine kinase whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase. PKA has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism. It should not be confused with 5'-AMP-activated protein kinase.

<span class="mw-page-title-main">Cyclic guanosine monophosphate</span> Chemical compound

Cyclic guanosine monophosphate (cGMP) is a cyclic nucleotide derived from guanosine triphosphate (GTP). cGMP acts as a second messenger much like cyclic AMP. Its most likely mechanism of action is activation of intracellular protein kinases in response to the binding of membrane-impermeable peptide hormones to the external cell surface. Through protein kinases activation, cGMP can relax smooth muscle. cGMP concentration in urine can be measured for kidney function and diabetes detection.

<i>lac</i> operon Set genes encoding proteins and enzymes for lactose metabolism

The lactose operon is an operon required for the transport and metabolism of lactose in E. coli and many other enteric bacteria. Although glucose is the preferred carbon source for most enteric bacteria, the lac operon allows for the effective digestion of lactose when glucose is not available through the activity of beta-galactosidase. Gene regulation of the lac operon was the first genetic regulatory mechanism to be understood clearly, so it has become a foremost example of prokaryotic gene regulation. It is often discussed in introductory molecular and cellular biology classes for this reason. This lactose metabolism system was used by François Jacob and Jacques Monod to determine how a biological cell knows which enzyme to synthesize. Their work on the lac operon won them the Nobel Prize in Physiology in 1965.

<span class="mw-page-title-main">Alfred G. Gilman</span> American pharmacologist

Alfred Goodman Gilman was an American pharmacologist and biochemist. He and Martin Rodbell shared the 1994 Nobel Prize in Physiology or Medicine "for their discovery of G-proteins and the role of these proteins in signal transduction in cells."

Glycogenesis is the process of glycogen synthesis, in which glucose molecules are added to chains of glycogen for storage. This process is activated during rest periods following the Cori cycle, in the liver, and also activated by insulin in response to high glucose levels.

Biological crosstalk refers to instances in which one or more components of one signal transduction pathway affects another. This can be achieved through a number of ways with the most common form being crosstalk between proteins of signaling cascades. In these signal transduction pathways, there are often shared components that can interact with either pathway. A more complex instance of crosstalk can be observed with transmembrane crosstalk between the extracellular matrix (ECM) and the cytoskeleton.

<span class="mw-page-title-main">Cholera toxin</span> Protein complex secreted by the bacterium Vibrio cholerae

Cholera toxin is an AB5 multimeric protein complex secreted by the bacterium Vibrio cholerae. CTX is responsible for the massive, watery diarrhea characteristic of cholera infection. It is a member of the heat-labile enterotoxin family.

Adenylate cyclase toxin is a virulence factor produced by some members of the genus Bordetella. Together with the pertussis toxin it is the most important virulence factor of the causative agent of whooping cough, Bordetella pertussis. Bordetella bronchiseptica and Bordetella parapertussis, also able to cause pertussis-like symptoms, also produce adenylate cyclase toxin. It is a toxin secreted by the bacteria to influence the host immune system.

G<sub>s</sub> alpha subunit Mammalian protein found in Homo sapiens

The Gs alpha subunit is a subunit of the heterotrimeric G protein Gs that stimulates the cAMP-dependent pathway by activating adenylyl cyclase. Gsα is a GTPase that functions as a cellular signaling protein. Gsα is the founding member of one of the four families of heterotrimeric G proteins, defined by the alpha subunits they contain: the Gαs family, Gαi/Gαo family, Gαq family, and Gα12/Gα13 family. The Gs-family has only two members: the other member is Golf, named for its predominant expression in the olfactory system. In humans, Gsα is encoded by the GNAS complex locus, while Golfα is encoded by the GNAL gene.

<span class="mw-page-title-main">PRKACA</span> Protein-coding gene in the species Homo sapiens

The catalytic subunit α of protein kinase A is a key regulatory enzyme that in humans is encoded by the PRKACA gene. This enzyme is responsible for phosphorylating other proteins and substrates, changing their activity. Protein kinase A catalytic subunit is a member of the AGC kinase family, and contributes to the control of cellular processes that include glucose metabolism, cell division, and contextual memory. PKA Cα is part of a larger protein complex that is responsible for controlling when and where proteins are phosphorylated. Defective regulation of PKA holoenzyme activity has been linked to the progression of cardiovascular disease, certain endocrine disorders and cancers.

<span class="mw-page-title-main">ADCY2</span> Protein-coding gene in the species Homo sapiens

Adenylyl cyclase type 2 is an enzyme typically expressed in the brain of humans, that is encoded by the ADCY2 gene. It belongs to the adenylyl cyclase class-3 or guanylyl cyclase family because it contains two guanylate cyclase domains. ADCY2 is one of ten different mammalian isoforms of adenylyl cyclases. ADCY2 can be found on chromosome 5 and the "MIR2113-POU3F2" region of chromosome 6, with a length of 1091 amino-acids. An essential cofactor for ADCY2 is magnesium; two ions bind per subunit.

