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Names | |
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IUPAC name (13R)-1α,6β,9α-Trihydroxy-11-oxo-8α,13-epoxylabd-14-en-7β-yl acetate | |
Systematic IUPAC name (3R,4aR,5S,6S,6aS,10S,10aR,10bS)-3-Ethenyl-6,10,10b-trihydroxy-3,4a,7,7,10a-pentamethyl-1-oxododecahydro-1H-naphtho[2,1-b]pyran-5-yl acetate | |
Identifiers | |
3D model (JSmol) | |
ChEBI | |
ChEMBL | |
ChemSpider | |
DrugBank | |
ECHA InfoCard | 100.060.354 |
PubChem CID | |
UNII | |
CompTox Dashboard (EPA) | |
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Properties | |
C22H34O7 | |
Molar mass | 410.507 g·mol−1 |
Solubility | Soluble in organic solvents such as ethanol, chloroform and DMSO [1] |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). |
Forskolin (coleonol) is a labdane diterpene produced by the plant Coleus barbatus (blue spur flower). Other names include pashanabhedi, Indian coleus, makandi, HL-362, mao hou qiao rui hua. [2] As with other members of the large diterpene class of plant metabolites, forskolin is derived from geranylgeranyl pyrophosphate (GGPP). Forskolin contains some unique functional elements, including the presence of a tetrahydropyran-derived heterocyclic ring. Forskolin is commonly used in laboratory research to increase levels of cyclic AMP by stimulation of adenylate cyclase. [2]
Forskolin is commonly used in biochemistry to raise levels of cyclic AMP (cAMP) in the study and research of cell physiology. [2] [3] Forskolin activates the enzyme adenylyl cyclase and increases intracellular levels of cAMP. cAMP is an important second messenger necessary for the proper biological response of cells to hormones and other extracellular signals. It is required for cell communication in the hypothalamus/pituitary gland axis and for the feedback control of hormones via induction of corticotropin-releasing factor gene transcription. [4] Cyclic AMP acts by activating cAMP-sensitive pathways such as protein kinase A and EPAC1.
Its derivatives include colforsin daropate, NKH477, [5] and FSK88, [6] which may be more potent than forskolin at raising cAMP. These derivatives may have pharmaceutical utility against bronchoconstriction and heart failure. [7] [8]
A total chemical synthesis has been reported. The key step of this chemical synthesis is photocyclization of a synthetic intermediate in presence of oxygen and methylene blue, followed by a singlet oxygen Diels-Alder reaction. [9]
The heterocyclic ring is synthesized after the formation of the trans-fused carbon ring systems formed by a carbocation mediated cyclization. The remaining tertiary carbocation is quenched by a molecule of water. After deprotonation, the remaining hydroxy group is free to form the heterocyclic ring. This cyclization can occur either by attack of the alcohol oxygen onto the allylic carbocation formed by loss of diphosphate, or by an analogous SN2'-like displacement of the diphosphate. [10] This forms the core ring system A of forskolin.
The remaining modifications of the core ring system A can putatively be understood as a series of oxidation reactions to form a poly-ol B which is then further oxidized and esterified to form the ketone and acetate ester moieties seen in forskolin. However, because the biosynthetic gene cluster has not been described, this putative synthesis could be incorrect in the sequence of oxidation/esterification events, which could occur in almost any order.
In animals, forskolin, or extracts of Coleus barbatus containing forskolin, reduce food intake, body weight, and fat mass. In humans, forskolin reduces body fat mass while increasing lean body mass. [11] [12] In mice, extracts of Coleus forskohlii exhibited dose-dependent liver toxicity although purified forskolin did not exhibit liver toxicity. [13]
Forskolin has been used in traditional medicine for treating heart failure. [2]
Adenylate cyclase is an enzyme with systematic name ATP diphosphate-lyase . It catalyzes the following reaction:
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.
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.
Guanylate cyclase is a lyase enzyme that converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP) and pyrophosphate:
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.
In enzymology, a RNA-3′-phosphate cyclase is an enzyme that catalyzes the chemical reaction
Adenylyl cyclase type 6 is an enzyme that in humans is encoded by the ADCY6 gene.
Adenylyl cyclase type 3 is an enzyme that in humans is encoded by the ADCY3 gene.
Adenylyl cyclase type 5 is an enzyme that in humans is encoded by the ADCY5 gene.
Adenylyl cyclase type 1 is an enzyme that in humans is encoded by the ADCY1 gene.
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.
Adenylyl cyclase type 7 is an enzyme that in humans is encoded by the ADCY7 gene.
Adenylyl cyclase type 9 is an enzyme that in humans is encoded by the ADCY9 gene.
Adenylyl cyclase type 8 is an enzyme that in humans is encoded by the ADCY8 gene.
Adenylyl cyclase type 4 is an enzyme that in humans is encoded by the ADCY4 gene.
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.
Bithionol is an antibacterial, anthelmintic, and algaecide. It is used to treat Anoplocephala perfoliata (tapeworms) in horses and Fasciola hepatica.
Adenylyl cyclase 10 also known as ADCY10 is an enzyme that, in humans, is encoded by the ADCY10 gene.
In molecular biology, this protein domain belongs to the terpene synthase family (TPS). Its role is to synthesize terpenes, which are part of primary metabolism, such as sterols and carotene, and also part of the secondary metabolism. This entry will focus on the C terminal domain of the TPS protein.
Ribose is a simple sugar and carbohydrate with molecular formula C5H10O5 and the linear-form composition H−(C=O)−(CHOH)4−H. The naturally-occurring form, d-ribose, is a component of the ribonucleotides from which RNA is built, and so this compound is necessary for coding, decoding, regulation and expression of genes. It has a structural analog, deoxyribose, which is a similarly essential component of DNA. l-ribose is an unnatural sugar that was first prepared by Emil Fischer and Oscar Piloty in 1891. It was not until 1909 that Phoebus Levene and Walter Jacobs recognised that d-ribose was a natural product, the enantiomer of Fischer and Piloty's product, and an essential component of nucleic acids. Fischer chose the name "ribose" as it is a partial rearrangement of the name of another sugar, arabinose, of which ribose is an epimer at the 2' carbon; both names also relate to gum arabic, from which arabinose was first isolated and from which they prepared l-ribose.