The gal operon is a prokaryotic operon, which encodes enzymes necessary for galactose metabolism. Repression of gene expression for this operon works via binding of repressor molecules to two operators. These repressors dimerize, creating a loop in the DNA. The loop as well as hindrance from the external operator prevent RNA polymerase from binding to the promoter, and thus prevent transcription. Additionally, since the metabolism of galactose in the cell is involved in both anabolic and catabolic pathways, a novel regulatory system using two promoters for differential repression has been identified and characterized within the context of the gal operon.

In the field of molecular biology, the cAMP-dependent pathway, also known as the adenylyl cyclase pathway, is a G protein-coupled receptor-triggered signaling cascade used in cell communication.

Adenylate cyclase toxin (CyaA) is released from bacterium Bordetella pertussis by the T1SS and released in the host’s respiratory tract in order to suppress its early innate and subsequent adaptive immune defense.

References

  1. Rahman N, Buck J, Levin LR (November 2013). "pH sensing via bicarbonate-regulated "soluble" adenylate cyclase (sAC)". Front Physiol. 4: 343. doi: 10.3389/fphys.2013.00343 . PMC   3838963 . PMID   24324443.
  2. Ali ES, Hua J, Wilson CH, Tallis GA, Zhou FH, Rychkov GY, Barritt GJ (2016). "The glucagon-like peptide-1 analogue exendin-4 reverses impaired intracellular Ca2+ signalling in steatotic hepatocytes". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1863 (9): 2135–46. doi: 10.1016/j.bbamcr.2016.05.006 . PMID   27178543.
  3. Bos, Johannes L. (December 2006). "Epac proteins: multi-purpose cAMP targets". Trends in Biochemical Sciences. 31 (12): 680–686. doi:10.1016/j.tibs.2006.10.002. PMID   17084085.
  4. Anderson, Peter A. V. (2013-11-11). Evolution of the First Nervous Systems. Springer Science & Business Media. ISBN   978-1-4899-0921-3.
  5. Abramovitch, Rinat; Tavor, Einat; Jacob-Hirsch, Jasmine; Zeira, Evelyne; Amariglio, Ninette; Pappo, Orit; Rechavi, Gideon; Galun, Eithan; Honigman, Alik (15 February 2004). "American Association for Cancer Research (cAMP-responsive Genes and Tumor Progression)". Cancer Research. 64 (4): 1338–1346. doi:10.1158/0008-5472.CAN-03-2089. PMID   14973073. S2CID   14047485.
  6. Dumaz, Nicolas; Hayward, Robert; Martin, Jan; Ogilvie, Lesley; Hedley, Douglas; Curtin, John A.; Bastian, Boris C.; Springer, Caroline; Marais, Richard (October 2006). "American Association for Cancer Research (cAMP Dysregulation and Melonoma)". Cancer Research. 66 (19): 9483–9491. doi: 10.1158/0008-5472.CAN-05-4227 . PMID   17018604.
  7. Simpson, B. J.; Ramage, A. D.; Hulme, M. J.; Burns, D. J.; Katsaros, D.; Langdon, S. P.; Miller, W. R. (January 1996). "American Association for Cancer Research (cAMP-binding Proteins' Presence in Tumors)". Clinical Cancer Research. 2 (1): 201–206.
  8. "ScienceDaily ::Brain Networks Strengthened By Closing Ion Channels, Research Could Lead To ADHD Treatment".
  9. Segatto, Marco (2021). "Neurogenic Inflammation: The Participant in Migraine and Recent Advancements in Translational Research". Biomedicines. 10 (1): 76. doi: 10.3390/biomedicines10010076 . PMC   8773152 . PMID   35052756.
  10. 1 2 Kather, H; Aktories, K (November 15, 1983). "cAMP-System und bakterielle Toxine [The cAMP system and bacterial toxins]". Klin Wochenschr. 61 (22): 1109–1114. doi:10.1007/BF01530837. PMID   6317939. S2CID   33162709 . Retrieved February 26, 2022.
  11. Amberlyn M Wands; Akiko Fujita (October 2015). "Fucosylation and protein glycosylation create functional receptors for cholera toxin". eLife. Vol. 4. doi: 10.7554/eLife.09545 .
  12. Cervin J, Wands AM, Casselbrant A, Wu H, Krishnamurthy S, Cvjetkovic A, et al. (2018) GM1 ganglioside-independent intoxication by Cholera toxin. PLoS Pathog 14(2): e1006862. https://doi.org/10.1371/journal.ppat.1006862
  13. Fucosylated Molecules Competitively Interfere with Cholera Toxin Binding to Host Cells; Amberlyn M. Wands, Jakob Cervin, He Huang, Ye Zhang, Gyusaang Youn, Chad A. Brautigam, Maria Matson Dzebo, Per Björklund, Ville Wallenius, Danielle K. Bright, Clay S. Bennett, Pernilla Wittung-Stafshede, Nicole S. Sampson, Ulf Yrlid, and Jennifer J. Kohler; ACS Infectious Diseases Article ASAP, DOI: 10.1021/acsinfecdis.7b00085
  14. Alasbahi, RH; Melzig, MF (January 2012). "Forskolin and derivatives as tools for studying the role of cAMP". Die Pharmazie. 67 (1): 5–13. PMID   22393824.